subject:(Hepatic metabolism)

University of Manchester

1. Wood, Francesca Leanne. Optimisation of In Vitro Methodology for Drug Metabolism Studies to Improve Prediction of Hepatic Drug Clearance.

Degree: 2016, University of Manchester

URL: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:301576

► As a critical parameter in pharmacokinetics, prediction of clearance is an integral aspect of drug discovery programmes. Since the liver is the major site of… (more)

▼ As a critical parameter in pharmacokinetics, prediction of clearance is an integral aspect of drug discovery programmes. Since the liver is the major site of xenobiotic biotransformation, accurate prediction of hepatic clearance (CLh) is vital. The use of cellular and subcellular in vitro systems for this purpose is common practice; however, prediction accuracy tends to be poor. The aim of this thesis was to explore potential contributing factors to the underprediction of in vivo clearance, specifically with relation to the in vitro methodology of hepatocyte clearance assays, which is largely unstandardised.Literature data analyses highlighted an overall clearance-dependent trend of underprediction in both human and rat hepatocytes, indicating a fundamental in vitro system bias which is independent of species. During initial investigation of incubation conditions, the format of hepatocyte assays (suspension in microcentrifuge tubes, 96-well plates, 24-well plates and short-term monolayer culture) was demonstrated to influence determined intrinsic clearance (CLint). Differences in midazolam CLint were observed not only between suspended and short-term cultured hepatocytes, but also between suspended hepatocytes in different vessels/plate formats. The applicability of 1 µM as a generic substrate incubation concentration for determination of CLint by substrate depletion was evaluated in rat hepatocytes using nine well-characterised drugs. For seven of the nine drugs, a statistically significantly (p < 0.05) higher CLint was observed in determinations of 0.1 µM substrate as opposed to 1 µM, highlighting the potential for false determinations using current practices.Cofactor depletion in isolated hepatocytes was investigated based on previous speculation as the cause of clearance-dependent underprediction of in vivo clearance. Although moderate increases in CLint were observed with the addition of NADPH to hepatocyte incubations, this was subsequently attributed to the replenishment of NADPH in membrane-damaged hepatocytes. Retained functionality of metabolic enzymes in cells which would generally be considered non-viable by trypan blue exclusion was indicated in comparisons of unpurified and Percoll-purified cryopreserved hepatocytes. This phenomenon was conclusively demonstrated in incubations of permeabilised hepatocytes supplemented with NADPH, revealing a need for re-evaluation of the use of plasma membrane integrity (trypan blue exclusion) as a measure of viability in metabolic studies. ATP content was considered as a potential alternative measure; however no significant correlations were found between ATP content, trypan blue exclusion and the CLint of nine drugs in associated preparations.The effect of shaking on CLint in rat hepatocytes was also examined. For 10 out of 12 drugs, CLint determined at 900 rpm was significantly (p < 0.05) higher than in static incubations. Three potential mechanisms were hypothesised: plasma membrane damage, increased substrate distribution throughout the bulk medium and reduction in… Advisors/Committee Members: HALLIFAX, DAVID D, Houston, James, Hallifax, David.

Subjects/Keywords: hepatocytes; hepatic clearance; drug metabolism

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Wood, F. L. (2016). Optimisation of In Vitro Methodology for Drug Metabolism Studies to Improve Prediction of Hepatic Drug Clearance. (Doctoral Dissertation). University of Manchester. Retrieved from http://www.manchester.ac.uk/escholar/uk-ac-man-scw:301576

Chicago Manual of Style (16^th Edition):

Wood, Francesca Leanne. “Optimisation of In Vitro Methodology for Drug Metabolism Studies to Improve Prediction of Hepatic Drug Clearance.” 2016. Doctoral Dissertation, University of Manchester. Accessed January 18, 2021. http://www.manchester.ac.uk/escholar/uk-ac-man-scw:301576.

MLA Handbook (7^th Edition):

Wood, Francesca Leanne. “Optimisation of In Vitro Methodology for Drug Metabolism Studies to Improve Prediction of Hepatic Drug Clearance.” 2016. Web. 18 Jan 2021.

Vancouver:

Wood FL. Optimisation of In Vitro Methodology for Drug Metabolism Studies to Improve Prediction of Hepatic Drug Clearance. [Internet] [Doctoral dissertation]. University of Manchester; 2016. [cited 2021 Jan 18]. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:301576.

Council of Science Editors:

Wood FL. Optimisation of In Vitro Methodology for Drug Metabolism Studies to Improve Prediction of Hepatic Drug Clearance. [Doctoral Dissertation]. University of Manchester; 2016. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:301576

Cornell University

2. McCarthy, Maris. Hepatic Energy Metabolism In Early Lactation Dairy Cows.

Degree: PhD, Animal Science, 2015, Cornell University

URL: http://hdl.handle.net/1813/41136

► In the period immediately following calving, feed intake is insufficient to support the high milk production of early lactation, resulting in a state of negative… (more)

▼ In the period immediately following calving, feed intake is insufficient to support the high milk production of early lactation, resulting in a state of negative energy balance. This state of negative energy balance results in many metabolic adaptations such as the increased mobilization of adipose tissue, manifested as the release of non-esterified fatty acids into circulation to be metabolized by the liver and other tissues and incorporated into milk fat in the mammary gland. Propionate that is produced via fermentation of starch in the rumen is the main precursor for hepatic glucose production, and higher feed and energy intake postpartum generally results in lower circulating non-esterified fatty acids and has been associated with improved health, performance, and less severe postpartum negative energy balance. The objectives herein were to: 1) evaluate the effects of different energetic nutritional strategies on postpartum production and metabolism; 2) evaluate the impact of these nutritional strategies on liver metabolism; 3) evaluate temporal changes in liver metabolism through the transition to lactation and the relationships between hepatic energy substrates; and 4) evaluate the association between the degree of early lactation inflammation with production and metabolism. Cows that were fed diets with greater propiogenic capacity during the postpartum period had improvements in production and metabolism, and increased in vitro conversion of propionate to glucose in the liver. Overall, alterations in fatty acid metabolism that lead to increased triglyceride accumulation during the transition period appear to impair postpartum hepatic gluconeogenesis, and cows that had elevated inflammation in the first week postpartum exhibited a diverse range of production responses, indicating that there is a large degree of variation in individual adaptation. Advisors/Committee Members: Overton,Thomas R (chair), Brenna,James Thomas (committee member), Van Amburgh,Michael E (committee member), Nydam,Daryl Van (committee member).

Subjects/Keywords: Transition dairy cow; Hepatic energy metabolism; Nutrition

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

McCarthy, M. (2015). Hepatic Energy Metabolism In Early Lactation Dairy Cows. (Doctoral Dissertation). Cornell University. Retrieved from http://hdl.handle.net/1813/41136

Chicago Manual of Style (16^th Edition):

McCarthy, Maris. “Hepatic Energy Metabolism In Early Lactation Dairy Cows.” 2015. Doctoral Dissertation, Cornell University. Accessed January 18, 2021. http://hdl.handle.net/1813/41136.

MLA Handbook (7^th Edition):

McCarthy, Maris. “Hepatic Energy Metabolism In Early Lactation Dairy Cows.” 2015. Web. 18 Jan 2021.

Vancouver:

McCarthy M. Hepatic Energy Metabolism In Early Lactation Dairy Cows. [Internet] [Doctoral dissertation]. Cornell University; 2015. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/1813/41136.

Council of Science Editors:

McCarthy M. Hepatic Energy Metabolism In Early Lactation Dairy Cows. [Doctoral Dissertation]. Cornell University; 2015. Available from: http://hdl.handle.net/1813/41136

University of Manchester

3. Wood, Francesca. Optimisation of in vitro methodology for drug metabolism studies to improve prediction of hepatic drug clearance.

Degree: PhD, 2016, University of Manchester

URL: https://www.research.manchester.ac.uk/portal/en/theses/optimisation-of-in-vitro-methodology-for-drug-metabolism-studies-to-improve-prediction-of-hepatic-drug-clearance(0786531a-2e10-48a7-9b35-e2e7e1935338).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.764443

► As a critical parameter in pharmacokinetics, prediction of clearance is an integral aspect of drug discovery programmes. Since the liver is the major site of… (more)

▼ As a critical parameter in pharmacokinetics, prediction of clearance is an integral aspect of drug discovery programmes. Since the liver is the major site of xenobiotic biotransformation, accurate prediction of hepatic clearance (CLh) is vital. The use of cellular and subcellular in vitro systems for this purpose is common practice; however, prediction accuracy tends to be poor. The aim of this thesis was to explore potential contributing factors to the underprediction of in vivo clearance, specifically with relation to the in vitro methodology of hepatocyte clearance assays, which is largely unstandardised. Literature data analyses highlighted an overall clearance-dependent trend of underprediction in both human and rat hepatocytes, indicating a fundamental in vitro system bias which is independent of species. During initial investigation of incubation conditions, the format of hepatocyte assays (suspension in microcentrifuge tubes, 96-well plates, 24-well plates and short-term monolayer culture) was demonstrated to influence determined intrinsic clearance (CLint). Differences in midazolam CLint were observed not only between suspended and short-term cultured hepatocytes, but also between suspended hepatocytes in different vessels/plate formats. The applicability of 1 µM as a generic substrate incubation concentration for determination of CLint by substrate depletion was evaluated in rat hepatocytes using nine well-characterised drugs. For seven of the nine drugs, a statistically significantly (p < 0.05) higher CLint was observed in determinations of 0.1 µM substrate as opposed to 1 µM, highlighting the potential for false determinations using current practices. Cofactor depletion in isolated hepatocytes was investigated based on previous speculation as the cause of clearance-dependent underprediction of in vivo clearance. Although moderate increases in CLint were observed with the addition of NADPH to hepatocyte incubations, this was subsequently attributed to the replenishment of NADPH in membrane-damaged hepatocytes. Retained functionality of metabolic enzymes in cells which would generally be considered non-viable by trypan blue exclusion was indicated in comparisons of unpurified and Percoll-purified cryopreserved hepatocytes. This phenomenon was conclusively demonstrated in incubations of permeabilised hepatocytes supplemented with NADPH, revealing a need for re-evaluation of the use of plasma membrane integrity (trypan blue exclusion) as a measure of viability in metabolic studies. ATP content was considered as a potential alternative measure; however no significant correlations were found between ATP content, trypan blue exclusion and the CLint of nine drugs in associated preparations. The effect of shaking on CLint in rat hepatocytes was also examined. For 10 out of 12 drugs, CLint determined at 900 rpm was significantly (p < 0.05) higher than in static incubations. Three potential mechanisms were hypothesised: plasma membrane damage, increased substrate distribution throughout the bulk medium and reduction…

Subjects/Keywords: 610; drug metabolism; hepatocytes; hepatic clearance

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Wood, F. (2016). Optimisation of in vitro methodology for drug metabolism studies to improve prediction of hepatic drug clearance. (Doctoral Dissertation). University of Manchester. Retrieved from https://www.research.manchester.ac.uk/portal/en/theses/optimisation-of-in-vitro-methodology-for-drug-metabolism-studies-to-improve-prediction-of-hepatic-drug-clearance(0786531a-2e10-48a7-9b35-e2e7e1935338).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.764443

Chicago Manual of Style (16^th Edition):

Wood, Francesca. “Optimisation of in vitro methodology for drug metabolism studies to improve prediction of hepatic drug clearance.” 2016. Doctoral Dissertation, University of Manchester. Accessed January 18, 2021. https://www.research.manchester.ac.uk/portal/en/theses/optimisation-of-in-vitro-methodology-for-drug-metabolism-studies-to-improve-prediction-of-hepatic-drug-clearance(0786531a-2e10-48a7-9b35-e2e7e1935338).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.764443.

MLA Handbook (7^th Edition):

Wood, Francesca. “Optimisation of in vitro methodology for drug metabolism studies to improve prediction of hepatic drug clearance.” 2016. Web. 18 Jan 2021.

Vancouver:

Wood F. Optimisation of in vitro methodology for drug metabolism studies to improve prediction of hepatic drug clearance. [Internet] [Doctoral dissertation]. University of Manchester; 2016. [cited 2021 Jan 18]. Available from: https://www.research.manchester.ac.uk/portal/en/theses/optimisation-of-in-vitro-methodology-for-drug-metabolism-studies-to-improve-prediction-of-hepatic-drug-clearance(0786531a-2e10-48a7-9b35-e2e7e1935338).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.764443.

Council of Science Editors:

Wood F. Optimisation of in vitro methodology for drug metabolism studies to improve prediction of hepatic drug clearance. [Doctoral Dissertation]. University of Manchester; 2016. Available from: https://www.research.manchester.ac.uk/portal/en/theses/optimisation-of-in-vitro-methodology-for-drug-metabolism-studies-to-improve-prediction-of-hepatic-drug-clearance(0786531a-2e10-48a7-9b35-e2e7e1935338).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.764443

University of Sydney

4. Wason, Sundeep Joshua. The role of Annexin A6 in lipid droplet formation of hepatocytes .

Degree: 2017, University of Sydney

URL: http://hdl.handle.net/2123/20148

► Non-alcoholic fatty liver disease (NAFLD) and Type 2 diabetes mellitus (T2DM) are hallmarks of the metabolic syndrome. Neutral lipid accumulation in lipid droplets (LDs) contributes… (more)

▼ Non-alcoholic fatty liver disease (NAFLD) and Type 2 diabetes mellitus (T2DM) are hallmarks of the metabolic syndrome. Neutral lipid accumulation in lipid droplets (LDs) contributes to the development of fatty liver and NAFLD. Together with insulin resistance and inflammation, this often leads to liver failure or hepatocarcinoma. Current treatments have limitations and identification of new targets that contribute to triglyceride accumulation and LD formation are urgently needed. Over the years, Grewal and colleagues have intensively studied Annexin A6 (AnxA6), a calcium (Ca2+) and membrane binding protein in the context of growth factor receptor signalling, cholesterol transport, as well as liver function and triglyceride metabolism. Recently, the Grewal laboratory identified that upregulation of hepatic AnxA6 increased LD numbers and triglyceride accumulation upon loading with oleic acid (OA), possibly involving cytoplasmic phospholipase A2 (cPLA2) -dependent pathways. Co-localization with LD markers suggested that AnxA6 may be associated with LD. This project aimed to substantiate these findings. Triglyceride levels in LD fractions from AnxA6 overexpressing HuH7 hepatocytes were elevated compared to controls. Western blot analysis after subcellular fractionation of rat liver tissue identified the association of AnxA6 with LD-enriched fractions. OA, as well as other lipid-modifying conditions, increased AnxA6 protein expression in HuH7 hepatocytes, while mRNA levels remained unchanged in OA-incubated hepatic cell lines. cPLA2 phosphorylation patterns, which are indicative of cPLA2 activity, are altered in HuH7 cell lines with stable overexpression or knockdown of AnxA6. Analysis of AnxA6 expression in genetic and dietary mouse models of insulin resistance, diabetes and obesity reveal only minor changes in AnxA6 levels, suggesting that changes in cellular localization and function may trigger an involvement in the development of fatty liver. In summary, this study supports recent findings from the Grewal laboratory that AnxA6 is a novel regulator in LD formation in hepatocytes. Hence, tissue-specific inhibition of AnxA6-dependent pathways that promote LD formation in hepatocytes could contribute to develop novel therapeutic strategies for the prevention of fatty liver disease.

Subjects/Keywords: Annexin; A6; Hepatic; Lipid; Metabolism; Liver

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Wason, S. J. (2017). The role of Annexin A6 in lipid droplet formation of hepatocytes . (Thesis). University of Sydney. Retrieved from http://hdl.handle.net/2123/20148

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Wason, Sundeep Joshua. “The role of Annexin A6 in lipid droplet formation of hepatocytes .” 2017. Thesis, University of Sydney. Accessed January 18, 2021. http://hdl.handle.net/2123/20148.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Wason, Sundeep Joshua. “The role of Annexin A6 in lipid droplet formation of hepatocytes .” 2017. Web. 18 Jan 2021.

Vancouver:

Wason SJ. The role of Annexin A6 in lipid droplet formation of hepatocytes . [Internet] [Thesis]. University of Sydney; 2017. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/2123/20148.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Wason SJ. The role of Annexin A6 in lipid droplet formation of hepatocytes . [Thesis]. University of Sydney; 2017. Available from: http://hdl.handle.net/2123/20148

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

5. Rao, P Prasada. Studies on the hepatic metabolism of fresh water fish tilapia mosambica peters exposure to heptachlor , an organochlorine pesticide; -.

Degree: Zoology, 2015, Sri Venkateswara University

URL: http://shodhganga.inflibnet.ac.in/handle/10603/44702

None

References p. 86-106

Advisors/Committee Members: Govindappa, S.

Subjects/Keywords: Hepatic; Metabolism; Mosambica; Studies; Tilapia

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Rao, P. P. (2015). Studies on the hepatic metabolism of fresh water fish tilapia mosambica peters exposure to heptachlor , an organochlorine pesticide; -. (Thesis). Sri Venkateswara University. Retrieved from http://shodhganga.inflibnet.ac.in/handle/10603/44702

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Rao, P Prasada. “Studies on the hepatic metabolism of fresh water fish tilapia mosambica peters exposure to heptachlor , an organochlorine pesticide; -.” 2015. Thesis, Sri Venkateswara University. Accessed January 18, 2021. http://shodhganga.inflibnet.ac.in/handle/10603/44702.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Rao, P Prasada. “Studies on the hepatic metabolism of fresh water fish tilapia mosambica peters exposure to heptachlor , an organochlorine pesticide; -.” 2015. Web. 18 Jan 2021.

Vancouver:

Rao PP. Studies on the hepatic metabolism of fresh water fish tilapia mosambica peters exposure to heptachlor , an organochlorine pesticide; -. [Internet] [Thesis]. Sri Venkateswara University; 2015. [cited 2021 Jan 18]. Available from: http://shodhganga.inflibnet.ac.in/handle/10603/44702.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Rao PP. Studies on the hepatic metabolism of fresh water fish tilapia mosambica peters exposure to heptachlor , an organochlorine pesticide; -. [Thesis]. Sri Venkateswara University; 2015. Available from: http://shodhganga.inflibnet.ac.in/handle/10603/44702

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Texas A&M University

6. Klipsic, Devon K. SCP-2/SCP-x Gene Ablation Exacerbates High Cholesterol Diet Induced Hepatic Lipid Accumulation.

Degree: MS, Laboratory Animal Medicine, 2015, Texas A&M University

URL: http://hdl.handle.net/1969.1/155122

► While a high-cholesterol diet has previously been shown to induce hepatic lipid accumulation in mice, the role of the intracellular cholesterol binding/transport proteins sterol carrier… (more)

▼ While a high-cholesterol diet has previously been shown to induce hepatic lipid accumulation in mice, the role of the intracellular cholesterol binding/transport proteins sterol carrier protein-2/sterol carrier protein-x (SCP-2/SCP-x) in this phenotype is unknown. Therefore, the impact of SCP-2/SCP-x gene ablation (double knockout, DKO) on hepatic and serum lipids as well as hepatic expression of proteins in cholesterol homeostasis was examined in mice fed control- and high-cholesterol diets. Cryopreserved liver, serum, and bile samples from DKO and wild-type, C57BL/6NCr mice which previously underwent a 29 day diet trial on a control- and high-cholesterol diet were utilized along with phenotypic and food consumption data gathered during the study. Liver, serum and biliary lipids were quantified using standard commercially available diagnostic kits. Hepatic mRNA levels of select genes and expression levels of select hepatic proteins involved in lipid metabolism were quantified via qRT-PCR and standard western blotting techniques. The high-cholesterol diet alone had no impact on food consumption or body weight gain in WT mice, but elicited hepatic accumulation of free and esterified cholesterol. High-cholesterol diet decreased hepatic expression of the SREBP2 target gene product HMGCR in females, but not other target gene proteins (SR-B1, LDL-R, cHMGCS) in either sex. Concomitantly, high-cholesterol also elicited hepatic glyceride accumulation, especially triglyceride, which was associated with increased hepatic SREBP1 protein and SREBP1 lipogenic target gene expression (Acc1, Fas). While the DKO did not alter food consumption, a significant decrease in BW gain was appreciated in both high-cholesterol diet and control-fed mice. The DKO also induced hepatic lipid accumulation in control-fed mice, especially of cholesteryl esters and glycerides, which was associated with: i) loss of SCP-2; ii) concomitant upregulation of L-FABP; and/or iii) increased protein levels of SREBP1 and SREBP2. Finally, DKO exacerbated the high-cholesterol diet-induced hepatic cholesterol and glyceride accumulation, but without further altering levels of SREBP2 target genes. Hepatic lipid secretion was impaired due to loss of SCP-2 and reducing Apo B, L-FABP and MTP protein expression. These findings suggested a potential role for SCP-2 in regulating hepatic accumulation of SREBP1 and SREBP2 proteins consistent with the ability of SCP-2 to facilitate intracellular cholesterol trafficking to endoplasmic reticulum from which SREBPs are derived. Advisors/Committee Members: Kier, Ann B (advisor), Gresham, Vincent (committee member), Schroeder, Friedhelm (committee member).

Subjects/Keywords: SCP-2; SCP-x; Mice; Hepatic lipid metabolism; Cholesterol

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Klipsic, D. K. (2015). SCP-2/SCP-x Gene Ablation Exacerbates High Cholesterol Diet Induced Hepatic Lipid Accumulation. (Masters Thesis). Texas A&M University. Retrieved from http://hdl.handle.net/1969.1/155122

Chicago Manual of Style (16^th Edition):

Klipsic, Devon K. “SCP-2/SCP-x Gene Ablation Exacerbates High Cholesterol Diet Induced Hepatic Lipid Accumulation.” 2015. Masters Thesis, Texas A&M University. Accessed January 18, 2021. http://hdl.handle.net/1969.1/155122.

MLA Handbook (7^th Edition):

Klipsic, Devon K. “SCP-2/SCP-x Gene Ablation Exacerbates High Cholesterol Diet Induced Hepatic Lipid Accumulation.” 2015. Web. 18 Jan 2021.

Vancouver:

Klipsic DK. SCP-2/SCP-x Gene Ablation Exacerbates High Cholesterol Diet Induced Hepatic Lipid Accumulation. [Internet] [Masters thesis]. Texas A&M University; 2015. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/1969.1/155122.

Council of Science Editors:

Klipsic DK. SCP-2/SCP-x Gene Ablation Exacerbates High Cholesterol Diet Induced Hepatic Lipid Accumulation. [Masters Thesis]. Texas A&M University; 2015. Available from: http://hdl.handle.net/1969.1/155122

Penn State University

7. Huang, Kuan-Hsun. Exogenous Lipids Regulate the Development of Hepatic Steatosis in a Lean NAFLD model-fed a High Carbohydrate Diet.

Degree: 2016, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/13342kxh359

► Non-alcoholic fatty liver disease (NAFLD), an umbrella term that encompasses hepatic steatosis, steatohepatitis, fibrosis, and cirrhosis, has become the most common chronic liver disease in… (more)

▼ Non-alcoholic fatty liver disease (NAFLD), an umbrella term that encompasses hepatic steatosis, steatohepatitis, fibrosis, and cirrhosis, has become the most common chronic liver disease in the developed countries. NAFLD has been shown to be positively associated with obesity, and thus not surprisingly the majority of NAFLD studies have utilized obese models to explore NAFLD causality. However, previous studies indicated that 25% of patients with NAFLD are not obese and that 7.4% of lean adults have steatosis, and they are more likely to be younger and female, suggesting that these people with lean NAFLD were metabolically obese. Additionally, insulin resistance is an independent risk factor to the development of lean NAFLD, which has been shown to be related to cardiovascular disease and diabetes mellitus. Therefore, understanding the etiology of lean NAFLD in the early stage of the development of steatosis becomes an urgent need. On the other hand, lifestyle modification intervention including diet and physical activity is believed to improve NAFLD or even reverse it, but very few studies have focused on the reversal of hepatic steatosis in the lean NAFLD model. Thus, the overall research hypothesis in this dissertation is that the exogenous lipids as a form of lipid emulsion (LE) and physical activity are capable to reverse hepatic triacylglycerol (TG) accumulation in the lean mouse model with preexisting steatosis. Previous work in our laboratory indicated that 13.5% (percent of total energy, en-%) Intralipid® given orally ameliorated TG accumulation in the liver of nonobese mice fed a high carbohydrate diet (HCD) for 5 weeks. Here, in my first study (chapter 3) I examined whether HCD can induce hepatic steatosis in a short period of time (8d) and whether Intralipid® and voluntary exercise can prevent liver triacylglycerol (TG) accumulation by regulating the de novo lipogenesis-associated transcripts and the concentrations of total fatty acids, in 8 d, on the development of steatosis in a lean mouse model. The results revealed that hepatic TG contents in the HCD-fed mice were significantly increased, confirmed by Oil Red O staining, suggesting the 8d period of induction of steatosis was sufficient to induce mild steatosis. Supplementation with 13.5% Intralipid®, with or without exercise, also suppressed HCD-induced steatosis. qRT-PCR analysis showed that including 13.5% Intralipid® to the HCD significantly decreased the transcript levels for lipogenesis-associated genes, whereas mice-fed HCD with exercise had less beneficial effect in the early stage of steatosis, as compared to HCD supplemented with 13.5% Intralipid®. Fatty acid profiling also showed a consistency with transcriptional data that the concentration of monounsaturated FA was decreased significantly. As noted in the previous study that HCD is capable to induce mild hepatic steatosis within 8d, I conducted a second study (chapter 4) to test whether the beneficial effect contributed by 13.5% Intralipid® supplementation will be extended to the mouse… Advisors/Committee Members: A. Catharine Ross, Dissertation Advisor/Co-Advisor, A. Catharine Ross, Committee Chair/Co-Chair, Michael H. Green, Committee Member, Connie J. Rogers, Committee Member, Andrew D. Patterson, Outside Member.

Subjects/Keywords: Lean NAFLD; Glucose metabolism; lipidmetabolism; hepatic steatosis; metabolomics; high carbohydrate diet

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Huang, K. (2016). Exogenous Lipids Regulate the Development of Hepatic Steatosis in a Lean NAFLD model-fed a High Carbohydrate Diet. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/13342kxh359

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Huang, Kuan-Hsun. “Exogenous Lipids Regulate the Development of Hepatic Steatosis in a Lean NAFLD model-fed a High Carbohydrate Diet.” 2016. Thesis, Penn State University. Accessed January 18, 2021. https://submit-etda.libraries.psu.edu/catalog/13342kxh359.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Huang, Kuan-Hsun. “Exogenous Lipids Regulate the Development of Hepatic Steatosis in a Lean NAFLD model-fed a High Carbohydrate Diet.” 2016. Web. 18 Jan 2021.

Vancouver:

Huang K. Exogenous Lipids Regulate the Development of Hepatic Steatosis in a Lean NAFLD model-fed a High Carbohydrate Diet. [Internet] [Thesis]. Penn State University; 2016. [cited 2021 Jan 18]. Available from: https://submit-etda.libraries.psu.edu/catalog/13342kxh359.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Huang K. Exogenous Lipids Regulate the Development of Hepatic Steatosis in a Lean NAFLD model-fed a High Carbohydrate Diet. [Thesis]. Penn State University; 2016. Available from: https://submit-etda.libraries.psu.edu/catalog/13342kxh359

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Wollongong

8. Cheng, Licai. The effects of distinct fatty acids on central leptin sensitivity, hypothalamic inflammation, and central-regulated hepatic metabolism.

Degree: PhD, 2015, University of Wollongong

URL: 1109 NEUROSCIENCES, 1111 NUTRITION AND DIETETICS, 1116 MEDICAL PHYSIOLOGY ; https://ro.uow.edu.au/theses/4622

► Consumption of a fat-rich diet is implicated in the development of central leptin resistance and obesity in modern societies. Epidemiological evidence suggests that saturated… (more)

▼ Consumption of a fat-rich diet is implicated in the development of central leptin resistance and obesity in modern societies. Epidemiological evidence suggests that saturated fatty acids (SFA) and n-6 polyunsaturated fatty acids (n-6 PUFA), highly consumed in Western diets, induce potent inflammation and impair leptin signalling in the hypothalamus, leading to the dysregulation of central leptin on body energy homeostasis and peripheral metabolism. However, n-3 PUFA and n-3 PUFA derivatives have well-known anti-inflammatory properties, and exert anti-obesity effects by improving central leptin sensitivity and its metabolic action in peripheral tissues. However, the role and mechanism of distinct fatty acids, especially directly act on central nervous system, regulate central leptin sensitivity, hypothalamic leptin signalling pathways, and hepatic energy homeostasis remain largely undiscovered. The present thesis aims to determine the effect of intracerebroventricular (icv) injection of distinct fatty acids on central leptin sensitivity in C57BL/6J male mice. Body energy homeostasis, hypothalamic leptin signalling, and centrally regulated hepatic glucose and lipid metabolism in response to distinct fatty acids will be characterised. The contribution of hypothalamic inflammatory effects induced by different fatty acids will also be investigated. The fatty acids to be examined are SFA palmitic acid (PA), n-6 PUFA arachidonic acid (ARA), n-3 PUFA docosahexaenoic acid (DHA), and n-3 PUFA derivative α-ethyl DHA ethyl ester. We demonstrate that the icv administration of PA and ARA induces central leptin resistance, evidenced by the inhibition of central leptin's suppression on food intake and body weight gain. In addition to central leptin resistance, the hypothalamic leptin JAK2- STAT3 and PI3K-Akt signalling pathways were impaired, with the down-regulation of leptin signalling mediators pSTAT3, pJAK2, pAkt, and pFOXO1. Furthermore, the central administration of PA and ARA blunted the leptin-induced decrease of hepatic gluconeogenesis, glucose transportation, lipogenesis, cholesterol synthesis, and increase in hepatic β-oxidation. PA and ARA induced potent hypothalamic pro-inflammatory effects and increased pro-inflammatory cytokines and inflammatory mediators, as well as increased leptin signalling negative regulator SOCS3. On the other hand, central injection of DHA and DHA derivative exerted an anorexigenic effect by reducing energy intake and body weight gain in high-fat diet (HFD) mice. Both DHA and DHA derivative improved leptin JAK2-STAT3 and PI3K-Akt signalling in the hypothalamus, and consequently restored central leptin-mediated hepatic glucose and lipid metabolism. In addition, we also demonstrate that PA and ARA can inhibit, while DHA can improve central leptin action in mediating hypothalamic sympathetic activity, which may associated with the impaired or promoted hepatic energy metabolism. In summary, elevated central PA and ARA concentrations induce leptin resistance and…

Subjects/Keywords: Fatty acids; central leptin resistance; hypothalamic inflammation; hepatic metabolism

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APA (6^th Edition):

Cheng, L. (2015). The effects of distinct fatty acids on central leptin sensitivity, hypothalamic inflammation, and central-regulated hepatic metabolism. (Doctoral Dissertation). University of Wollongong. Retrieved from 1109 NEUROSCIENCES, 1111 NUTRITION AND DIETETICS, 1116 MEDICAL PHYSIOLOGY ; https://ro.uow.edu.au/theses/4622

Chicago Manual of Style (16^th Edition):

Cheng, Licai. “The effects of distinct fatty acids on central leptin sensitivity, hypothalamic inflammation, and central-regulated hepatic metabolism.” 2015. Doctoral Dissertation, University of Wollongong. Accessed January 18, 2021. 1109 NEUROSCIENCES, 1111 NUTRITION AND DIETETICS, 1116 MEDICAL PHYSIOLOGY ; https://ro.uow.edu.au/theses/4622.

MLA Handbook (7^th Edition):

Cheng, Licai. “The effects of distinct fatty acids on central leptin sensitivity, hypothalamic inflammation, and central-regulated hepatic metabolism.” 2015. Web. 18 Jan 2021.

Vancouver:

Cheng L. The effects of distinct fatty acids on central leptin sensitivity, hypothalamic inflammation, and central-regulated hepatic metabolism. [Internet] [Doctoral dissertation]. University of Wollongong; 2015. [cited 2021 Jan 18]. Available from: 1109 NEUROSCIENCES, 1111 NUTRITION AND DIETETICS, 1116 MEDICAL PHYSIOLOGY ; https://ro.uow.edu.au/theses/4622.

Council of Science Editors:

Cheng L. The effects of distinct fatty acids on central leptin sensitivity, hypothalamic inflammation, and central-regulated hepatic metabolism. [Doctoral Dissertation]. University of Wollongong; 2015. Available from: 1109 NEUROSCIENCES, 1111 NUTRITION AND DIETETICS, 1116 MEDICAL PHYSIOLOGY ; https://ro.uow.edu.au/theses/4622

University of Ottawa

9. Choi, Kevin. Glucose Kinetics of Hyperglycemic Rainbow Trout: Effects of Exogenous Glucose and Exercise .

Degree: 2015, University of Ottawa

URL: http://hdl.handle.net/10393/32856

► This thesis investigates the ability of rainbow trout to modulate hepatic glucose production (Ra) and disposal (Rd). My goals were to determine: (1) if resting… (more)

Subjects/Keywords: Hepatic glucose production; Glucoregulation; Exogenous glucose; Carbohydrate metabolism; Swimming; Continuous tracer

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APA (6^th Edition):

Choi, K. (2015). Glucose Kinetics of Hyperglycemic Rainbow Trout: Effects of Exogenous Glucose and Exercise . (Thesis). University of Ottawa. Retrieved from http://hdl.handle.net/10393/32856

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Choi, Kevin. “Glucose Kinetics of Hyperglycemic Rainbow Trout: Effects of Exogenous Glucose and Exercise .” 2015. Thesis, University of Ottawa. Accessed January 18, 2021. http://hdl.handle.net/10393/32856.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Choi, Kevin. “Glucose Kinetics of Hyperglycemic Rainbow Trout: Effects of Exogenous Glucose and Exercise .” 2015. Web. 18 Jan 2021.

Vancouver:

Choi K. Glucose Kinetics of Hyperglycemic Rainbow Trout: Effects of Exogenous Glucose and Exercise . [Internet] [Thesis]. University of Ottawa; 2015. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/10393/32856.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Choi K. Glucose Kinetics of Hyperglycemic Rainbow Trout: Effects of Exogenous Glucose and Exercise . [Thesis]. University of Ottawa; 2015. Available from: http://hdl.handle.net/10393/32856

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Minnesota

10. Chiney, Manoj Shriram. Effect of obesity on hepatic drug metabolism.

Degree: PhD, Experimental & Clinical Pharmacology, 2013, University of Minnesota

URL: http://purl.umn.edu/159655

► Obesity has increased markedly over the last few decades and is now a major public health crisis in the U.S. affecting over 1/3 of the… (more)

▼ Obesity has increased markedly over the last few decades and is now a major public health crisis in the U.S. affecting over 1/3 of the US population. Optimization of dosing in obese individuals is a challenge due to the lack of knowledge regarding changes in the pharmacokinetics (PK) of therapeutic agents in obese individuals. Thus the aim of this thesis was to determine the effect of obesity on drug metabolism and evaluate methods that could potentially predict changes in pharmacokinetics in the obese population. The impact of obesity on drug metabolism in children has not been determined and our clinical study (Chapter 2) was the first of its kind to examine the effect of childhood obesity on CYP1A2, CYP2D6, CYP3A4, xanthine oxidase, and NAT2 activity using caffeine and dextromethorphan as probe drugs. Our results conclusively indicate that obesity results in an elevation of xanthine oxidase and NAT2 enzyme activities in obese children as compared to lean children, whereas there was no difference in CYP1A2, CYP2D6 and CYP3A4 activity between obese and lean children. This study provides a potential mechanism of altered 6-mercaptopurine exposure in the obese pediatric cancer population. While clinical studies would provide the most optimum method to predict clearance of therapeutic agents in humans, studies have reported that clearance can also be predicted using animal data. In Chapter 3, we examined mouse, rat and porcine model of obesity in order to determine the utility of these animal models to predict PK in obese humans and to identify a model that would best reflect the human obesity mediated changes in drug metabolism. The study indicated species dependent differences in CLint of various drugs that were due to, either changes in expression of drug metabolizing enzymes or changes in enzyme substrate affinity. The study demonstrated that obesity can alter enzyme activity in a species and model dependent manner. Furthermore this study identified that the rat High Fat Diet animal model of obesity is the best representation of the obesity mediated alterations in humans. In Chapter 4, in collaboration with Drs. Scott Rector and Jim Perfield, University of Missouri, Columbia, we demonstrated obesity mediated alterations of drug metabolism enzyme activity can be prevented by sterculic oil dietary supplementation. These effects are mediated through signal transduction pathways which regulate CAR and PXR transcription factors. These results establish that obesity mediated changes are biochemically dependent and not weight dependent. In Chapter 5, we developed a proof of concept that would help generate biochemically obese hepatocytes. In absence of hepatocytes from obese individuals, these hepatocytes can be used as a tool to predict obesity mediated changes in drug clearance. Our studies indicate that individually, leptin, resistin, IL-6 and TNF-α can modulate expression of various DMEs in a concentration dependent and isoform specific manner. This study demonstrates that the obesity microenvironment is…

Subjects/Keywords: Animal models; Drug metabolism; Hepatic; Hepatocytes; Obesity; Pediatric

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APA (6^th Edition):

Chiney, M. S. (2013). Effect of obesity on hepatic drug metabolism. (Doctoral Dissertation). University of Minnesota. Retrieved from http://purl.umn.edu/159655

Chicago Manual of Style (16^th Edition):

Chiney, Manoj Shriram. “Effect of obesity on hepatic drug metabolism.” 2013. Doctoral Dissertation, University of Minnesota. Accessed January 18, 2021. http://purl.umn.edu/159655.

MLA Handbook (7^th Edition):

Chiney, Manoj Shriram. “Effect of obesity on hepatic drug metabolism.” 2013. Web. 18 Jan 2021.

Vancouver:

Chiney MS. Effect of obesity on hepatic drug metabolism. [Internet] [Doctoral dissertation]. University of Minnesota; 2013. [cited 2021 Jan 18]. Available from: http://purl.umn.edu/159655.

Council of Science Editors:

Chiney MS. Effect of obesity on hepatic drug metabolism. [Doctoral Dissertation]. University of Minnesota; 2013. Available from: http://purl.umn.edu/159655

11. Deursen, Diederik. Transcriptional Regulation of the Human Hepatic Lipase Gene: Relation to Glucose and Lipid Metabolism.

Degree: 2012, Erasmus University Medical Center

URL: http://hdl.handle.net/1765/32747

► textabstractHepatic Lipase (HL; EC 3.1.1.3) is an extracellular glycoprotein with phospholipase A1 and triacylglycerol hydrolase activity. The human HL protein is encoded by the LIPC… (more)

▼ textabstractHepatic Lipase (HL; EC 3.1.1.3) is an extracellular glycoprotein with phospholipase A1 and triacylglycerol hydrolase activity. The human HL protein is encoded by the LIPC gene on chromosome 15q21. Most of this protein is synthesized in the parenchymal cells of the liver and secreted into the space of Disse where it binds to heparin sulfate proteoglycans. Some synthesis of HL was also observed in macrophages. The HL protein is also present in the steroidogenic adrenal glands, ovaries and, in small amounts, in the testes. By using heparin, HL protein is displaced from its binding site. Human HL protein is a homodimer, the monomer has a molecular weight of 65 kDa. In the metabolism of plasma lipoproteins HL plays an important role; it mediates the conversion of high density lipoprotein subfraction 2 (HDL2) to high density lipoprotein subfraction 3 (HDL3), the conversion of intermediate density lipoprotein (IDL) to low density lipoproteins (LDL), and the formation of small dense LDL (sdLDL) from large buoyant LDL. HL has a role in postprandial lipid transport where it facilitates the clearance of remnant lipoproteins by the liver. In adrenals and ovaries the HL enzyme facilitates the delivery of HDL cholesterol for steroidogenesis, at least in the rat. HL expression is determined by genetic, hormonal and nutritional factors, and by body composition. HL activity is associated with a risk for Coronary Artery Diseases (CAD). Whether high HL expression is anti- or pro-atherogenic depends on other genetic or metabolic factors, e.g. concomitant hypertriglyceridemia [1,19]. Humans with visceral obesity and insulin resistance or type 2 diabetes show increased levels of HL expression. How HL gene expression is altered in insulin-resistant conditions is unknown. Relative to the common LIPC C-allele (referring to the C/T polymorphism at the -514 position), carriers of the T-allele have reduced post-heparin HL activity, and the T-allele is associated with dyslipidemia and insulin resistance in healthy controls and in Familial Combined Hyperlipidemia (FCH). In cell culture experiments using human HepG2 hepatoma cells, HL expression was found to be increased by elevated levels of fatty acids and glucose, conditions that prevail in insulin resistance. How these metabolic factors affect HL expression is largely unknown.

Subjects/Keywords: Hepatic Lipase; metabolism; proteins

…Chapter 1 1.2 Hepatic Lipase and the metabolism of lipoproteins 10 | Chapter 1 Chylomicron… …target in the treatment of CAD [57]. 1.4 Hepatic Lipase and glucose metabolism and… …8 | Chapter 1 1.1 Introduction to Hepatic Lipase Hepatic Lipase (HL; EC 3.1.1.3… …homodimer, the monomer has a molecular weight of 65 kDa. In the metabolism of plasma lipoproteins… …lipolytic enzyme important in plasma lipoprotein metabolism [3]. HL plays a role in the…

10 more images…

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Deursen, D. (2012). Transcriptional Regulation of the Human Hepatic Lipase Gene: Relation to Glucose and Lipid Metabolism. (Doctoral Dissertation). Erasmus University Medical Center. Retrieved from http://hdl.handle.net/1765/32747

Chicago Manual of Style (16^th Edition):

Deursen, Diederik. “Transcriptional Regulation of the Human Hepatic Lipase Gene: Relation to Glucose and Lipid Metabolism.” 2012. Doctoral Dissertation, Erasmus University Medical Center. Accessed January 18, 2021. http://hdl.handle.net/1765/32747.

MLA Handbook (7^th Edition):

Deursen, Diederik. “Transcriptional Regulation of the Human Hepatic Lipase Gene: Relation to Glucose and Lipid Metabolism.” 2012. Web. 18 Jan 2021.

Vancouver:

Deursen D. Transcriptional Regulation of the Human Hepatic Lipase Gene: Relation to Glucose and Lipid Metabolism. [Internet] [Doctoral dissertation]. Erasmus University Medical Center; 2012. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/1765/32747.

Council of Science Editors:

Deursen D. Transcriptional Regulation of the Human Hepatic Lipase Gene: Relation to Glucose and Lipid Metabolism. [Doctoral Dissertation]. Erasmus University Medical Center; 2012. Available from: http://hdl.handle.net/1765/32747

Deakin University

12. BOND, SIMON. The Role of Glyceraldehyde-3-Phosphate Dehydrogenase Acetylation in liver metabolism.

Degree: School of Medicine, 2015, Deakin University

URL: http://hdl.handle.net/10536/DRO/DU:30088825

Post translational modifications to metabolic enzymes regulate metabolism Advisors/Committee Members: McGee, Sean, Walder Ken, Howlett Kirsten.

Subjects/Keywords: Diabetes; Hepatic insulin resistance; Hepatic glucose metabolism

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APA (6^th Edition):

BOND, S. (2015). The Role of Glyceraldehyde-3-Phosphate Dehydrogenase Acetylation in liver metabolism. (Thesis). Deakin University. Retrieved from http://hdl.handle.net/10536/DRO/DU:30088825

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

BOND, SIMON. “The Role of Glyceraldehyde-3-Phosphate Dehydrogenase Acetylation in liver metabolism.” 2015. Thesis, Deakin University. Accessed January 18, 2021. http://hdl.handle.net/10536/DRO/DU:30088825.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

BOND, SIMON. “The Role of Glyceraldehyde-3-Phosphate Dehydrogenase Acetylation in liver metabolism.” 2015. Web. 18 Jan 2021.

Vancouver:

BOND S. The Role of Glyceraldehyde-3-Phosphate Dehydrogenase Acetylation in liver metabolism. [Internet] [Thesis]. Deakin University; 2015. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/10536/DRO/DU:30088825.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

BOND S. The Role of Glyceraldehyde-3-Phosphate Dehydrogenase Acetylation in liver metabolism. [Thesis]. Deakin University; 2015. Available from: http://hdl.handle.net/10536/DRO/DU:30088825

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

RMIT University

13. Sun, R. The role of ER stress in lipogenesis and insulin resistance in response to over nutrition.

Degree: 2014, RMIT University

URL: http://researchbank.rmit.edu.au/view/rmit:161524

► Insulin resistance is one of the major defect of type 2 diabetes. Excess lipid and endoplasmic reticulum (ER) stress have been suggested to induce hepatic… (more)

▼ Insulin resistance is one of the major defect of type 2 diabetes. Excess lipid and endoplasmic reticulum (ER) stress have been suggested to induce hepatic insulin resistance. However, the mechanisms of the development of insulin resistance relating to excess lipid or ER stress remain unclear. The aims of the thesis were to investigate: 1) the role of ER stress in lipogensis and development of hepatic insulin resistance and, 2) the relationship between ER stress and lipogenesis. The first study was to determine the contribution of ER stress and excess lipid on the onset of hepatic insulin resistance in high fructose (HFru)-fed mice. After feeding with HFru for one day, IRE1/XBP1 branch of the ER stress was activated. Simultaneously, lipogenic enzymes, transcription factor and triglyceride content in the liver increased. Insulin-stimulated phosphorylated Akt was suppressed. Blocking IRE1 activity by TUDCA abolished fructose-dependent increases in JNK activity and IRS serine phosphorylation, and improved Akt phosphorylation without altering hepatic steatosis or PKCϵ. The second study was to interrogate the role of excess lipid or JNK in hepatic insulin resistance in HFru-fed mice. Mice were fed with HFru for 2 weeks. Fenofibrate (FB), a PPARα agonist, was administrated to reduce lipid accumulation. FB treatment eliminated glucose intolerance, hepatic steatosis and insulin signaling transduction. Both IRE1/XBP1 and PEKR/eIF2α branches of ER stress were activated. FB administration increased fatty acid oxidation and reduced diacyglycerols levels. The results from these HFru studies suggested that: 1) ER stress and lipogenesis both contribute to HFru-induced hepatic insulin resistance; 2) activation of JNK rather than lipid accumulation is a key early trigger of ER stress related hepatic insulin resistance induced by HFru feeding and; 3) lipid accumulation, rather than JNK or IKK activation, is pivotal for ER stress to cause hepatic insulin resistance when the mice were challenged with HFru diet for a long time. To further explore the interaction between ER stress and lipogenesis, fructose was used to induce ER stress in cultured cells. Betulin was applied to cells treated with fructose. Lipogenic enzymes were significantly diminished by betulin. The magnified fructose-induced phosphorylation of IRE1 and eIF2α was not altered, suggesting that increasing lipogenesis does not contribute to the activation of IRE1 and PERK branches in context of fructose. In another study, mice were fed with a high fat (HFat) diet for one day or 2 weeks. Hepatic diacyglycerols were increased in HFat-fed mice. Interestingly, HFat-fed mice did not show activated ER stress. These results indicated that hepatic insulin resistance was induced via different mechanisms in the face of fatty acid influx. These observations also suggested that ER stress is unlikely to result from excess lipid. In summary, ER stress might be more critical at early stage of insulin resistance in the context of HFru feeding and this…

Subjects/Keywords: Fields of Research; Hepatic insulin resistance; Endoplasmic reticulum stress; lipid metabolism; Fructose; Liver

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APA (6^th Edition):

Sun, R. (2014). The role of ER stress in lipogenesis and insulin resistance in response to over nutrition. (Thesis). RMIT University. Retrieved from http://researchbank.rmit.edu.au/view/rmit:161524

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Sun, R. “The role of ER stress in lipogenesis and insulin resistance in response to over nutrition.” 2014. Thesis, RMIT University. Accessed January 18, 2021. http://researchbank.rmit.edu.au/view/rmit:161524.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Sun, R. “The role of ER stress in lipogenesis and insulin resistance in response to over nutrition.” 2014. Web. 18 Jan 2021.

Vancouver:

Sun R. The role of ER stress in lipogenesis and insulin resistance in response to over nutrition. [Internet] [Thesis]. RMIT University; 2014. [cited 2021 Jan 18]. Available from: http://researchbank.rmit.edu.au/view/rmit:161524.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Sun R. The role of ER stress in lipogenesis and insulin resistance in response to over nutrition. [Thesis]. RMIT University; 2014. Available from: http://researchbank.rmit.edu.au/view/rmit:161524

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Universiteit Utrecht

14. Waterschoot, R.A.B. van. Interplay between CYP3A and drug transporters.

Degree: 2009, Universiteit Utrecht

URL: http://dspace.library.uu.nl:8080/handle/1874/35859

► Cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp/MDR1) are two important detoxifying systems that protect us against many potentially harmful xenobiotics but their activity also strongly… (more)

▼ Cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp/MDR1) are two important detoxifying systems that protect us against many potentially harmful xenobiotics but their activity also strongly limits the absorption of a wide variety of drugs. Both CYP3A and P-gp have a very broad substrate spectrum and it is noteworthy that there is a large overlap between their substrates. In view of this, it has been hypothesized that it is the combined (intestinal) activity of CYP3A and P-gp that makes for efficient first-pass metabolism of many orally administered drugs. P-gp may reduce the probability of CYP3A4 saturation and would also give the enzyme repeated access to its substrates. However, little in vivo evidence for functional synergy between CYP3A and P-gp is currently available. By generating and utilizing novel mouse models we aimed to obtain more insight into the importance of intestinal CYP3A-dependent metabolism and the functional interplay between CYP3A and P-gp. The studies described in this thesis demonstrate the value of knockout and transgenic mouse models to investigate the individual and combined impact of CYP3A and drug transporters such as P-gp on the pharmacokinetics of drugs. For example, the importance of intestinal metabolism has long been a matter of debate but our studies with tissue-specific CYP3A4 transgenic mice have provided unequivocal evidence that the impact of intestinal CYP3A4-dependent metabolism can even surpass that of hepatic metabolism after oral drug administration. The generation of Cyp3a/P-gp-/- mice has provided a novel in vivo tool to get more insight into how CYP3A and P-gp may work together. We demonstrated that the combined absence of both CYP3A and P-gp can result in a dramatic, disproportionate increase in drug exposure with a concomitantly increased (and possibly qualitatively altered) risk of toxicity. Especially with drugs that have a narrow therapeutic window, there are serious risks when such drugs are deliberately or unintentionally co-administered with other drugs or food constituents that interfere with CYP3A and P-gp activity. The risk of such drug-drug and drug-food interactions is especially relevant given the high number and large overlap in substrates and inhibitors for CYP3A and P-gp. Variable activity of CYP3A alone can lead to lethal overdosing or subtherapeutic underdosing of orally taken drugs. It is clear from the work in this thesis that interfering with both CYP3A and P-gp activity could drastically exacerbate such consequences, and should therefore be considered with caution during further drug development and application. Advisors/Committee Members: Beijnen, J.H., Schinkel, A.H..

Subjects/Keywords: Farmacie; Intestinal and hepatic drug metabolism; drug transport; drug toxicity; pharmacokinetics CYP3A; P-glycoprotein; MRP2

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Waterschoot, R. A. B. v. (2009). Interplay between CYP3A and drug transporters. (Doctoral Dissertation). Universiteit Utrecht. Retrieved from http://dspace.library.uu.nl:8080/handle/1874/35859

Chicago Manual of Style (16^th Edition):

Waterschoot, R A B van. “Interplay between CYP3A and drug transporters.” 2009. Doctoral Dissertation, Universiteit Utrecht. Accessed January 18, 2021. http://dspace.library.uu.nl:8080/handle/1874/35859.

MLA Handbook (7^th Edition):

Waterschoot, R A B van. “Interplay between CYP3A and drug transporters.” 2009. Web. 18 Jan 2021.

Vancouver:

Waterschoot RABv. Interplay between CYP3A and drug transporters. [Internet] [Doctoral dissertation]. Universiteit Utrecht; 2009. [cited 2021 Jan 18]. Available from: http://dspace.library.uu.nl:8080/handle/1874/35859.

Council of Science Editors:

Waterschoot RABv. Interplay between CYP3A and drug transporters. [Doctoral Dissertation]. Universiteit Utrecht; 2009. Available from: http://dspace.library.uu.nl:8080/handle/1874/35859

Vanderbilt University

15. Rojas, Jennifer Marie. Obesity dyslipidemia: the effect of central nervous system neuropeptide Y on hepatic lipoprotein metabolism.

Degree: PhD, Molecular Physiology and Biophysics, 2013, Vanderbilt University

URL: http://hdl.handle.net/1803/10888

► Elevated very low-density lipoprotein (VLDL)-triglyceride (TG) secretion from liver contributes to atherogenic dyslipidemia that is associated with obesity, diabetes, and the metabolic syndrome. Numerous models… (more)

▼ Elevated very low-density lipoprotein (VLDL)-triglyceride (TG) secretion from liver contributes to atherogenic dyslipidemia that is associated with obesity, diabetes, and the metabolic syndrome. Numerous models of obesity are characterized by increased central nervous system (CNS) neuropeptide Y (NPY) tone which contributes to positive energy balance and obesity. In fact, an acute, single intracerebroventricular (ICV) administration of NPY in lean fasted rats elevates hepatic VLDL-TG secretion. Thus, our overarching hypothesis is that elevated CNS NPY action contributes to dyslipidemia by activating central circuits that modulate liver lipid metabolism. Our studies focused on identifying molecular determinants in the hypothalamus and the liver by which increased CNS NPY signaling modulates hepatic lipoprotein metabolism. First, we sought to determine if the effects of NPY on feeding and/or obesity are dissociable from effects on hepatic VLDL-TG secretion. ICV NPY-treated chow-fed rats pair-fed to vehicle-treated controls develop hypertriglyceridemia in the absence of increased food intake and body fat accumulation. Acute ICV injection of selective Y1, Y2, Y4, and Y5 receptor agonists all induced hyperphagia in lean ad-libitum fed rats with the Y2 receptor agonist having the most pronounced effect. The NPY Y1 receptor agonist robustly stimulated hepatic VLDL-TG secretion, while a Y2 receptor agonist had a modest effect on VLDL-TGs, and no effect was observed for Y4 and Y5 receptor agonists in lean fasted rats. These findings raise the possibility that NPY regulates feeding and lipoprotein metabolism partially via separate NPY receptor systems and/or mechanisms. Lastly, we sought to identify novel regulatory mechanisms in the liver engaged by CNS NPY signaling. We observed, in ICV NPY- and Y1 agonist-treated lean fasted rats, that oleic and linoleic acid were enriched in the liver phospholipid (PL) pool and secreted into plasma TGs. Furthermore, CNS NPY signaling via the Y1 receptor robustly activated key hepatic regulatory enzymes, ADP-ribosylation factor-1 and lipin-1, involved in remodeling liver PL into TG for VLDL maturation and secretion. Altogether, this body of work has overarching implications in further understanding how obesity-related CNS dysfunction contributes to the pathophysiology of atherogenic dyslipidemia associated with obesity, diabetes, and the metabolic syndrome. Advisors/Committee Members: Owen P. McGuinness (committee member), Richard M. O’Brien (committee member), John M. Stafford (committee member), Kevin D. Niswender (committee member), Alyssa H. Hasty (Committee Chair).

Subjects/Keywords: lipin-1; brain; hepatic lipid metabolism; obesity dyslipidemia; NPY receptors; hepatocyte-specific deletion of rictor

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APA (6^th Edition):

Rojas, J. M. (2013). Obesity dyslipidemia: the effect of central nervous system neuropeptide Y on hepatic lipoprotein metabolism. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/10888

Chicago Manual of Style (16^th Edition):

Rojas, Jennifer Marie. “Obesity dyslipidemia: the effect of central nervous system neuropeptide Y on hepatic lipoprotein metabolism.” 2013. Doctoral Dissertation, Vanderbilt University. Accessed January 18, 2021. http://hdl.handle.net/1803/10888.

MLA Handbook (7^th Edition):

Rojas, Jennifer Marie. “Obesity dyslipidemia: the effect of central nervous system neuropeptide Y on hepatic lipoprotein metabolism.” 2013. Web. 18 Jan 2021.

Vancouver:

Rojas JM. Obesity dyslipidemia: the effect of central nervous system neuropeptide Y on hepatic lipoprotein metabolism. [Internet] [Doctoral dissertation]. Vanderbilt University; 2013. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/1803/10888.

Council of Science Editors:

Rojas JM. Obesity dyslipidemia: the effect of central nervous system neuropeptide Y on hepatic lipoprotein metabolism. [Doctoral Dissertation]. Vanderbilt University; 2013. Available from: http://hdl.handle.net/1803/10888

Universidade do Rio Grande do Sul

16. Rocha, Débora Santos. Estudo do metabolismo de ratos diabéticos submetidos ao tratamento com erva-mate (Ilex paraguariensis).

Degree: 2016, Universidade do Rio Grande do Sul

URL: http://hdl.handle.net/10183/141248

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Está bem estabelecido que o diabetes melito está associado a uma série de distúrbios clínicos que envolvem a alteração no metabolismo de carboidratos, proteínas e… (more)

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Está bem estabelecido que o diabetes melito está associado a uma série de distúrbios clínicos que envolvem a alteração no metabolismo de carboidratos, proteínas e lipídios. Tem-se observado aumento importante da morbidade e mortalidade associadas a esta doença, sendo que dentre as causas, em ambos os tipos de diabetes (1 e 2), têm-se o aumento de fatores de risco, como o sobrepeso ou obesidade e o estilo de vida sedentário. A erva-mate (Ilex paraguariensis) tem apresentado grande potencialidade para utilização preventiva e terapêutica no diabetes graças à atividade biotiva dos seus compostos (metilxantinas, polifenóis e saponinas), capazes de alterar o metabolismo tecidual energético tanto em protocolos experimentais com animais de laboratório quanto humanos. Assim sendo, o objetivo deste trabalho foi elucidar o efeito da administração do chá de mate em ratos Wistar diabéticos, tendo como foco o metabolismo tecidual muscular e hepático. Para tanto, ratos Wistar machos foram submetidos a indução do diabetes experimental com injeção de estreptozotocina (65 mg/kg, i.p.) e posteriormente tratados com o extrato aquoso de erva-mate através da água de beber por 30 dias. Ao final do tratamento, os animais foram eutanasiados e os tecidos (soro, músculo, fígado e tecido adiposo retroperitoneal e epididimal) foram coletados para análise.

There is a well known relationship between metabolic disturbances and clinical events related to diabetes and a dangerous prevalence increase worldwide for both types of this disease (diabetes type 1 and 2). This enhancement is caused by overweight, sedentary lifestyle and other risk factors associated to occidental habits. Yerba-mate (Ilex paraguariensis) has been presented a potential use to preventive and therapeutical aspects of diabetes due to its bioactive fractions (methylxanthines, saponins and polyphenols), which have a capability to improve energetic metabolism in murine models and human. The aim of this study was to elucidate the effect of yerba-mate on hepatic and muscle energetic metabolism of diabetic rats. To perform the diabetes inducing protocol Wistar rats received streptozotocin (65mg/kg i.p.), then the mate treatment protocol was performed daily and offered as a drink tea. After a 30-day treatment, the animals were weighed and euthanized to evaluate metabolic parameters on liver, adipose tissue, muscle and serum.

Advisors/Committee Members: Kucharski, Luiz Carlos Rios.

Subjects/Keywords: Metabolismo energetico; Diabetes; Yerba-mate; Diabetes mellitus; Ilex paraguariensis; Erva-mate; Muscle metabolism; Músculo esquelético; Fígado; Hepatic metabolism

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Rocha, D. S. (2016). Estudo do metabolismo de ratos diabéticos submetidos ao tratamento com erva-mate (Ilex paraguariensis). (Thesis). Universidade do Rio Grande do Sul. Retrieved from http://hdl.handle.net/10183/141248

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Rocha, Débora Santos. “Estudo do metabolismo de ratos diabéticos submetidos ao tratamento com erva-mate (Ilex paraguariensis).” 2016. Thesis, Universidade do Rio Grande do Sul. Accessed January 18, 2021. http://hdl.handle.net/10183/141248.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Rocha, Débora Santos. “Estudo do metabolismo de ratos diabéticos submetidos ao tratamento com erva-mate (Ilex paraguariensis).” 2016. Web. 18 Jan 2021.

Vancouver:

Rocha DS. Estudo do metabolismo de ratos diabéticos submetidos ao tratamento com erva-mate (Ilex paraguariensis). [Internet] [Thesis]. Universidade do Rio Grande do Sul; 2016. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/10183/141248.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Rocha DS. Estudo do metabolismo de ratos diabéticos submetidos ao tratamento com erva-mate (Ilex paraguariensis). [Thesis]. Universidade do Rio Grande do Sul; 2016. Available from: http://hdl.handle.net/10183/141248

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

17. Dubuquoy, Céline. Expression et fonction de l’adiponutrine/PNPLA3 dans le foie : Relation entre la voie Wnt/β-caténine, la sensibilité à l’insuline et la stéatose hépatique : Adiponutrin/PNPLA3 expression and function in mice liver : Cross-talk between Wnt/ β-catenin pathway, insulin sensitivity and hepatic steatosis.

Degree: Docteur es, Biologie cellulaire, 2012, Université Paris Descartes – Paris V

URL: http://www.theses.fr/2012PA05T008

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La prévalence du syndrome métabolique (MetS) est en constante augmentation dans les pays industrialisés. La stéatose hépatique, caractérisée par une accumulation massive de lipides dans… (more)

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La prévalence du syndrome métabolique (MetS) est en constante augmentation dans les pays industrialisés. La stéatose hépatique, caractérisée par une accumulation massive de lipides dans les hépatocytes est une des manifestations du MetS. Parmi les SNP (Single Nucleotide Polymorphism) associés au MetS et à la stéatose hépatique, le SNP I148M de l’adiponutrine/PNPLA3 (Patatin-like Phospholipase Domain-Containing) est décrit comme un nouveau marqueur de la stéatose et également de la sévérité des différentes atteintes hépatiques des NAFLD (Non-alcoholic Fatty Liver diseases). L’objectif de ma thèse a été de déterminer le rôle de l’adiponutrine dans le foie, d’une part, en étudiant sa régulation transcriptionnelle par les facteurs de transcription SREBP1c (Sterol Responive Element Binding Protein) et ChREBP (Carbohydrate Responsive Element Binding Protein) en réponse à l’insuline et au glucose et d’autre part, en étudiant l’impact de sa surexpression sur le métabolisme glucido-lipidique dans le foie de souris. L’adiponutrine est régulée de façon semblable aux enzymes lipogéniques et semble avoir un impact sur le métabolisme lipidique dans le foie. Comme l’adiponutrine, différents SNP des médiateurs de la voie Wnt/β-caténine sont également associés au syndrome métabolique et au diabète. La voie Wnt/β-caténine joue un rôle déterminant dans la zonation du lobule hépatique. Nous nous sommes intéressés à la régulation de cette voie par les conditions nutritionnelles et dans un contexte physiopathologique de stéatose et de résistance à l’insuline. Nos résultats montrent la régulation de cette voie par les hormones pancréatiques (insuline et glucagon) dans le foie favorisant ainsi l’orientation métabolique des hépatocytes en fonction des besoins. De plus, cette voie est dérégulée dans le foie d’animaux résistants à l’insuline, suggérant qu’elle pourrait avoir une fonction dans ce désordre métabolique.

The prevalence of metabolic syndrome (MetS) has increased in industrial countries. The hallmark of MetS in the liver is an excessive accumulation of triglyceride, which is called hepatic steatosis. Different SNP (Single Nucleotide Polymorphism) are associated with hepatic steatosis or MetS. One of them is found on adiponutrin/PNPLA3 (Patatin-like Phospholipase Domain-Containing) gene (SNP I148M) and is now considered as a new marker of hepatic steatosis and severity of NAFLD (Non-alcoholic Fatty Liver diseases). In order to understand the physiological role of adiponutrin in the liver, we studied its transcriptional regulation by SREBP1c (Sterol Responive Element Binding Protein) and ChREBP (Carbohydrate Responsive Element Binding Protein), mediators of insulin and glucose respectively. Moreover, by overexpressing adiponutrin in mice liver, we investigated its role in hepatic carbohydrate and lipid metabolism. We showed that adiponutrin is regulated as lipogenic genes and could have a role lipid metabolism. As for adiponutrin I148M, different SNP are found on substrats of Wnt/β-catenin pathway, a major pathway controlling…

Advisors/Committee Members: Burnol, Anne-Françoise (thesis director).

Subjects/Keywords: Stéatose hépatique; Zonation hépatique; Métabolisme lipidique; Adiponutrine/PNPLA3; Voie Wnt/β-caténine; Hepatic steatosis; Hepatic zonation; Lipid metabolism; Adiponutrin/PNPLA3; Wnt/β-catenin pathway

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Dubuquoy, C. (2012). Expression et fonction de l’adiponutrine/PNPLA3 dans le foie : Relation entre la voie Wnt/β-caténine, la sensibilité à l’insuline et la stéatose hépatique : Adiponutrin/PNPLA3 expression and function in mice liver : Cross-talk between Wnt/ β-catenin pathway, insulin sensitivity and hepatic steatosis. (Doctoral Dissertation). Université Paris Descartes – Paris V. Retrieved from http://www.theses.fr/2012PA05T008

Chicago Manual of Style (16^th Edition):

Dubuquoy, Céline. “Expression et fonction de l’adiponutrine/PNPLA3 dans le foie : Relation entre la voie Wnt/β-caténine, la sensibilité à l’insuline et la stéatose hépatique : Adiponutrin/PNPLA3 expression and function in mice liver : Cross-talk between Wnt/ β-catenin pathway, insulin sensitivity and hepatic steatosis.” 2012. Doctoral Dissertation, Université Paris Descartes – Paris V. Accessed January 18, 2021. http://www.theses.fr/2012PA05T008.

MLA Handbook (7^th Edition):

Dubuquoy, Céline. “Expression et fonction de l’adiponutrine/PNPLA3 dans le foie : Relation entre la voie Wnt/β-caténine, la sensibilité à l’insuline et la stéatose hépatique : Adiponutrin/PNPLA3 expression and function in mice liver : Cross-talk between Wnt/ β-catenin pathway, insulin sensitivity and hepatic steatosis.” 2012. Web. 18 Jan 2021.

Vancouver:

Dubuquoy C. Expression et fonction de l’adiponutrine/PNPLA3 dans le foie : Relation entre la voie Wnt/β-caténine, la sensibilité à l’insuline et la stéatose hépatique : Adiponutrin/PNPLA3 expression and function in mice liver : Cross-talk between Wnt/ β-catenin pathway, insulin sensitivity and hepatic steatosis. [Internet] [Doctoral dissertation]. Université Paris Descartes – Paris V; 2012. [cited 2021 Jan 18]. Available from: http://www.theses.fr/2012PA05T008.

Council of Science Editors:

Dubuquoy C. Expression et fonction de l’adiponutrine/PNPLA3 dans le foie : Relation entre la voie Wnt/β-caténine, la sensibilité à l’insuline et la stéatose hépatique : Adiponutrin/PNPLA3 expression and function in mice liver : Cross-talk between Wnt/ β-catenin pathway, insulin sensitivity and hepatic steatosis. [Doctoral Dissertation]. Université Paris Descartes – Paris V; 2012. Available from: http://www.theses.fr/2012PA05T008

Texas A&M University

18. Scott, Maya Millicent. Canine hepatic slices as a model for studying drug toxicity and metabolism.

Degree: PhD, Toxicology, 2006, Texas A&M University

URL: http://hdl.handle.net/1969.1/3731

► Tissue slices can be made from organs, such as liver, kidney, brain, and heart, and from various species including humans, dogs, non-human primates, rats and… (more)

▼ Tissue slices can be made from organs, such as liver, kidney, brain, and heart, and from various species including humans, dogs, non-human primates, rats and mice. It has been demonstrated that human and rat liver slices are viable for up to 2 days, and liver slices have been extensively used as an in vitro method to study hepatic drug metabolism and toxicity in humans. The objective of this study was to determine the utility of canine hepatic slices as an in vitro model for studying drug metabolism and hepatotoxicity in dogs. Canine hepatic slices were incubated in media containing various drugs to determine the hepatotoxicity of the agents and the ability of the slices to metabolize the drugs. The toxicity of phenobarbital, primidone, lidocaine and carprofen to canine hepatic slices was assessed by determining changes in supernatant concentrations of potassium ions and adenosine triphosphate (ATP); histologic lesions were determined as necrosis, extent of vacuolation and severity of vacuolation. Xenobiotic drug metabolizing enzymatic activity was investigated by determining the metabolism of lidocaine to monoethylglycinexylidide (MEGX), and administration of phenobarbital plus primidone was used as a positive control for hepatotoxicity in dogs. The function of drug-metabolizing enzymes was demonstrated by the successful metabolism of lidocaine to MEGX. Carprofen, a drug which causes idiosyncratic hepatic disease in dogs, did not show any hepatotoxicity at concentrations of 10, 50 and 100 Âµg/ml using potassium ion levels, ATP concentrations and histology as indicators of hepatotoxicity. Slices incubated in media without drug showed no toxicity over 24 hours based on potassium ion and ATP supernatant concentrations while significant increases in histologic lesions were noted at 8, 12 and 24 hours. Canine hepatic slices were a useful model for examining drug metabolism and toxicity for up to 24 hours. Advisors/Committee Members: Boothe, Dawn M. (advisor), Safe, Stephen H. (advisor), Kochevar, Deborah T. (committee member), Russell, Karen E. (committee member).

Subjects/Keywords: hepatic slices; liver slices; drug metabolism; drug toxicity

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Scott, M. M. (2006). Canine hepatic slices as a model for studying drug toxicity and metabolism. (Doctoral Dissertation). Texas A&M University. Retrieved from http://hdl.handle.net/1969.1/3731

Chicago Manual of Style (16^th Edition):

Scott, Maya Millicent. “Canine hepatic slices as a model for studying drug toxicity and metabolism.” 2006. Doctoral Dissertation, Texas A&M University. Accessed January 18, 2021. http://hdl.handle.net/1969.1/3731.

MLA Handbook (7^th Edition):

Scott, Maya Millicent. “Canine hepatic slices as a model for studying drug toxicity and metabolism.” 2006. Web. 18 Jan 2021.

Vancouver:

Scott MM. Canine hepatic slices as a model for studying drug toxicity and metabolism. [Internet] [Doctoral dissertation]. Texas A&M University; 2006. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/1969.1/3731.

Council of Science Editors:

Scott MM. Canine hepatic slices as a model for studying drug toxicity and metabolism. [Doctoral Dissertation]. Texas A&M University; 2006. Available from: http://hdl.handle.net/1969.1/3731

19. Gjorgjieva, Monika. Identification des mécanismes moléculaires impliqués dans le développement des pathologies hépatiques et rénales dans des modèles murins de glycogénose de type 1a : Identification of molecular mechanisms involved in the development of hepatic and renal pathologies in mouse models of glycogen storage disease type 1a.

Degree: Docteur es, Biologie, 2018, Lyon

URL: http://www.theses.fr/2018LYSE1007

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La glycogénose de type I (GSDI) est une maladie génétique rare, due à une déficience en glucose-6 phosphatase (G6Pase), enzyme clé de la production endogène… (more)

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La glycogénose de type I (GSDI) est une maladie génétique rare, due à une déficience en glucose-6 phosphatase (G6Pase), enzyme clé de la production endogène de glucose. En plus des hypoglycémies sévères, la perte de l'activité G6Pase conduit à l'accumulation de glycogène, mais aussi de lipides dans le foie et les reins. A long-terme, la plupart des patients développent des tumeurs hépatiques et une maladie rénale chronique (MRC).Le but de cette thèse a été de caractériser les mécanismes moléculaires impliqués dans la carcinogenèse hépatique et la MRC grâce à des modèles murins viables et uniques, avec une délétion de la G6Pase spécifiquement dans le foie ou les reins, reproduisant respectivement toutes les caractéristiques de la pathologie hépatique ou rénale.Au niveau du foie, notre étude a permis de mettre en évidence une reprogrammation métabolique « Warburg-like » très similaire à celle des cellules cancéreuses, associée à une perte des défenses cellulaires et des suppresseurs de tumeur. De plus, nous avons montré que les adénomes hépatocellulaires, se transformant ensuite en carcinomes, se développent en absence de fibrose, en accord avec l'absence d'activation des voies pro-fibrotiques. Au niveau des reins, l'étude de la MRC a mis en évidence le développement de kystes rénaux chez les souris atteintes de GSDI, observés aussi chez les patients à un stade avancé de la MRC. Finalement, une dernière étude portant sur l'activation de l'oxydation des lipides, par un traitement des souris au fénofibrate, a permis de suggérer le rôle délétère de l'accumulation des lipides dans le développement des pathologies hépatique et rénale

Glycogen storage disease type I (GSDI) is a rare genetic disease, due to a deficiency in glucose-6 phosphatase (G6Pase), a key enzyme in the endogenous glucose production. Besides severe hypoglycemia, the loss of G6Pase leads to the accumulation of glycogen and lipids in the liver and kidneys. On the long term, most patients develop hepatic tumors and chronic kidney disease (CKD).The goal of this thesis was to characterize the molecular mechanisms involved in hepatic carcinogenesis and CKD, thanks to viable and unique mouse models with specific deletion of G6Pase in the liver or kidneys, which exhibit all hallmarks of hepatic and renal pathologies, respectively.On a hepatic level, our study allowed us to highlight a « Warburg-like » metabolic reprogramming, very similar to what is observed in cancer cells, associated with a loss of cellular defenses and tumor suppressors. Furthermore, we showed that formation of hepatocellular adenoma, which transform later in carcinoma, occurs in the absence of liver fibrosis, due to the fact that pro-fibrotic pathways are not activated. In the kidneys, the study of CKD highlighted the development of renal cysts in mice with GSDI, as well as in the patients presenting an advanced stage of CKD. Finally, the last study on the activation of the oxidation of lipids, by treating the mice with fenofibrate, allowed us to suggest a deleterious role of lipid…

Advisors/Committee Members: Rajas, Fabienne (thesis director).

Subjects/Keywords: Glycogénose; Stéatose; Tumeur hépatique; Néphropathie; Effet Warburg; Lipides; Métabolisme; Glycogen storage disease; Steatosis; Hepatic tumor; Nephropathy; Warburg effect; Lipids; Metabolism; 570

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Gjorgjieva, M. (2018). Identification des mécanismes moléculaires impliqués dans le développement des pathologies hépatiques et rénales dans des modèles murins de glycogénose de type 1a : Identification of molecular mechanisms involved in the development of hepatic and renal pathologies in mouse models of glycogen storage disease type 1a. (Doctoral Dissertation). Lyon. Retrieved from http://www.theses.fr/2018LYSE1007

Chicago Manual of Style (16^th Edition):

Gjorgjieva, Monika. “Identification des mécanismes moléculaires impliqués dans le développement des pathologies hépatiques et rénales dans des modèles murins de glycogénose de type 1a : Identification of molecular mechanisms involved in the development of hepatic and renal pathologies in mouse models of glycogen storage disease type 1a.” 2018. Doctoral Dissertation, Lyon. Accessed January 18, 2021. http://www.theses.fr/2018LYSE1007.

MLA Handbook (7^th Edition):

Gjorgjieva, Monika. “Identification des mécanismes moléculaires impliqués dans le développement des pathologies hépatiques et rénales dans des modèles murins de glycogénose de type 1a : Identification of molecular mechanisms involved in the development of hepatic and renal pathologies in mouse models of glycogen storage disease type 1a.” 2018. Web. 18 Jan 2021.

Vancouver:

Gjorgjieva M. Identification des mécanismes moléculaires impliqués dans le développement des pathologies hépatiques et rénales dans des modèles murins de glycogénose de type 1a : Identification of molecular mechanisms involved in the development of hepatic and renal pathologies in mouse models of glycogen storage disease type 1a. [Internet] [Doctoral dissertation]. Lyon; 2018. [cited 2021 Jan 18]. Available from: http://www.theses.fr/2018LYSE1007.

Council of Science Editors:

Gjorgjieva M. Identification des mécanismes moléculaires impliqués dans le développement des pathologies hépatiques et rénales dans des modèles murins de glycogénose de type 1a : Identification of molecular mechanisms involved in the development of hepatic and renal pathologies in mouse models of glycogen storage disease type 1a. [Doctoral Dissertation]. Lyon; 2018. Available from: http://www.theses.fr/2018LYSE1007

20. ten Have, Gabriëlla Adriana Maria. Pig interorgan balance studies in health and disease.

Degree: 2017, Maastricht University

URL: https://cris.maastrichtuniversity.nl/en/publications/40915ba0-1f89-4122-b415-13fe82d2253a ; urn:nbn:nl:ui:27-40915ba0-1f89-4122-b415-13fe82d2253a ; 40915ba0-1f89-4122-b415-13fe82d2253a ; 10.26481/dis.20170913gth ; urn:nbn:nl:ui:27-40915ba0-1f89-4122-b415-13fe82d2253a ; https://cris.maastrichtuniversity.nl/en/publications/40915ba0-1f89-4122-b415-13fe82d2253a

► This dissertation describes a clinically relevant pig model that provides insight into metabolic changes in severe sepsis and acute hepatic failure. By using new tracer… (more)

Subjects/Keywords: food; protein quality; metabolism; sepsis; hepatic failure

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

ten Have, G. A. M. (2017). Pig interorgan balance studies in health and disease. (Doctoral Dissertation). Maastricht University. Retrieved from https://cris.maastrichtuniversity.nl/en/publications/40915ba0-1f89-4122-b415-13fe82d2253a ; urn:nbn:nl:ui:27-40915ba0-1f89-4122-b415-13fe82d2253a ; 40915ba0-1f89-4122-b415-13fe82d2253a ; 10.26481/dis.20170913gth ; urn:nbn:nl:ui:27-40915ba0-1f89-4122-b415-13fe82d2253a ; https://cris.maastrichtuniversity.nl/en/publications/40915ba0-1f89-4122-b415-13fe82d2253a

Chicago Manual of Style (16^th Edition):

ten Have, Gabriëlla Adriana Maria. “Pig interorgan balance studies in health and disease.” 2017. Doctoral Dissertation, Maastricht University. Accessed January 18, 2021. https://cris.maastrichtuniversity.nl/en/publications/40915ba0-1f89-4122-b415-13fe82d2253a ; urn:nbn:nl:ui:27-40915ba0-1f89-4122-b415-13fe82d2253a ; 40915ba0-1f89-4122-b415-13fe82d2253a ; 10.26481/dis.20170913gth ; urn:nbn:nl:ui:27-40915ba0-1f89-4122-b415-13fe82d2253a ; https://cris.maastrichtuniversity.nl/en/publications/40915ba0-1f89-4122-b415-13fe82d2253a.

MLA Handbook (7^th Edition):

ten Have, Gabriëlla Adriana Maria. “Pig interorgan balance studies in health and disease.” 2017. Web. 18 Jan 2021.

Vancouver:

ten Have GAM. Pig interorgan balance studies in health and disease. [Internet] [Doctoral dissertation]. Maastricht University; 2017. [cited 2021 Jan 18]. Available from: https://cris.maastrichtuniversity.nl/en/publications/40915ba0-1f89-4122-b415-13fe82d2253a ; urn:nbn:nl:ui:27-40915ba0-1f89-4122-b415-13fe82d2253a ; 40915ba0-1f89-4122-b415-13fe82d2253a ; 10.26481/dis.20170913gth ; urn:nbn:nl:ui:27-40915ba0-1f89-4122-b415-13fe82d2253a ; https://cris.maastrichtuniversity.nl/en/publications/40915ba0-1f89-4122-b415-13fe82d2253a.

Council of Science Editors:

ten Have GAM. Pig interorgan balance studies in health and disease. [Doctoral Dissertation]. Maastricht University; 2017. Available from: https://cris.maastrichtuniversity.nl/en/publications/40915ba0-1f89-4122-b415-13fe82d2253a ; urn:nbn:nl:ui:27-40915ba0-1f89-4122-b415-13fe82d2253a ; 40915ba0-1f89-4122-b415-13fe82d2253a ; 10.26481/dis.20170913gth ; urn:nbn:nl:ui:27-40915ba0-1f89-4122-b415-13fe82d2253a ; https://cris.maastrichtuniversity.nl/en/publications/40915ba0-1f89-4122-b415-13fe82d2253a

21. Pioche, Tracy. La stéatose hépatique chez le canard mulard : étude cinétique du métabolisme intermédiaire, stress cellulaire, autophagie et nouvelle approche par les microARNs : Hepatic steatosis in mule ducks : kinetic study of intermediate metabolism, cellular stress, autophagy and new approach by microRNAs.

Degree: Docteur es, Physiologie et biologie des organismes - populations - interactions, 2019, Pau

URL: http://www.theses.fr/2019PAUU3043

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L’objectif principal de cette thèse était de poursuivre les investigations menées sur les mécanismes sous-jacents au développement du foie gras chez le canard mulard. Ce… (more)

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L’objectif principal de cette thèse était de poursuivre les investigations menées sur les mécanismes sous-jacents au développement du foie gras chez le canard mulard. Ce processus appelé stéatose hépatique et induit par le gavage nécessite d’être davantage étudié afin de contribuer à l’optimisation du gavage. Une étude cinétique de l’expression des gènes en lien avec la stéatose hépatique, le métabolisme intermédiaire et le stress cellulaire chez le canard mulard a permis de mettre en évidence, outre la forte mobilisation des métabolismes glucidique et lipidique, une induction significative de la voie de signalisation de l’insuline mTOR et l’activation de mécanismes de protection cellulaire au sein des hépatocytes leur permettant de lutter contre l’apport accru d’amidon apporté par le gavage. Parmi ces différents mécanismes protecteurs, l’autophagie a fait l’objet d’une étude poussée chez des canards gavés dont la stéatose a été à peine induite comparés à des canards non gavés. Les mesures de flux autophagique (LC3-II) ont montré que le gavage induisait une inhibition du processus autophagique dans les hépatocytes de canards mulards dès la phase précoce du développement de la stéatose hépatique. Cette même étude a permis de constater que les mécanismes associés au stress cellulaires tels que le stress oxydant, le stress du réticulum endoplasmique ou encore l’apoptose ne se sont pas induits dès le début du développement de la stéatose hépatique mais bien plus tardivement. Il en est de même pour l’impact du gavage sur la voie mTOR. Par ailleurs, l’étude cinétique a également permis de mettre en évidence l’induction significative du métabolisme du cholestérol corrélé au gain de poids de foie des canards au cours du gavage. Ces résultats ont suscité l’intérêt de rechercher des biomarqueurs plasmatiques du développement de la stéatose hépatique en lien avec le métabolisme du cholestérol parmi les microARNs. Ainsi, le miRNome plasmatique du canard a été séquencé et a permis de définir les microARNs les plus différentiellement exprimés dans le plasma des canards mulards mais également de déceler des microARNs (miR-122, miR-107 et miR-194) candidats comme potentiels biomarqueurs utilisables pour le suivi du développement du foie gras.L’ensemble de ces travaux contribuent à l’avancée de la recherche sur la compréhension des mécanismes de l’établissement de la stéatose hépatique chez le canard mulard.

The main objective of this thesis was to continue the investigations carried out on the mechanisms underlying the development of foie gras in mule ducks. This process, known as hepatic steatosis and induced by overfeeding, needs to be further studied in order to contribute to overfeeding optimization.A kinetic study of the expression of genes related to hepatic steatosis, intermediate metabolism and cellular stress in mule ducks highlighted firstly the strong mobilization of carbohydrate and lipid metabolisms. Secondly a significant induction of the insulin / mTOR signalling pathway and the activation of various cellular…

Advisors/Committee Members: Skiba, Sandrine (thesis director), Gontier, Karine (thesis director).

Subjects/Keywords: Stéatose hépatique; Canard mulard; Gavage; Métabolismes; Autophagie; MicroARNs; Hepatic steatosis; Mule duck; Overfeeding; Metabolism; Autophagy; MicroRNAs; 571

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Pioche, T. (2019). La stéatose hépatique chez le canard mulard : étude cinétique du métabolisme intermédiaire, stress cellulaire, autophagie et nouvelle approche par les microARNs : Hepatic steatosis in mule ducks : kinetic study of intermediate metabolism, cellular stress, autophagy and new approach by microRNAs. (Doctoral Dissertation). Pau. Retrieved from http://www.theses.fr/2019PAUU3043

Chicago Manual of Style (16^th Edition):

Pioche, Tracy. “La stéatose hépatique chez le canard mulard : étude cinétique du métabolisme intermédiaire, stress cellulaire, autophagie et nouvelle approche par les microARNs : Hepatic steatosis in mule ducks : kinetic study of intermediate metabolism, cellular stress, autophagy and new approach by microRNAs.” 2019. Doctoral Dissertation, Pau. Accessed January 18, 2021. http://www.theses.fr/2019PAUU3043.

MLA Handbook (7^th Edition):

Pioche, Tracy. “La stéatose hépatique chez le canard mulard : étude cinétique du métabolisme intermédiaire, stress cellulaire, autophagie et nouvelle approche par les microARNs : Hepatic steatosis in mule ducks : kinetic study of intermediate metabolism, cellular stress, autophagy and new approach by microRNAs.” 2019. Web. 18 Jan 2021.

Vancouver:

Pioche T. La stéatose hépatique chez le canard mulard : étude cinétique du métabolisme intermédiaire, stress cellulaire, autophagie et nouvelle approche par les microARNs : Hepatic steatosis in mule ducks : kinetic study of intermediate metabolism, cellular stress, autophagy and new approach by microRNAs. [Internet] [Doctoral dissertation]. Pau; 2019. [cited 2021 Jan 18]. Available from: http://www.theses.fr/2019PAUU3043.

Council of Science Editors:

Pioche T. La stéatose hépatique chez le canard mulard : étude cinétique du métabolisme intermédiaire, stress cellulaire, autophagie et nouvelle approche par les microARNs : Hepatic steatosis in mule ducks : kinetic study of intermediate metabolism, cellular stress, autophagy and new approach by microRNAs. [Doctoral Dissertation]. Pau; 2019. Available from: http://www.theses.fr/2019PAUU3043

Wayne State University

22. Pant, Asmita. Farnesol-Mediated Regulation Of Hepatic Lipid Metabolism In Heparg Cells.

Degree: PhD, Pharmacology, 2016, Wayne State University

URL: https://digitalcommons.wayne.edu/oa_dissertations/1471

► Non-alcoholic fatty liver disease is emerging as one of the most common liver disorders worldwide and is characterized by accumulation of triglycerides (TGs) in… (more)

▼ Non-alcoholic fatty liver disease is emerging as one of the most common liver disorders worldwide and is characterized by accumulation of triglycerides (TGs) in liver. The endogenous isoprenoid farnesol reduces hepatic TG levels in rodents, and this effect appears to involve at least two nuclear receptors, peroxisome proliferator-activated receptor α and farnesoid X receptor (FXR). However, farnesol’s effects on human hepatic lipid metabolism are currently unknown. The objective of this study is to evaluate how farnesol treatment would affect hepatic lipid accumulation and metabolism in a cellular model of human hepatic steatosis that was created by incubating the hepatocyte-like HepaRG cell line with oleic acid. Farnesol treatment suppressed the OA-induced TGs accumulation in HepaRG cells by 25%. Farnesol upregulated the activity of lipid-sensing nuclear receptors PPARα and constitutive androstane receptor (CAR), which was evident by the increase in the expression of their respective target genes, PLIN2 and CYP2B6; however, farnesol had no effect on FXR activity in HepaRG cells. Gene expression analysis through customized arrays revealed that farnesol modulated mRNA levels of several hepatic lipid- and drug-metabolizing enzymes in both control and OA-overloaded HepaRG cells, and the expression pattern was similar to that achieved through activation of PPARα rather than through CAR or FXR. In OA-overloaded HepaRG cells, farnesol treatment induced overall fatty acid oxidation rate, which was accompanied by upregulation in the mRNA levels of PPARα target genes involved in hepatic mitochondrial fatty acid oxidation, such as HADHB, ACADS and ACOT12. This effect was lost when cells were co-treated with the PPARα antagonist except for ACOT12. Farnesol had no effect on genes regulating peroxisomal oxidation. OA-induced changes in drug-metabolizing enzymes, such as CYP3A4, CYP2B6, CYP1A2 and CYP2E1 were also attenuated by co-treatment with farnesol. Our findings show for the first time that farnesol regulates human hepatic lipid metabolism and suppresses lipid accumulation in HepaRG cells under steatogenic conditions by upregulating mitochondrial fatty acid oxidation, primarily through PPARα pathway. Farnesyl pyrophosphate (FPP) is a branch-point intermediate in the mevalonate pathway that is normally converted mainly to squalene by squalene synthase in the first committed step of sterol biosynthesis. Treatment with the squalene synthase inhibitor squalestatin 1 (SQ1) causes accumulation of FPP, its dephosphorylated metabolite farnesol, and several oxidized farnesol-derived metabolites. Also, SQ1 treatment of primary cultured rat hepatocytes increases CYP2B expression through a mechanism that requires FPP synthesis and activation of the constitutive androstane receptor (CAR). Because direct farnesol treatment also increases CYP2B expression, it seems likely that SQ1-mediated CAR activation requires FPP dephosphorylation to farnesol. The lipid phosphatase, phosphatidic acid phosphatase… Advisors/Committee Members: Thomas A. Kocarek.

Subjects/Keywords: Cholesterol biosynthesis pathway; Farnesol; Gene expression; Hepatic Steatosis; Lipid metabolism; Non-alcoholic fatty liver disease; Pharmacology; Toxicology

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Pant, A. (2016). Farnesol-Mediated Regulation Of Hepatic Lipid Metabolism In Heparg Cells. (Doctoral Dissertation). Wayne State University. Retrieved from https://digitalcommons.wayne.edu/oa_dissertations/1471

Chicago Manual of Style (16^th Edition):

Pant, Asmita. “Farnesol-Mediated Regulation Of Hepatic Lipid Metabolism In Heparg Cells.” 2016. Doctoral Dissertation, Wayne State University. Accessed January 18, 2021. https://digitalcommons.wayne.edu/oa_dissertations/1471.

MLA Handbook (7^th Edition):

Pant, Asmita. “Farnesol-Mediated Regulation Of Hepatic Lipid Metabolism In Heparg Cells.” 2016. Web. 18 Jan 2021.

Vancouver:

Pant A. Farnesol-Mediated Regulation Of Hepatic Lipid Metabolism In Heparg Cells. [Internet] [Doctoral dissertation]. Wayne State University; 2016. [cited 2021 Jan 18]. Available from: https://digitalcommons.wayne.edu/oa_dissertations/1471.

Council of Science Editors:

Pant A. Farnesol-Mediated Regulation Of Hepatic Lipid Metabolism In Heparg Cells. [Doctoral Dissertation]. Wayne State University; 2016. Available from: https://digitalcommons.wayne.edu/oa_dissertations/1471

23. Coum, Amandine. Développement de méthodes de SRM à 4,7 T pour l'étude in vivo du métabolisme lipidique chez la souris. : Methodological development for the in vivo study of lipid metabolism by MRS in mice.

Degree: Docteur es, Génie Biologique et Médical, 2015, Rennes 1

URL: http://www.theses.fr/2015REN1B025

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Motivées par l'observation mondiale de l'augmentation de la morbidité et de la mortalité associées à des pathologies liées à l'obésité, dont la stéatose, les études… (more)

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Motivées par l'observation mondiale de l'augmentation de la morbidité et de la mortalité associées à des pathologies liées à l'obésité, dont la stéatose, les études pré-cliniques et cliniques s'intéressent à la recherche de nouveaux biomarqueurs pour le diagnostic de la stéatose. Actuellement, la stéatose est diagnostiquée et gradée par des analyses histologiques à partir d'une biopsie du foie. Dans l'intérêt du patient, et afin de permettre un suivi de la stéatose lors d'un régime ou d'un traitement, il est apparu important de se tourner vers des modalités de diagnostic moins invasives. Dans ce cadre, la spectroscopie par résonance magnétique (SRM), non-invasive et non-ionisante, est une méthode de choix pour le diagnostic de la stéatose par la mesure de la fraction lipidique hépatique. De plus, à partir des informations observables sur un spectre de SRM acquis au niveau hépatique, il est possible d'envisager une quantification de la composition en acides gras (AG) des lipides hépatiques, potentiel biomarqueur pour le suivi d'une stéatose. Les travaux de cette thèse ont été réalisés à partir d'objets-tests, et dans le cadre d'études pré-cliniques (4,7 T) et cliniques (3,0 T). Une étude du protocole d'acquisition de spectres de SRM pour la quantification de la composition en AG des lipides a été réalisée, avec notamment un questionnement quant à la nécessité de l'utilisation d'un module de suppression du signal de l'eau. Un état de l'art des algorithmes de quantification de la composition en AG des lipides a été effectué, et des tests de validations de ces algorithmes ont été réalisés afin de déterminer le plus approprié à la problématique hépatique, dans nos conditions expérimentales. Enfin, toujours dans l'objectif de déterminer des nouveaux biomarqueurs de la stéatose, une méthode de mesure par SRM in vivo du T1 de l'eau et de la résonance majeure des lipides hépatiques (LOREEDE pour LOngitudinal RElaxation time Evaluation from Dynamic Equilibrium) a été développée, et validée au cours d'une étude préliminaire sur des objets-tests et in vivo sur modèles murins.

In recent years, there has been an unprecedented increase in the morbidity and mortality associated with diseases such as the steatosis, linked to obesity. In this context, pre-clinical and clinical studies are of interest in the search for new biomarkers allowing the diagnosis of steatosis. Currently, steatosis is diagnosed and graded by histological analyzes from a liver biopsy. On the other hand, it is advantageous to use non-invasive diagnostic modalities, especially in longitudinal studies. In this context, magnetic resonance spectroscopy (MRS), as a non-invasive and non-ionizing approach, is an attractive alternative method for the diagnosis of steatosis by measuring the hepatic fat fraction. Moreover, from the MRS spectrum acquired in the liver, it is possible to quantify the fatty acids (FA) composition of the hepatic lipids, which could be a potential biomarker for the follow-up of steatosis. The work of this thesis has been performed in vitro…

Advisors/Committee Members: Gambarota, Guilio (thesis director), Noury, Fanny (thesis director).

Subjects/Keywords: Spectroscopie par résonance magnétique nucléaire; Lipides - Métabolisme; Stéatose hépatique.; Nuclear magnetic resonance spectroscopy; Lipids - Metabolism; Hepatic steatosis.

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Coum, A. (2015). Développement de méthodes de SRM à 4,7 T pour l'étude in vivo du métabolisme lipidique chez la souris. : Methodological development for the in vivo study of lipid metabolism by MRS in mice. (Doctoral Dissertation). Rennes 1. Retrieved from http://www.theses.fr/2015REN1B025

Chicago Manual of Style (16^th Edition):

Coum, Amandine. “Développement de méthodes de SRM à 4,7 T pour l'étude in vivo du métabolisme lipidique chez la souris. : Methodological development for the in vivo study of lipid metabolism by MRS in mice.” 2015. Doctoral Dissertation, Rennes 1. Accessed January 18, 2021. http://www.theses.fr/2015REN1B025.

MLA Handbook (7^th Edition):

Coum, Amandine. “Développement de méthodes de SRM à 4,7 T pour l'étude in vivo du métabolisme lipidique chez la souris. : Methodological development for the in vivo study of lipid metabolism by MRS in mice.” 2015. Web. 18 Jan 2021.

Vancouver:

Coum A. Développement de méthodes de SRM à 4,7 T pour l'étude in vivo du métabolisme lipidique chez la souris. : Methodological development for the in vivo study of lipid metabolism by MRS in mice. [Internet] [Doctoral dissertation]. Rennes 1; 2015. [cited 2021 Jan 18]. Available from: http://www.theses.fr/2015REN1B025.

Council of Science Editors:

Coum A. Développement de méthodes de SRM à 4,7 T pour l'étude in vivo du métabolisme lipidique chez la souris. : Methodological development for the in vivo study of lipid metabolism by MRS in mice. [Doctoral Dissertation]. Rennes 1; 2015. Available from: http://www.theses.fr/2015REN1B025

24. Cox, Julie. Evaluation of Strategies to Improve In Vitro Mutagenicity Assessment: Alternative Sources of S9 Exogenous Metabolic Activation and the Development of an In Vitro Assay Based on MutaMouse Primary Hepatocytes .

Degree: 2019, University of Ottawa

URL: http://hdl.handle.net/10393/39340

► In vitro genetic toxicity tests using cultured bacterial or mammalian cells provide a cost- and time-effective alternative to animal tests. Unfortunately, existing in vitro assays… (more)

▼ In vitro genetic toxicity tests using cultured bacterial or mammalian cells provide a cost- and time-effective alternative to animal tests. Unfortunately, existing in vitro assays are not always reliable. This is in part due to the limited metabolic capacity of the cells used, which is often critical to accurately assess chemical genotoxicity. This limited metabolic capacity necessitates the use of exogenous sources of mammalian metabolic enzymes that can simulate in vivo mammalian metabolic activation reactions. In response to this, and other limitations, alongside the worldwide trend to reduce animal testing, there is an acute need to consider various strategies to improve in vitro mutagenicity assessment. This thesis first examined the utility of exogenous metabolic activation systems based on human hepatic S9, relative to conventional induced rat liver S9, for routine genetic toxicity assessment. This was accomplished by critically evaluating existing literature, as well as new experimental data. The results revealed the limitations of human liver S9 for assessment of chemical mutagenicity. More specifically, the analyses concluded that, due to the increased risk of false negative results, human liver S9 should not be used as a replacement for induced rat liver S9. To address the limitations of conventional mammalian cell genetic toxicity assays that require exogenous hepatic S9, the thesis next evaluated the utility of an in vitro mutagenicity assay based on metabolically-competent primary hepatocytes (PHs) derived from the transgenic MutaMouse. Cultured MutaMouse PHs were thoroughly characterized, and found to temporarily retain the phenotypic attributes of hepatocytes in vivo; they express hepatocyte-specific proteins, exhibit the karyotype of typical hepatocytes, and maintain metabolic activity for at least the first 24 hours after isolation. Preliminary validation of the in vitro MutaMouse PH gene mutation assay, using a panel of thirteen mutagenic and non-mutagenic chemicals, demonstrated excellent sensitivity and specificity. Moreover, inclusion of substances requiring a diverse array of metabolic activation pathways revealed comprehensive metabolic competence. Finally, the thesis further investigated the applicability domain of the in vitro MutaMouse PH assay by challenging the assay with selected azo compounds. Comparison of these results with those obtained using the in vivo MutaMouse TGR (transgenic rodent) assay revealed that MutaMouse PHs can carry out some forms of reductive metabolism. Overall, this thesis demonstrated that a gene mutation assay based on MutaMouse PHs holds great promise for routine assessments of chemical mutagenicity.

Subjects/Keywords: Human hepatic metabolism; Ames; Micronucleus; Genetic toxicology; Transgenic rodent; Liver; Primary culture; Metabolic enzymes; Regulatory toxicology; Chemical mutagens

10 more images…

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Cox, J. (2019). Evaluation of Strategies to Improve In Vitro Mutagenicity Assessment: Alternative Sources of S9 Exogenous Metabolic Activation and the Development of an In Vitro Assay Based on MutaMouse Primary Hepatocytes . (Thesis). University of Ottawa. Retrieved from http://hdl.handle.net/10393/39340

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Cox, Julie. “Evaluation of Strategies to Improve In Vitro Mutagenicity Assessment: Alternative Sources of S9 Exogenous Metabolic Activation and the Development of an In Vitro Assay Based on MutaMouse Primary Hepatocytes .” 2019. Thesis, University of Ottawa. Accessed January 18, 2021. http://hdl.handle.net/10393/39340.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Cox, Julie. “Evaluation of Strategies to Improve In Vitro Mutagenicity Assessment: Alternative Sources of S9 Exogenous Metabolic Activation and the Development of an In Vitro Assay Based on MutaMouse Primary Hepatocytes .” 2019. Web. 18 Jan 2021.

Vancouver:

Cox J. Evaluation of Strategies to Improve In Vitro Mutagenicity Assessment: Alternative Sources of S9 Exogenous Metabolic Activation and the Development of an In Vitro Assay Based on MutaMouse Primary Hepatocytes . [Internet] [Thesis]. University of Ottawa; 2019. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/10393/39340.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Cox J. Evaluation of Strategies to Improve In Vitro Mutagenicity Assessment: Alternative Sources of S9 Exogenous Metabolic Activation and the Development of an In Vitro Assay Based on MutaMouse Primary Hepatocytes . [Thesis]. University of Ottawa; 2019. Available from: http://hdl.handle.net/10393/39340

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

25. Belghit, Khadidja Ikram. Effet de la composition en macronutriments de l’aliment sur les mécanismes de contrôle de l’autophagie chez la truite arc-enciel (Oncorhynchus mykiss) : Effect of macronutrients composition of the diets on autophagy control in rainbow trout (Oncorhynchus mykiss).

Degree: Docteur es, Sciences agronomiques, biotechnologies agro-alimentaires, 2015, Pau

URL: http://www.theses.fr/2015PAUU3002

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Très peu de données sont aujourd’hui disponibles sur le rôle des nutriments et de leurs interactions in vivo dans la régulation de l’autophagie. L'objectif principal… (more)

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Très peu de données sont aujourd’hui disponibles sur le rôle des nutriments et de leurs interactions in vivo dans la régulation de l’autophagie. L'objectif principal de cette thèse était donc d’étudier l’effet de la qualité nutritionnelle de l’aliment sur le contrôle de cette fonction cellulaire. Une première étude a permis de montrer que les différents ratios en protéines et en glucides influencent significativement les mécanismes de contrôle de l’autophagie dans le muscle de truite arc-en-ciel (Oncorhynchus mykiss). Ces résultats ont été renforcés par une étude sur culture primaire de myoblaste de truite montrant que l’addition d’acides aminés dans le milieu de culture inhibe l’autophagie alors que le glucose à un effet inverse (article 1). Une seconde étude a porté sur la fraction protéique de l’aliment et notamment sur la teneur en méthionine, dont le niveau est trop faible dans les aliments pour poissons à base de végétaux. Les résultats obtenus indiquent que la machinerie autophagosomale mais également les principaux facteurs du renouvellement des protéines musculaires sont sensible aux variations de la teneur en méthionine de l’aliment et que la réponse qui en résulte peut fortement affecter la croissance (article 2). L’ensemble des données obtenues dans les deux premières études reposaient sur la mesure du taux d’un marqueur de l’autophagie (LC3-II) qui est à la fois produite et dégradée au cours du processus (flux) autophagique. Ainsi, dans l’optique de préciser les résultats obtenus dans les deux premiers articles, une troisième étude a été effectuée afin de déterminer s’il est possible de bloquer le flux autophagique dans le muscle de truite par l’emploi de différents agents pharmacologiques (inhibiteurs du flux autophagique). Il s’agissait également de déterminer les limites de l’utilisation de tels inhibiteurs chez cette espèce. Les essais effectués n’ont pas permis de mesurer le flux autophagique dans le muscle. En revanche, l’injection intrapéritonéale de colchicine a bien bloqué le flux autophagique dans le foie, ouvrant ainsi un nouveau champ d’investigations sur le rôle de l’autophagie dans le métabolisme intermédiaire. En conclusion, l’ensemble de ces travaux montre que l’autophagie n’est pas uniquement sensible à l’état nutritionnel (jeûne/nourris) mais également à la nature des aliments consommés. Outre leurs intérêts agronomique et thérapeutique, ces résultats ouvrent de nouvelles perspectives pour une meilleure compréhension des mécanismes d’action de l’autophagie au niveau cellulaire et métabolique mais également de son rôle dans l’adaptation des espèces au cours l’évolution.

Few data has been published on the role of nutrients and their interactions in vivo in the regulation of autophagy. The main objective of this thesis was therefore to characterize the response of the autophagic/lysosomal pathway to the macronutrients composition of the diets. The first study showed that different ratio of proteins and carbohydrates in the diet significantly affect the controls of autophagy in the…

Advisors/Committee Members: Panserat, Stéphane (thesis director).

Subjects/Keywords: Truite arc-en-ciel; Composition des macronutriments; Muscle; Flux autophagique; Métabolisme hépatique.; Rainbow trout; Macronutrients composition; Muscle; Autophagic flux,; Hepatic metabolism.

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Belghit, K. I. (2015). Effet de la composition en macronutriments de l’aliment sur les mécanismes de contrôle de l’autophagie chez la truite arc-enciel (Oncorhynchus mykiss) : Effect of macronutrients composition of the diets on autophagy control in rainbow trout (Oncorhynchus mykiss). (Doctoral Dissertation). Pau. Retrieved from http://www.theses.fr/2015PAUU3002

Chicago Manual of Style (16^th Edition):

Belghit, Khadidja Ikram. “Effet de la composition en macronutriments de l’aliment sur les mécanismes de contrôle de l’autophagie chez la truite arc-enciel (Oncorhynchus mykiss) : Effect of macronutrients composition of the diets on autophagy control in rainbow trout (Oncorhynchus mykiss).” 2015. Doctoral Dissertation, Pau. Accessed January 18, 2021. http://www.theses.fr/2015PAUU3002.

MLA Handbook (7^th Edition):

Belghit, Khadidja Ikram. “Effet de la composition en macronutriments de l’aliment sur les mécanismes de contrôle de l’autophagie chez la truite arc-enciel (Oncorhynchus mykiss) : Effect of macronutrients composition of the diets on autophagy control in rainbow trout (Oncorhynchus mykiss).” 2015. Web. 18 Jan 2021.

Vancouver:

Belghit KI. Effet de la composition en macronutriments de l’aliment sur les mécanismes de contrôle de l’autophagie chez la truite arc-enciel (Oncorhynchus mykiss) : Effect of macronutrients composition of the diets on autophagy control in rainbow trout (Oncorhynchus mykiss). [Internet] [Doctoral dissertation]. Pau; 2015. [cited 2021 Jan 18]. Available from: http://www.theses.fr/2015PAUU3002.

Council of Science Editors:

Belghit KI. Effet de la composition en macronutriments de l’aliment sur les mécanismes de contrôle de l’autophagie chez la truite arc-enciel (Oncorhynchus mykiss) : Effect of macronutrients composition of the diets on autophagy control in rainbow trout (Oncorhynchus mykiss). [Doctoral Dissertation]. Pau; 2015. Available from: http://www.theses.fr/2015PAUU3002

University of Southern California

26. Liu, Shanshan. Factors impacting drug disposition and clinical outcomes: age, hepatic metabolism, renal elimination and pharmacogentetics.

Degree: PhD, Pharmaceutical Sciences, 2009, University of Southern California

URL: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/248933/rec/2726

► Objective: This dissertation aims to evaluate factors impacting drug disposition and clinical outcomes.; Methods: Pharmacokinetic studies were conducted for gemcitabine in urothelial cancer, paclitaxel in… (more)

▼ Objective: This dissertation aims to evaluate factors impacting drug disposition and clinical outcomes.; Methods: Pharmacokinetic studies were conducted for gemcitabine in urothelial cancer, paclitaxel in breast cancer and capecitabine in colorectal caner among patients stratified into young and elderly groups. Cocktail consisting of chlorzoxazone (CYP2E1), caffeine (CYP1A2), dapsone (CYP3A4), mephenytoin (CYP2C19) and debrisoquine (CYP2D6) were administrated to OLTx patients to evaluate enzyme activity relating to recipient’s age and post-operative duration. To assess renal P-gp activity in cystic fibrosis (CF) patients, disposition of fexofenadine was evaluated and P-gp efflux activity in peripheral T cells was measured by flow cytometry. To assess interactions between tenofovir and ritonavir, renal function of HIV-infected patients were evaluated and tenofovir disposition was compared relating to regiments administrated. Kidney cell lines, MDCKII and HEK293, were treated with tenofovir alone or in combination with ritonavir or MK571 to assess the impact of ritonavir on intracellular tenofovir accumulation.; Results: Compared to patients less than 60, elderly patients (>70 years) had significantly greater AUCs and less clearance for paclitaxel and capecitabine and greater AUC of dFdU. The CYP2E1 activity was significantly elevated and CYP2C19 function was markedly reduced in OLTx patients, where CYP2D6 capacity was impaired in older OLTx patients within 30 days postoperatively compared to healthy controls. The P-gp efflux activity in peripheral T cells was not significantly different between CF and HV. Fexofenadine pharmacokinetics was similar in CF and HV when administered alone or with probenecid. ABCB1 3435 C/T carriers showed increased basal P-gp activity in peripheral T cells and decreased fexofenadine AUC. Patients receiving concurrent TDF+PI/r treatment had greater reductions in CrCl and lower TFV Kel compared to patients taking TDF+NNRTI. TFV was substrate of MRP2, MRP4 and MRP5, where RTV was a potent inhibitor of MRP2 leading to nephrotoxicity with TDF-RTV coadministration.; Conclusion: Impaired renal elimination and hepatic metabolic capacity are major factors accounting for altered pharmacokinetics in elderly patients. Inhibition of transporters contributes to variations in drug disposition. Genetic polymorphisms in enzymes and transporters add to complexities of inter-individual differences in pharmacokinetics and clinical outcomes. Advisors/Committee Members: Louie, Stan (Committee Chair), Shen, Wei-Chiang (Committee Member), D'Argenio, David (Committee Member).

Subjects/Keywords: drug disposition; age; hepatic metabolism; renal elimination; pharmacogenetics

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APA (6^th Edition):

Liu, S. (2009). Factors impacting drug disposition and clinical outcomes: age, hepatic metabolism, renal elimination and pharmacogentetics. (Doctoral Dissertation). University of Southern California. Retrieved from http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/248933/rec/2726

Chicago Manual of Style (16^th Edition):

Liu, Shanshan. “Factors impacting drug disposition and clinical outcomes: age, hepatic metabolism, renal elimination and pharmacogentetics.” 2009. Doctoral Dissertation, University of Southern California. Accessed January 18, 2021. http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/248933/rec/2726.

MLA Handbook (7^th Edition):

Liu, Shanshan. “Factors impacting drug disposition and clinical outcomes: age, hepatic metabolism, renal elimination and pharmacogentetics.” 2009. Web. 18 Jan 2021.

Vancouver:

Liu S. Factors impacting drug disposition and clinical outcomes: age, hepatic metabolism, renal elimination and pharmacogentetics. [Internet] [Doctoral dissertation]. University of Southern California; 2009. [cited 2021 Jan 18]. Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/248933/rec/2726.

Council of Science Editors:

Liu S. Factors impacting drug disposition and clinical outcomes: age, hepatic metabolism, renal elimination and pharmacogentetics. [Doctoral Dissertation]. University of Southern California; 2009. Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/248933/rec/2726

27. Popineau, Lucie. Régulation de l’homéostasie métabolique hépatique : contrôle par Grb14 de la sensibilité à l’insuline et influence de la stéatose sur la carcinogenèse : Hepatic metabolic homeostasis regulation : Grb14 control of insuline sensitivity and steatosis impact on carcinogenesis.

Degree: Docteur es, Biologie cellulaire, 2013, Université Paris Descartes – Paris V

URL: http://www.theses.fr/2013PA05T028

►

La prévalence de l’obésité et du diabète de type 2 est en constante augmentation dans les pays industrialisés. Ces pathologies sont associées à des troubles… (more)

▼

La prévalence de l’obésité et du diabète de type 2 est en constante augmentation dans les pays industrialisés. Ces pathologies sont associées à des troubles de l’équilibre énergétique de l’organisme, ce qui se traduit au niveau hépatique par le développement de NAFLD (Non‐alcoholic Fatty Liver Disease). La NAFLD est engendrée par l’accumulation excessive de lipides dans les hépatocytes ou stéatose et est associée à la résistance à l’insuline. L’insulinorésistance hépatique est dite sélective car l’insuline n’est plus capable d’inhiber la production hépatique de glucose, contribuant à l’hyperglycémie, alors que la synthèse lipidique est exacerbée, induisant une stéatose hépatique. La stéatose peut évoluer en pathologies plus graves, telles que la fibrose, la cirrhose ou le cancer hépatocellulaire (CHC). L’objectif de ma thèse a été d’étudier les mécanismes moléculaires pouvant contribuer à la sélectivité de la résistance à l’insuline hépatique et à l’évolution de la stéatose simple vers le CHC. Dans un premier temps, nous avons étudié le rôle de l’adaptateur moléculaire Grb14, un inhibiteur de l’activité kinase du récepteur de l’insuline, dans la régulation du métabolisme hépatique chez la souris. L’invalidation de Grb14 dans le foie conduit d’une part à une activation de la signalisation de l’insuline et une amélioration de tolérance au glucose, et d’autre part à une diminution de la lipogenèse consécutive à l’inhibition du facteur lipogénique LXR via la voie Nrf2. L’invalidation de Grb14 dans le foie de souris obèses et diabétiques permet de ramener la glycémie et la stéatose hépatique à des valeurs similaires aux témoins. Ces données suggèrent que Grb14 est un nouvel acteur impliqué dans la sélectivité de la résistance à l’insuline du foie. La seconde étude a permis de montrer l’implication de la stéatose hépatique induite par un régime hypercalorique sur le développement de CHC. En effet, sur un fond génétique favorisant la carcinogenèse, un régime riche en graisse et en sucre contribuant à l’insulinorésistance hépatique accélère la cinétique d’apparition des tumeurs et augmente leur nombre.

The prevalence of metabolic diseases, including obesity and type 2 diabetes, are expanding in a worldwide epidemic way. These diseases are associated with metabolic disorders, resulting in the development of NAFLD (Non‐alcoholic Fatty Liver Disease) in the liver. NAFLD is generated by excessive accumulation of lipids in hepatocytes, and is associated with insulin resistance. In liver, insulin resistance leads to a blunted inhibitory action on hepatic glucose production, inducing hyperglycemia, whereas de novo lipogenesis, which is positively regulated by insulin, is paradoxically exacerbated, contributing to hepatic steatosis. Steatosis may also evolve into more serious diseases such as fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The aim of my thesis was to study the molecular mechanisms that may contribute to the selectivity of hepatic insulin resistance and the development of HCC. Initially, we studied the…

Advisors/Committee Members: Burnol, Anne-Françoise (thesis director).

Subjects/Keywords: Métabolisme; Stéatose hépatique; Insulinorésistance; Grb14; Cancer hépatocellulaire; Metabolism; Hepatic steatosis; Insulin resistance; Grb14; Hepatocellular carcinoma; 612.022

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Popineau, L. (2013). Régulation de l’homéostasie métabolique hépatique : contrôle par Grb14 de la sensibilité à l’insuline et influence de la stéatose sur la carcinogenèse : Hepatic metabolic homeostasis regulation : Grb14 control of insuline sensitivity and steatosis impact on carcinogenesis. (Doctoral Dissertation). Université Paris Descartes – Paris V. Retrieved from http://www.theses.fr/2013PA05T028

Chicago Manual of Style (16^th Edition):

Popineau, Lucie. “Régulation de l’homéostasie métabolique hépatique : contrôle par Grb14 de la sensibilité à l’insuline et influence de la stéatose sur la carcinogenèse : Hepatic metabolic homeostasis regulation : Grb14 control of insuline sensitivity and steatosis impact on carcinogenesis.” 2013. Doctoral Dissertation, Université Paris Descartes – Paris V. Accessed January 18, 2021. http://www.theses.fr/2013PA05T028.

MLA Handbook (7^th Edition):

Popineau, Lucie. “Régulation de l’homéostasie métabolique hépatique : contrôle par Grb14 de la sensibilité à l’insuline et influence de la stéatose sur la carcinogenèse : Hepatic metabolic homeostasis regulation : Grb14 control of insuline sensitivity and steatosis impact on carcinogenesis.” 2013. Web. 18 Jan 2021.

Vancouver:

Popineau L. Régulation de l’homéostasie métabolique hépatique : contrôle par Grb14 de la sensibilité à l’insuline et influence de la stéatose sur la carcinogenèse : Hepatic metabolic homeostasis regulation : Grb14 control of insuline sensitivity and steatosis impact on carcinogenesis. [Internet] [Doctoral dissertation]. Université Paris Descartes – Paris V; 2013. [cited 2021 Jan 18]. Available from: http://www.theses.fr/2013PA05T028.

Council of Science Editors:

Popineau L. Régulation de l’homéostasie métabolique hépatique : contrôle par Grb14 de la sensibilité à l’insuline et influence de la stéatose sur la carcinogenèse : Hepatic metabolic homeostasis regulation : Grb14 control of insuline sensitivity and steatosis impact on carcinogenesis. [Doctoral Dissertation]. Université Paris Descartes – Paris V; 2013. Available from: http://www.theses.fr/2013PA05T028

University of Sydney

28. Kimble, Benjamin. Pharmacokinetic aspects of meloxicam in koalas: including its hepatic microsomal metabolism compared with other selected species .

Degree: 2015, University of Sydney

URL: http://hdl.handle.net/2123/13996

► Prior to this research, no disposition studies of meloxicam (nor any other non steroidal anti-inflammatory drugs) had been conducted in koalas (a specialist Eucalyptus spp.… (more)

▼ Prior to this research, no disposition studies of meloxicam (nor any other non steroidal anti-inflammatory drugs) had been conducted in koalas (a specialist Eucalyptus spp. foliage feeder) despite being readily administered to this species, in the field. Thus, aspects of the in-vivo pharmacokinetic profile of meloxicam in the koala and the in-vitro metabolism of meloxicam in the koala and selected species were investigated. In the first stage of the research, a simple, sensitive and improved method using high performance liquid chromatography equipped with photo diode array detection was developed and validated to determine meloxicam concentrations in koala plasma, applicable for in-vivo pharmacokinetic study. Following intravenous injection, meloxicam exhibited a rapid plasma clearance of 0.44 ± 0.20 L/h/kg in koalas (n = 5). Median plasma terminal elimination t1/2 was 1.19 h (range 0.71 to 1.62 h). In koalas, bioavailability after the subcutaneous injection was approximately 56 to 70 % where oral bioavailability was negligible. Plasma protein binding of meloxicam was about 98%. Three hydroxylated metabolites of meloxicam (M1, M2 and M3) were detected in the koala plasma with one (M1) identified as the 5-hydroxy methyl metabolite. According to the in-vitro hepatic microsomal metabolism of meloxicam, it was demonstrated that biotransformation of meloxicam, likely mediated via cytochrome P450 enzymes, were much faster in koalas (and also in other Eucalyptus spp. foliage feeders: ringtail possums and brushtail possums) compared to rats or dogs. The rank order of apparent in-vitro intrinsic clearance was brushtail possums (n = 3) (mean: 394 μL/min/mg protein) > koalas (n = 6) (50 μL/min/mg protein) > ringtail possums (n = 2) (36 μL/min/mg protein) (with no significant difference between koalas and ringtail possums) > pooled rats (3.2 μL/min/mg protein) > pooled dogs (not determined as the rate of metabolism was too slow). According to the in-vitro study, single hydroxylated metabolite (M1) was determined as the major product of meloxicam in brushtail possums and the rat whereas multiple hydroxylated metabolites were observed in the koala (M1, M2, and M3) and the ringtail possum (M1 and M3). Using a well-stirred model, this research showed applicability of predicting in-vivo clearance of meloxicam in koalas and the rat from the apparent in-vitro intrinsic clearance data (average fold error for prediction was less than 2). While cytochrome P4502C9 is the major responsible enzymes for metabolism of meloxicam, the research also found that the stability of other cytochrome P4502C9 substrates, particularly non steroidal anti-inflammatory drugs were also generally not stable in hepatic microsomes of koala and other Eucalyptus.spp foliage feeders than the rat. Particularly, there was some similarity on the pattern of CYP2C9 substrates stabilities between koala and ringtail possum (Eucalyptus spp. foliage specialist feeders). This research demonstrated that koalas exhibited rapid plasma clearance and extremely poor oral…

Subjects/Keywords: Pharmacokinetics; Hepatic metabolism; Cytochromes P450; (in-vitro intrinsic) clearance; Meloxicam; NSAIDs; Koala; Eucalyptus spp. foliage feeders

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Kimble, B. (2015). Pharmacokinetic aspects of meloxicam in koalas: including its hepatic microsomal metabolism compared with other selected species . (Thesis). University of Sydney. Retrieved from http://hdl.handle.net/2123/13996

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Kimble, Benjamin. “Pharmacokinetic aspects of meloxicam in koalas: including its hepatic microsomal metabolism compared with other selected species .” 2015. Thesis, University of Sydney. Accessed January 18, 2021. http://hdl.handle.net/2123/13996.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Kimble, Benjamin. “Pharmacokinetic aspects of meloxicam in koalas: including its hepatic microsomal metabolism compared with other selected species .” 2015. Web. 18 Jan 2021.

Vancouver:

Kimble B. Pharmacokinetic aspects of meloxicam in koalas: including its hepatic microsomal metabolism compared with other selected species . [Internet] [Thesis]. University of Sydney; 2015. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/2123/13996.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Kimble B. Pharmacokinetic aspects of meloxicam in koalas: including its hepatic microsomal metabolism compared with other selected species . [Thesis]. University of Sydney; 2015. Available from: http://hdl.handle.net/2123/13996

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

York University

29. Uthayakumar, Abinas. The Effect of High-Fat Diet and Exercise on Non-Alcoholic Fatty Liver Disease and Glycemic Control.

Degree: MSc -MS, Kinesiology & Health Science, 2015, York University

URL: http://hdl.handle.net/10315/30735

► This study investigates the effects of chronic high-fat diet (HFD) and endurance training on Non-Alcoholic Fatty Liver Disease (NAFLD) and glycemic control. Here we report… (more)

Subjects/Keywords: Kinesiology; Physiology; obesity; exercise; high-fat diet; hepatic glucose production; gluconeogenesis; glycogen synthesis; hepatic steatosis; non-alcoholic fatty liver disease; insulin resistance; lipogenesis; liver; lipid oxidation; chronic endurance training; glucose 6-phosphate; glucose; metabolism; glucose tolerance test; pyruvate tolerance test; insulin signalling; diabetes; NAFLD

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Uthayakumar, A. (2015). The Effect of High-Fat Diet and Exercise on Non-Alcoholic Fatty Liver Disease and Glycemic Control. (Masters Thesis). York University. Retrieved from http://hdl.handle.net/10315/30735

Chicago Manual of Style (16^th Edition):

Uthayakumar, Abinas. “The Effect of High-Fat Diet and Exercise on Non-Alcoholic Fatty Liver Disease and Glycemic Control.” 2015. Masters Thesis, York University. Accessed January 18, 2021. http://hdl.handle.net/10315/30735.

MLA Handbook (7^th Edition):

Uthayakumar, Abinas. “The Effect of High-Fat Diet and Exercise on Non-Alcoholic Fatty Liver Disease and Glycemic Control.” 2015. Web. 18 Jan 2021.

Vancouver:

Uthayakumar A. The Effect of High-Fat Diet and Exercise on Non-Alcoholic Fatty Liver Disease and Glycemic Control. [Internet] [Masters thesis]. York University; 2015. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/10315/30735.

Council of Science Editors:

Uthayakumar A. The Effect of High-Fat Diet and Exercise on Non-Alcoholic Fatty Liver Disease and Glycemic Control. [Masters Thesis]. York University; 2015. Available from: http://hdl.handle.net/10315/30735

30. Theurey, Pierre. Implication of mitochondria endoplasmic-reticulum interactions in the control of hepatic metabolism : Implication des interactions mitochondrie-réticulum endoplasmique dans le contrôle du métabolisme hépatique.

Degree: Docteur es, Physiologie. Biologie cellulaire, 2015, Université Claude Bernard – Lyon I

URL: http://www.theses.fr/2015LYO10104

►

Le foie est un organe indispensable dans le contrôle de l'homéostasie énergétique du corps humain. En particulier, le métabolisme hépatique est crucial pour l'homéostasie glucidique… (more)

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Le foie est un organe indispensable dans le contrôle de l'homéostasie énergétique du corps humain. En particulier, le métabolisme hépatique est crucial pour l'homéostasie glucidique et lipidique. Les voies cataboliques et anaboliques sont en équilibre constant et régulées de façon synergique en fonction de la disponibilité en nutriments et de la demande en énergie. La perturbation de cet équilibre, notamment en cas d'obésité, peut conduire à l'accumulation intra-hépatique de lipides, qui est une des causes principales de la survenue de l'insulino-résistance hépatique (IRH), conduisant à l'hyperglycémie chronique et au diabète de type 2 (DT2). La cellule eucaryote est une structure hautement compartimentée, et à ce titre la compartimentalisation des processus cataboliques et anaboliques est une part intégrante de la gestion des voies métaboliques. Dans cet ensemble, la mitochondrie est un organite clef, qui abrite l'oxydation des lipides, le cycle de l'acide citrique (CAC) et la respiration cellulaire. De cette manière, la fonction mitochondriale est un élément crucial dans le maintien de l'état énergétique et d'oxydation-réduction de la cellule dans une gamme physiologique, ainsi que dans la régulation de l'activité du métabolisme du glucose et des lipides pour l'homéostasie du corps entier. La fonction mitochondriale est directement régulée par son interaction avec le réticulum endoplasmique (RE) via des zones de proximité entre les organites appelées Mitochondria-Associated-Endoplasmic-Reticulum-Membranes ou MAM. Dans ce contexte, j'ai participé au cours de mon travail de thèse à une étude qui a montré l'importance des interactions mitochondrie-RE dans la signalisation de l'insuline et mise en lumière la perturbation des MAM comme acteur principal dans l'IRH. De plus, j'ai étudié la régulation des MAM dans le contexte physiologique de la transition nutritionnelle dans le foie sain et insulino-résistant (IR)

The liver is an essential organ in the control of energetic homeostasis of the human body. Particularly, hepatic metabolism is crucial for glucose and lipid homeostasis. Catabolism and anabolism of both substrates are in constant equilibrium and synergically regulated in regard of nutrient availability and energetic demand. Disruption of this equilibrium, especially in the case of obesity, can lead to hepatic accumulation of lipids, which is a major cause of hepatic insulin resistance (HIR) leading to chronic hyperglycaemia and type 2 diabetes (T2D). The eukaryotic cell is a highly compartmented structure, and in this respect compartmentation of anabolic and catabolic processes is an integral part of managing metabolic pathways together. In this context, the mitochondrion is a key organelle, housing oxidation of lipids, the tricarboxylic acid (TCA) cycle and cellular respiration. In this way, mitochondrial function is a crucial element in maintaining energetic and reductionoxidation state of the cell within physiological ranges, as well in regulating the proper activity of glucose and lipid metabolism for the…

Advisors/Committee Members: Rieusset, Jennifer (thesis director).

Subjects/Keywords: Mitochondrie; Réticulum endoplasmique; MAM; Dynamique mitochondriale; Fonction mitochondriale; Métabolisme hépatique; Insulino-résistance hépatique; Glucose; PP2A; Mitochondria; Endoplasmic reticulum; MAM; Mitochondria dynamics; Mitochondria function; Hepatic metabolism; Hepatic insulin resistance; Glucose sensing; PP2A; 571

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Theurey, P. (2015). Implication of mitochondria endoplasmic-reticulum interactions in the control of hepatic metabolism : Implication des interactions mitochondrie-réticulum endoplasmique dans le contrôle du métabolisme hépatique. (Doctoral Dissertation). Université Claude Bernard – Lyon I. Retrieved from http://www.theses.fr/2015LYO10104

Chicago Manual of Style (16^th Edition):

Theurey, Pierre. “Implication of mitochondria endoplasmic-reticulum interactions in the control of hepatic metabolism : Implication des interactions mitochondrie-réticulum endoplasmique dans le contrôle du métabolisme hépatique.” 2015. Doctoral Dissertation, Université Claude Bernard – Lyon I. Accessed January 18, 2021. http://www.theses.fr/2015LYO10104.

MLA Handbook (7^th Edition):

Theurey, Pierre. “Implication of mitochondria endoplasmic-reticulum interactions in the control of hepatic metabolism : Implication des interactions mitochondrie-réticulum endoplasmique dans le contrôle du métabolisme hépatique.” 2015. Web. 18 Jan 2021.

Vancouver:

Theurey P. Implication of mitochondria endoplasmic-reticulum interactions in the control of hepatic metabolism : Implication des interactions mitochondrie-réticulum endoplasmique dans le contrôle du métabolisme hépatique. [Internet] [Doctoral dissertation]. Université Claude Bernard – Lyon I; 2015. [cited 2021 Jan 18]. Available from: http://www.theses.fr/2015LYO10104.

Council of Science Editors:

Theurey P. Implication of mitochondria endoplasmic-reticulum interactions in the control of hepatic metabolism : Implication des interactions mitochondrie-réticulum endoplasmique dans le contrôle du métabolisme hépatique. [Doctoral Dissertation]. Université Claude Bernard – Lyon I; 2015. Available from: http://www.theses.fr/2015LYO10104

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