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Universiteit Utrecht

1. Engbers, H.M. Neurodevelopmental disorders; yield of extended investigations.

Degree: 2009, Universiteit Utrecht

URL: http://dspace.library.uu.nl:8080/handle/1874/37457

► Summary Chapter 1 addresses general aspects of neurodevelopmental disorders and gives an outline of this thesis. Neurodevelopmental disorders (NDD), are an important health care problem… (more)

▼ Summary Chapter 1 addresses general aspects of neurodevelopmental disorders and gives an outline of this thesis. Neurodevelopmental disorders (NDD), are an important health care problem with a prevalence of 2-3% in the general population. The widespread etiological causes for NDD comprise exogenic factors (teratogens, infections and trauma) and genetic causes (including metabolic diseases). The complicated diagnostic work-up in NDD is described. Chapter 2 describes the importance of metabolic investigations in the diagnostic pathway of NDD. We studied the yield of metabolic investigations in patients with neurodevelopmental disorders of unknown origin and found a yield of 2.8 % despite performed metabolic investigations before referral. As seen in this study, additional metabolic investigations can even extend the metabolic yield in an already screened population. Chapter 3 describes the findings of MRI scans in patients with unexplained NDD. In 30.7 % of the patients abnormal MRI scans were observed and in 5.4 % the MRI scans lead to an etiologic diagnosis. This study shows in a large population of patients with NDD that neurological findings are indicative for having an abnormal or diagnostic MRI. In our specialised centre 5.4 % of the patients had a diagnostic MRI scan, despite initial metabolic and genetic investigations before referral. This study confirms for the first time in a large population of patients with unexplained NDD, the value of an MRI scan of the brain, in the diagnostic work-up for NDD. Chapter 4 describes the yield of MRI imaging in patients with NDD in association with dysmorphic features. Dysmorphic features could indicate an altered embryonic, foetal or post-natal development, likely to increase the chance of abnormal developmental patterning of the brain. This study showed a higher number of craniofacial dysmorphic features in patients with NDD increasing the yield of brain abnormalities of those patients. This might aid the search for an etiological diagnosis. In chapter 5 the frequency of specific pregnancy and delivery features in children with NDD was compared with the frequency of pregnancy and delivery features in children of the general Dutch population. The study established associations between NDD and gestational diabetes, polyhydramnion, postterm pregnancy, Low Birth Weight (LBW Advisors/Committee Members: Berger, R., Visser, Gepke.

Subjects/Keywords: Econometric and Statistical Methods: General; Geneeskunde(GENK)

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APA (6^th Edition):

Engbers, H. M. (2009). Neurodevelopmental disorders; yield of extended investigations. (Doctoral Dissertation). Universiteit Utrecht. Retrieved from http://dspace.library.uu.nl:8080/handle/1874/37457

Chicago Manual of Style (16^th Edition):

Engbers, H M. “Neurodevelopmental disorders; yield of extended investigations.” 2009. Doctoral Dissertation, Universiteit Utrecht. Accessed April 18, 2021. http://dspace.library.uu.nl:8080/handle/1874/37457.

MLA Handbook (7^th Edition):

Engbers, H M. “Neurodevelopmental disorders; yield of extended investigations.” 2009. Web. 18 Apr 2021.

Vancouver:

Engbers HM. Neurodevelopmental disorders; yield of extended investigations. [Internet] [Doctoral dissertation]. Universiteit Utrecht; 2009. [cited 2021 Apr 18]. Available from: http://dspace.library.uu.nl:8080/handle/1874/37457.

Council of Science Editors:

Engbers HM. Neurodevelopmental disorders; yield of extended investigations. [Doctoral Dissertation]. Universiteit Utrecht; 2009. Available from: http://dspace.library.uu.nl:8080/handle/1874/37457

Universiteit Utrecht

2. van Beekum, P.O. Novel mechanisms in PPARy-mediated adipogenesis.

Degree: 2008, Universiteit Utrecht

URL: http://dspace.library.uu.nl:8080/handle/1874/27576

► Obesity-induced type 2 diabetes mellitus (T2DM) has grown to epidemic proportions in the last decades. The number of adults with T2DM in the United States… (more)

▼ Obesity-induced type 2 diabetes mellitus (T2DM) has grown to epidemic proportions in the last decades. The number of adults with T2DM in the United States has increased rapidly by almost 50% between 1991 and 2000 according to the Center for Disease Control and Prevention (CDC). Furthermore, the World Health Organisation (WHO) predicts that the number of T2DM patiens worldwide will grow to as much as 300 million in the year 2025. T2DM is not characeterised by the lack of insulin production found for the much less common type 1 diabetes mellitus, but manifests itself by decreased sensitivity towards insulin. In both types of diabetes similar complications arise as a result of impaired insulin signalling and lack of response to increased glucose levels. Serious complications, mostly resulting from vascular problems, like kidney failure and blindness are often found in untreated diabetic patients. Both types of diabetes can be treated and, in the case of T2DM, this often involves administration of insulin sensitizing drugs. A commonly used group of insulin sensitizers are the thiazolidinediones (TZDs). In 1995 it was found that TZDs function as ligands for the transcription factor PPAR a member of the nuclear receptor superfamily and the TZDs rosiglitazone and pioglitazone are now well known compounds, both in clinical and experimental settings. The importance of the different chromatin remodelling complexes in adipogenesis and PPARmediated gene expression has become evident from various studies. Ribozyme mediated decrease of the histone acetyltransferases CBP and p300 expression, inhibited PPARmediated gene expression and adipogenesis. In accordance with these findings CBP-deficient as well as heterozygous mice show a reduced fat mass due to undeveloped white adipose tissue. Furthermore expression of dominant negative BRG-1 or BRM, components of the ATP-dependent chromatin remodelling SWI/SNF complex, also decreased PPAR mediated gene activation. The main role of the TRAP complex, which is related to the yeast mediator proteins, lies in direct communication between the various coactivators and the general transcription complex. TRAP220 is an essential subunit of the TRAP complex, interacting with various nuclear receptors including PPAR. By using TRAP220-/- fibroblasts it was shown that the TRAP complex plays an essential role in adipogenesis, acting as a PPARmediator complex. These data underscore the important function of coactivator complexes in PPAR signalling and thereby regulation of energy metabolism. Therefore, further understanding of PPAR activity is important since novel PPAR modifiers could offer the possibility of therapeutic modulation and provide new ways of improving insulin sensitivity (see also chapter 2). Therefore, as described in this thesis, we set out to investigate the different levels at which coactivators function in PPAR2 activation and also how mutant forms of PPARare affected in their associations with coactivator proteins (chapter 3). In an effort to identify novel… Advisors/Committee Members: Berger, R., Kalkhoven, E.

Subjects/Keywords: Econometric and Statistical Methods: General; Geneeskunde(GENK)

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APA (6^th Edition):

van Beekum, P. O. (2008). Novel mechanisms in PPARy-mediated adipogenesis. (Doctoral Dissertation). Universiteit Utrecht. Retrieved from http://dspace.library.uu.nl:8080/handle/1874/27576

Chicago Manual of Style (16^th Edition):

van Beekum, P O. “Novel mechanisms in PPARy-mediated adipogenesis.” 2008. Doctoral Dissertation, Universiteit Utrecht. Accessed April 18, 2021. http://dspace.library.uu.nl:8080/handle/1874/27576.

MLA Handbook (7^th Edition):

van Beekum, P O. “Novel mechanisms in PPARy-mediated adipogenesis.” 2008. Web. 18 Apr 2021.

Vancouver:

van Beekum PO. Novel mechanisms in PPARy-mediated adipogenesis. [Internet] [Doctoral dissertation]. Universiteit Utrecht; 2008. [cited 2021 Apr 18]. Available from: http://dspace.library.uu.nl:8080/handle/1874/27576.

Council of Science Editors:

van Beekum PO. Novel mechanisms in PPARy-mediated adipogenesis. [Doctoral Dissertation]. Universiteit Utrecht; 2008. Available from: http://dspace.library.uu.nl:8080/handle/1874/27576

Universiteit Utrecht

3. van den Berghe, P.V.E. Posttranslational regulation of copper transporters.

Degree: 2009, Universiteit Utrecht

URL: http://dspace.library.uu.nl:8080/handle/1874/33547

► The transition metal copper is an essential cofactor for many redox-active enzymes, but excessive copper can generate toxic reactive oxygen species. Copper homeostasis is maintained… (more)

▼ The transition metal copper is an essential cofactor for many redox-active enzymes, but excessive copper can generate toxic reactive oxygen species. Copper homeostasis is maintained by highly conserved proteins, to balance copper uptake, distribution and export on the systemic and cellular level. The research in this thesis entitled “Posttranslational regulation of copper transporters” aims to unravel the mechanisms that regulate cellular copper uptake and export in relation to the molecular pathogenesis of Wilson disease (WD), a hereditary copper overload disorder. To allow quantitative, sensitive and high-throughput assessment of changes in cellular copper homeostasis, we developed the MRE-Luciferase reporter that was able to monitor bio-available copper in a copper-concentration-dependent manner. The human high-affinity copper transporter 1 (hCTR1) is essential for cellular copper uptake, but several observations have indicated the existence of hCTR1-independent copper uptake pathways. We characterized the homologous human CTR2 (hCTR2) as a bona fide copper uptake protein with low affinity for copper compared to hCTR1 using our MRE-Luciferase reporter. hCTR1 was localized at the plasma membrane and in intracellular organelles, whereas hCTR2 was exclusively localized in late endosomes and lysosomes. Hence, we speculate that hCTR2 enables mobilization of copper from lysosomal copper pools in analogy with its function in yeast. Electron microscopic crystallography of recombinant hCTR1 had revealed that hCTR1 subunits assemble in oligomeric complexes comprising three hCTR1 subunits. Here, we assessed the necessity of hCTR1 oligomerization in functional copper uptake. hCTR1-dependent copper uptake was completely abolished by conversion of two highly conserved methionine residues in the second transmembrane helix of hCTR1 into isoleucines (hCTR1 M150I-M154I). Co-expression of hCTR1 M150I-M154I with wild type (WT) hCTR1 did not affect oligomerization, expression or cellular localization of WT hCTR1, but WT hCTR1-dependent copper uptake was inhibited in a dominant fashion. Similar results were obtained for hCTR2, suggesting that oligomerization of hCTR1 and hCTR2 is required for copper transport activity by permitting the formation of a copper permeable channel. Hepatic copper excretion is mediated by ATP7B, and mutations in ATP7B result in WD. We investigated the possibility that defects arising from some WD mutations are ameliorated by drug treatment to improve protein folding and function. Homology modeling of distinct ATP7B missense mutations suggested that most mutations result in misfolded ATP7B proteins. Indeed, almost all tested mutations resulted in reduced ATP7B protein expression. Furthermore, physiological localization of ATP7B to the trans-Golgi network was abrogated, and mutant ATP7B was retained in the endoplasmic reticulum instead. The increased expression and normalization of localization after culturing cells at 30C suggested that these proteins were indeed misfolded. Four distinct mutations exhibited… Advisors/Committee Members: Berger, R., Klomp, L.W.J..

Subjects/Keywords: Econometric and Statistical Methods: General; Geneeskunde(GENK)

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

APA (6^th Edition):

van den Berghe, P. V. E. (2009). Posttranslational regulation of copper transporters. (Doctoral Dissertation). Universiteit Utrecht. Retrieved from http://dspace.library.uu.nl:8080/handle/1874/33547

Chicago Manual of Style (16^th Edition):

van den Berghe, P V E. “Posttranslational regulation of copper transporters.” 2009. Doctoral Dissertation, Universiteit Utrecht. Accessed April 18, 2021. http://dspace.library.uu.nl:8080/handle/1874/33547.

MLA Handbook (7^th Edition):

van den Berghe, P V E. “Posttranslational regulation of copper transporters.” 2009. Web. 18 Apr 2021.

Vancouver:

van den Berghe PVE. Posttranslational regulation of copper transporters. [Internet] [Doctoral dissertation]. Universiteit Utrecht; 2009. [cited 2021 Apr 18]. Available from: http://dspace.library.uu.nl:8080/handle/1874/33547.

Council of Science Editors:

van den Berghe PVE. Posttranslational regulation of copper transporters. [Doctoral Dissertation]. Universiteit Utrecht; 2009. Available from: http://dspace.library.uu.nl:8080/handle/1874/33547

Universiteit Utrecht

4. Jeninga, E.H. The role of PPARgamma in lipid metabolism.

Degree: 2009, Universiteit Utrecht

URL: http://dspace.library.uu.nl:8080/handle/1874/33702

► Due to a sedentary lifestyle and an energy-dense diet the prevalence obesity rapidly increases in industrialized countries. This is a major health concern as adiposity… (more)

▼ Due to a sedentary lifestyle and an energy-dense diet the prevalence obesity rapidly increases in industrialized countries. This is a major health concern as adiposity is highly associated with major complications such as insulin resistance, type II diabetes, dyslipidemia and hypertension (components of the metabolic syndrome). Although diet and environmental intervention (i.e. caloric restriction and increased physical exercise, respectively) can prevent or delay the onset of the metabolic syndrome, this is not always sufficient and the prevalence of the metabolic syndrome keeps on rising. This underscores the importance of the development of novel therapies to treat metabolic disorders thereby reducing morbidity and mortality. Interestingly, not only an excess of fat, but also the absence of fat as found in subjects with lipodystrophy is associated with these complications. So, apparently a normal amount and/or distribution of fat are required for the maintenance of whole body metabolism. The ligand-inducible nuclear receptor Peroxisome Proliferator Activated Receptor gamma (PPARgamma) plays an important role in the differentiation, maintenance and function of adipocytes. In addition, it is the molecular target of the insulin-sensitizing thiazoledinedione (TZD) drugs. Although these TZDs were promising drugs ameliorating insulin sensitivity, some of them have already been discarded because of undesired side-effects. Nowadays, research focuses on specific PPARgamma modulators, so called SPARMs, which in theory would only exert the beneficial effects. The development of these SPARMs requires a better understanding of PPARgamma function in metabolism and its role in modulating insulin sensitivity. For this reason we studied the functional consequences of rare naturally occurring PPARgamma mutations in patients with familial partial lipodystrophy type 3 (FPLD3). FPLD3 is characterized by the loss of subcutaneous fat from the extremities and accumulation of excess fat in the intra-abdominal region and associated with metabolic complications (e.g. insulin resistance and dyslipidemia). We report a novel PPARgamma mutation (R194W) located in the DNA binding domain. As this residue contacts the phosphate backbone of DNA, disruption of this residue impaired DNA binding resulting in a transcriptionally inactive protein. In addition we showed that another FPLD3-associated PPARgamma mutation (R425C) located in the ligand binding domain affects PPARgamma function on multiple levels (e.g. ligand and DNA binding) resulting in reduced transcriptional activity. To gain more insights in the molecular mechanisms underlying the TZD effects we performed a transcriptome analysis in human mature adipocytes treated with TZDs. Using this approach we discovered two novel genes (i.e. GPR81 and RNF125) regulated by TZD-mediated PPARgamma activation. GPR81 encodes the antilipolytic G-protein-coupled receptor 81 that is exclusively expressed in adipocytes. Activation of this receptor results in the inhibition of adipocyte lipolysis. One of the… Advisors/Committee Members: Berger, R., Kalkhoven, E.

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

APA (6^th Edition):

Jeninga, E. H. (2009). The role of PPARgamma in lipid metabolism. (Doctoral Dissertation). Universiteit Utrecht. Retrieved from http://dspace.library.uu.nl:8080/handle/1874/33702

Chicago Manual of Style (16^th Edition):

Jeninga, E H. “The role of PPARgamma in lipid metabolism.” 2009. Doctoral Dissertation, Universiteit Utrecht. Accessed April 18, 2021. http://dspace.library.uu.nl:8080/handle/1874/33702.

MLA Handbook (7^th Edition):

Jeninga, E H. “The role of PPARgamma in lipid metabolism.” 2009. Web. 18 Apr 2021.

Vancouver:

Jeninga EH. The role of PPARgamma in lipid metabolism. [Internet] [Doctoral dissertation]. Universiteit Utrecht; 2009. [cited 2021 Apr 18]. Available from: http://dspace.library.uu.nl:8080/handle/1874/33702.

Council of Science Editors:

Jeninga EH. The role of PPARgamma in lipid metabolism. [Doctoral Dissertation]. Universiteit Utrecht; 2009. Available from: http://dspace.library.uu.nl:8080/handle/1874/33702

Universiteit Utrecht

5. Gao, Y. The role of Tip60 in adipogenesis.

Degree: 2013, Universiteit Utrecht

URL: http://dspace.library.uu.nl:8080/handle/1874/261034

► Besides providing insulation and protection against mechanical stress, white adipose tissue (WAT) has long been recognized as a storage depot for excess energy. WAT also… (more)

▼ Besides providing insulation and protection against mechanical stress, white adipose tissue (WAT) has long been recognized as a storage depot for excess energy. WAT also releases a wide range of adipokines, which for example regulate immune responses, blood pressure and reproduction. Expansion of WAT, as seen during the development of increased bodyweight and obesity, involves an increase in adipocyte size and the formation of new adipocytes from precursor cells (adipogenesis). Since WAT is increasingly being recognized as a key regulator of whole-body energy homeostasis and consequently as a prime therapeutic target for metabolic syndrome, adipocyte differentiation and biology are under intensive study. A complex cascade of transcriptional events regulates adipogenesis. Recently, we identified the coregulator protein Tip60 as an essential player in adipogenesis. In this thesis we investigated the exact role of the Tip60 in adipogenesis. Previous studies had indicated that Tip60 protein expression but not mRNA expression was upregulated during adipocyte differentiation. We therefore examined whether the protein is normally degraded by the ubiquitin-proteasome system (UPS) and protected from degradation by deubiquitination during adipogenesis. USP7, a dominant deubiquitinating enzyme (DUB) in 3T3-L1 adipocytes and mouse adipose tissue, deubiquitinated Tip60 both in intact cells and in vitro, and increased Tip60 protein levels. Inhibition of USP7 expression and activity decreased adipogenesis. Transcriptome analysis revealed several cell cycle genes to be co-regulated by both Tip60 and USP7. Knock down of either factor resulted in impaired mitotic clonal expansion, an early step in adipogenesis. These results therefore reveal deubiquitination of a transcriptional coregulator to be a key mechanism in the regulation of early adipogenesis. We also tried to identify the ubiquitin E3 ligase responsible for Tip60 ubiquitination in adipocytes. In contrast to the Tip60 protein, expression of the candidate E3 ligase mdm2 was relatively constant during 3T3-L1 adipogenesis. In mdm2-negative MEFs, Tip60 could still be ubiquitinated. These findings indicate that E3 ubiquitin ligases other than mdm2 are probably responsible for Tip60 degradation during early adipogenesis. Next we investigated the role of Tip60 on adipocyte differentiation and function, and possible consequences on energy homeostasis, in vivo. As homozygous inactivation results in early embryonic lethality, Tip60+/- mice were used, and no major metabolic effects were observed. While Tip60 mRNA was reduced to 50% in adipose tissue, the protein levels were unaltered, suggesting compensation by the intact allele. These findings indicate that the in vivo role of Tip60 in adipocyte differentiation and function cannot be properly addressed in Tip60+/- mice, but requires the generation of adipose tissue-specific knock out animals or specific knock-in mice. Finally we developed a novel method to identify adipogenic factors using RNAi-mediated knock down libraries (siRNA… Advisors/Committee Members: Berger, R., Kalkhoven, E.

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APA (6^th Edition):

Gao, Y. (2013). The role of Tip60 in adipogenesis. (Doctoral Dissertation). Universiteit Utrecht. Retrieved from http://dspace.library.uu.nl:8080/handle/1874/261034

Chicago Manual of Style (16^th Edition):

Gao, Y. “The role of Tip60 in adipogenesis.” 2013. Doctoral Dissertation, Universiteit Utrecht. Accessed April 18, 2021. http://dspace.library.uu.nl:8080/handle/1874/261034.

MLA Handbook (7^th Edition):

Gao, Y. “The role of Tip60 in adipogenesis.” 2013. Web. 18 Apr 2021.

Vancouver:

Gao Y. The role of Tip60 in adipogenesis. [Internet] [Doctoral dissertation]. Universiteit Utrecht; 2013. [cited 2021 Apr 18]. Available from: http://dspace.library.uu.nl:8080/handle/1874/261034.

Council of Science Editors:

Gao Y. The role of Tip60 in adipogenesis. [Doctoral Dissertation]. Universiteit Utrecht; 2013. Available from: http://dspace.library.uu.nl:8080/handle/1874/261034

Universiteit Utrecht

6. van der Velden, L.M. Cellular consequences of ATP8B1 deficiency.

Degree: 2010, Universiteit Utrecht

URL: http://dspace.library.uu.nl:8080/handle/1874/44742

► Mutations in the ATP8B1 gene cause a spectrum of familial intrahepatic cholestasis syndromes which we collectively refer to as ATP8B1 deficiency. Patients with ATP8B1 deficiency… (more)

▼ Mutations in the ATP8B1 gene cause a spectrum of familial intrahepatic cholestasis syndromes which we collectively refer to as ATP8B1 deficiency. Patients with ATP8B1 deficiency present with intrahepatic cholestasis (impairment of bile flow) as primary complication. These patients may also present with extrahepatic symptoms, such as diarrhea, pancreatitis and hearing loss. ATP8B1 is next to liver, also expressed in intestine, pancreas and cochlear hair cells. Aberrant ATP8B1 protein function in these tissues probably accounts for the observed extrahepatic symptoms. After more than a decade following the initial cloning of ATP8B1, we still do not fully understand how mutations in ATP8B1 mechanistically result in intrahepatic cholestasis and the extraheptic symptoms reported. ATP8B1 belongs to the family of P4 P-type ATPases (P4 ATPases), which are putative (amino-) phospholipid translocators. It is believed that P4 ATPases maintain the asymmetrical distribution of phospholipids in the plasma membrane, which is important for signal transduction, vesicular trafficking and membrane stability. These P4 ATPase-specific functions, together with the expression of ATP8B1 in tissues unrelated to bile flow, suggest that ATP8B1 plays a general role in cell physiology. The aim of this thesis was therefore to study the cellular consequences of ATP8B1 deficiency. First the question was addressed why different mutations cause ATP8B1 deficiency at the molecular level. Seven distinct ATP8B1 mutations were systematically characterized. The results indicated that most mutations resulted in protein misfolfing. Treatment with 4-phenylbutyrate, a clinically approved pharmacological chaperone, partially restored defects in expression and localization of some ATP8B1 substitutions. We propose that treatment with pharmacological chaperones may represent an effective therapeutic strategy to ameliorate cholestasis in some patients with ATP8B1 deficiency. ATP8B1 protein expression in the intestine is much more pronounced than in liver. Therefore, the cellular consequences of ATP8B1 deficiency were studied in Caco-2 cells in vitro. Caco-2 cells can be differentiated into polarized monolayers that highly resemble the intestinal epithelium. A loss of function model in Caco-2 cells was constructed by stable expression of short hairpin RNAs (shRNA) complementary to ATP8B1 mRNA. This thesis describes the recent novel insights in the cellular consequences of ATP8B1 deficiency in a model for human enterocytes. The most prominent cellular defect of ATP8B1 depletion is loss of microvilli and the reduction of expression of apically localized plasma membrane proteins. Bile salt import in ATP8B1-depleted Caco-2 cells is severely compromised, but unrelated to decreased FXR expression and function. Together, these results may clarify the etiology of diarrhea in patients with ATP8B1 deficiency. Importantly, shortening and loss of microvilli are also described in other cells with aberrant ATP8B1 protein function, such as hepatocytes and cochlear hair cells.… Advisors/Committee Members: Berger, R., Klomp, L.W.J..

Subjects/Keywords: Econometric and Statistical Methods: General; Geneeskunde (GENK); Geneeskunde(GENK)

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

APA (6^th Edition):

van der Velden, L. M. (2010). Cellular consequences of ATP8B1 deficiency. (Doctoral Dissertation). Universiteit Utrecht. Retrieved from http://dspace.library.uu.nl:8080/handle/1874/44742

Chicago Manual of Style (16^th Edition):

van der Velden, L M. “Cellular consequences of ATP8B1 deficiency.” 2010. Doctoral Dissertation, Universiteit Utrecht. Accessed April 18, 2021. http://dspace.library.uu.nl:8080/handle/1874/44742.

MLA Handbook (7^th Edition):

van der Velden, L M. “Cellular consequences of ATP8B1 deficiency.” 2010. Web. 18 Apr 2021.

Vancouver:

van der Velden LM. Cellular consequences of ATP8B1 deficiency. [Internet] [Doctoral dissertation]. Universiteit Utrecht; 2010. [cited 2021 Apr 18]. Available from: http://dspace.library.uu.nl:8080/handle/1874/44742.

Council of Science Editors:

van der Velden LM. Cellular consequences of ATP8B1 deficiency. [Doctoral Dissertation]. Universiteit Utrecht; 2010. Available from: http://dspace.library.uu.nl:8080/handle/1874/44742

Universiteit Utrecht

7. Tasdelen, I. Modulation of the adipogenic master regulator PPARγ.

Degree: 2014, Universiteit Utrecht

URL: http://dspace.library.uu.nl:8080/handle/1874/290608

► Obesity is regarded as a major public health problem by the World Health Organization. Obesity is characterized by an increase in adipose tissue, both through… (more)

▼ Obesity is regarded as a major public health problem by the World Health Organization. Obesity is characterized by an increase in adipose tissue, both through an increase in the amount of fat stored per adipocyte, and the generation of new adipocytes through differentiation of pre-adipocyte (adipogenesis), a process in which the transcription factor PPARγ plays a significant role. In this thesis we described different aspects of PPARγ, adipose tissue and adipogenesis. PPARγ is necessary for adipogenesis, maintenance of adipose tissue and is able to regulate many “adipocyte genes” that are necessary for lipid and glucose metabolism. Many aspects of PPARγ are under intense study, here we focused on the modulation of the expression and activity this factor. It is known that PPARγ is subject to post-translational modifications (PTM) such as phosphorylation, ubiquitination, acetylation and sumoylation. All of these marks have an effect on the activity of PPARγ. However, not much was known about the opposite process: de-modification. We have identified PPM1B to be a phosphatase for PPARγ. PPM1B was capable of directly binding to PPARγ and dephosphorylating a serine residue at position 112. In general, S112 phosphorylation lowers PPARγ activity, subsequently leading to decreased target gene expression. Knocking down PPM1B indicated that this was indeed the case for a subset of genes. This led to the conclusion that PPARγ (de)phosphorylation at S112 had subtle effects which could be seen in terms of specific target gene expression, but not on adipogenesis as a whole. Interestingly, a second phosphorylation site was recently identified on PPARγ, but no link has been made between S273 phosphorylation and PPM1B. Adipogenesis occurs in at least two waves; genes such as C/EBPβ, C/EBPδ, KLF5, CREB, SREBP-1c and Krox20 come up early in adipogenesis and ultimately lead to the expression of PPARγ and C/EBPα, which can than regulate genes that have a direct role in glucose and lipid metabolism. We investigated which other proteins would be capable of regulating the PPARG gene and thus adipogenesis. Consequently we developed an siRNA based knockdown screen and subsequently found Baf57, a subunit of the SWI/SNF chromatin remodeling complex, and Phf12 a “chromatin-associated” factor that has mainly been implicated in transcriptional repression, to regulate PPARG expression and adipogenesis. Knockdown of Baf57/Phf12 impairs adipogenesis; transcriptome analysis reveals that the genes that are inhibited are to a large extent the same as the genes that are inhibited by PPARγ knockdown. The genes that are affected are the so-called late adipocyte genes, rather than the early genes mentioned above. Further analysis indicated that Baf57/Phf12 directly binds to the PPARG promotor to induce its expression in both human and murine adipocyte cell lines. Finally we discuss PPARγ as a potential target for clinical intervention. Modulation of PPARγ may be used in order to ameliorate obesity if done properly. Full agonists of PPARγ lead to many severe… Advisors/Committee Members: Berger, R., Kalkhoven, E.

Subjects/Keywords: PPAR gamma; Obesity; Adipocyte; Adipogenesis

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

APA (6^th Edition):

Tasdelen, I. (2014). Modulation of the adipogenic master regulator PPARγ. (Doctoral Dissertation). Universiteit Utrecht. Retrieved from http://dspace.library.uu.nl:8080/handle/1874/290608

Chicago Manual of Style (16^th Edition):

Tasdelen, I. “Modulation of the adipogenic master regulator PPARγ.” 2014. Doctoral Dissertation, Universiteit Utrecht. Accessed April 18, 2021. http://dspace.library.uu.nl:8080/handle/1874/290608.

MLA Handbook (7^th Edition):

Tasdelen, I. “Modulation of the adipogenic master regulator PPARγ.” 2014. Web. 18 Apr 2021.

Vancouver:

Tasdelen I. Modulation of the adipogenic master regulator PPARγ. [Internet] [Doctoral dissertation]. Universiteit Utrecht; 2014. [cited 2021 Apr 18]. Available from: http://dspace.library.uu.nl:8080/handle/1874/290608.

Council of Science Editors:

Tasdelen I. Modulation of the adipogenic master regulator PPARγ. [Doctoral Dissertation]. Universiteit Utrecht; 2014. Available from: http://dspace.library.uu.nl:8080/handle/1874/290608

Universiteit Utrecht

8. Labuschagne, C.F. Targeted metabolomics to study lipid peroxidation in biological systems.

Degree: 2013, Universiteit Utrecht

URL: http://dspace.library.uu.nl:8080/handle/1874/287436

► During normal cellular metabolism reactive oxygen species (ROS) are inevitably formed as by-products of respiration. ROS are extremely reactive molecules and can react with and… (more)

▼ During normal cellular metabolism reactive oxygen species (ROS) are inevitably formed as by-products of respiration. ROS are extremely reactive molecules and can react with and damage surrounding DNA, protein and lipid molecules and subsequently alter their normal function in the cell. This oxidative damage is counter balanced by antioxidant and repair mechanisms, which are present in every aerobic cell. When the levels of oxidative damage increase or the antioxidant and repair capacity is inefficient to protect against this damage a state of oxidative stress occurs. Oxidative stress is associated with various pathological conditions including cancer, diabetes, atherosclerosis, coronary heart disease and aging. Oxidative stress can be reversed through lifestyle and therapeutic intervention and it is therefore an important parameter to monitor to ensure good health. ROS are extremely short-lived molecules and directly measuring in vivo levels in biological samples is technically almost impossible and therefore requires indirect measurements like the use of molecular ROS probes and by measuring products of oxidative damage. ROS probes are very useful in in vitro settings to give information about ROS levels however, for in vivo studies products of oxidative damage to DNA, protein and lipids are more often measured. In order to answer important questions like the involvement of ROS and its damage in complex processes like aging and other age related diseases we need good methodologies for in vivo ROS and oxidative damage levels in biological systems like cell cultures, model organism and humans. Here we present an overview of current methods for measuring oxidative damage and reactive oxygen species in model organisms of aging. Reactive oxygen species have been associated with aging ever since the formulation of the Free Radical Theory of Aging, which explains aging as the accumulation of oxidatively damaged macro-molecules leading to an alteration in function and stability and ultimately manifesting as the phenotype of aging. We furthermore describe for the first time the formation of a new marker of oxidative damage in C. elegans, an important model organism for studying aging. This marker is F3-isoprostanes, which are formed upon oxidative damage to the polyunsaturated fatty acids in this worm. This is a novel method for accurate measurement of lipid peroxidation in C. elegans and we used it to look at oxidative damage during aging in a longitudinal manner. We found that long-lived C. elegans mutants have unexpectedly high levels of oxidative damage early in life, which possibly leads to the increased lifespan as a result of an adaptive response to these high levels of damage. Next we developed a protocol for measuring F2-isoprostanes in cellular systems. F2-isoprostanes are similar to the F3-isoprostanes described above, except they are formed from the polyunsaturated fatty acids present in mammalian cells. Cellular systems are important biological model systems, which are used to study various physiological… Advisors/Committee Members: Berger, R., Brenkman, Arjan B..

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

APA (6^th Edition):

Labuschagne, C. F. (2013). Targeted metabolomics to study lipid peroxidation in biological systems. (Doctoral Dissertation). Universiteit Utrecht. Retrieved from http://dspace.library.uu.nl:8080/handle/1874/287436

Chicago Manual of Style (16^th Edition):

Labuschagne, C F. “Targeted metabolomics to study lipid peroxidation in biological systems.” 2013. Doctoral Dissertation, Universiteit Utrecht. Accessed April 18, 2021. http://dspace.library.uu.nl:8080/handle/1874/287436.

MLA Handbook (7^th Edition):

Labuschagne, C F. “Targeted metabolomics to study lipid peroxidation in biological systems.” 2013. Web. 18 Apr 2021.

Vancouver:

Labuschagne CF. Targeted metabolomics to study lipid peroxidation in biological systems. [Internet] [Doctoral dissertation]. Universiteit Utrecht; 2013. [cited 2021 Apr 18]. Available from: http://dspace.library.uu.nl:8080/handle/1874/287436.

Council of Science Editors:

Labuschagne CF. Targeted metabolomics to study lipid peroxidation in biological systems. [Doctoral Dissertation]. Universiteit Utrecht; 2013. Available from: http://dspace.library.uu.nl:8080/handle/1874/287436

Universiteit Utrecht

9. van Veelen, W. Molecular genetics of medullary thyroid carcinoma: multistep tumorigenesis.

Degree: 2008, Universiteit Utrecht

URL: http://dspace.library.uu.nl:8080/handle/1874/26874

► The genetic mechanisms underlying the multistep process of medullary thyroid carcinoma (MTC) development is at present largely unknown. About 60% of all MTCs occur as… (more)

▼ The genetic mechanisms underlying the multistep process of medullary thyroid carcinoma (MTC) development is at present largely unknown. About 60% of all MTCs occur as sporadic cancer and the remaining 40% occur as familial cancer. Activation of RET, a receptor tyrosine kinase, initiates hereditary MTC development and could be involved in sporadic MTC development as well. Additional oncogenic events are required, but remain to be elucidated. In chapter 1, an overview is provided of all RET and non-RET genetic alterations detected in human MTCs. In addition, an overview of all RET and non-RET mouse models that develop MTC, is provided. Genes affected in these non-RET models might be involved in human MTC tumorigenesis as well, which should be further investigated. In chapter 2, we show the presence of somatic inactivating mutations in P18 in human sporadic and MEN 2-associated MTCs, and MEN 2-associated pheochromocytomas (PCs). Each mutation causes an amino acid substitution in the cyclin dependent kinase-interacting region of P18. We have shown that these mutations inhibit P18 function and cause reduced stability. Our findings implicate P18 as a tumor suppressor gene involved in human MTC and PC development. In chapter 3, we describe the detection of a synergistic effect of oncogenic RET and loss of p18 on MTC development, age-of-onset and MTC size. In addition, somatic loss of p18 expression, correlating with MTC growth, has been detected, indicating that loss of p18 in combination with oncogenic RET not only increases the risk for MTC development, it also enhances MTC progression. In chapter 4, we demonstrate nuclear localization in MEN 2-associated primary MTCs and their metastases. We show that RET is able to interact with, and tyrosine phosphorylate beta-catenin. As a result, beta-catenin escapes cytosolic downregulation by the APC/AXIN/GSK3 complex and accumulates in the nucleus, where it stimulates transcriptional programs. Downregulation of beta-catenin activity decreases RET-mediated cell proliferation, colony formation, and tumor growth in nude mice. These data show that the RET kinase-beta-catenin pathway is a critical contributor to the development and metastasis of human MTC. Thirty to 55% of sporadic MTC patients are not cured after initial surgical treatment. A literature study, described in chapter 5, revealed that re-operation of patients with postoperative hypercalcitoninemia results in low biochemical cure rates. This chapter provides an overview of currently used and putative novel biomarkers, like RET, plasma CT and CEA, radiopharmaceuticals and regulatory peptides, for the diagnosis, treatment and prediction of progression of MTC. Chapter 6 provides an integrated model describing our current knowledge of the molecular mechanisms underlying multistep MTC tumorigenesis. Via several downstream pathways, RET signaling may be involved in all the essential steps for tumorigenesis. These pathways may involve activation of beta-Catenin-mediated signaling through tyrosine phosphorylation by RET. In… Advisors/Committee Members: Lips, C.J.M., Berger, R., Hoppener, Jo W.M..

Subjects/Keywords: Econometric and Statistical Methods: General; Geneeskunde(GENK)

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

APA (6^th Edition):

van Veelen, W. (2008). Molecular genetics of medullary thyroid carcinoma: multistep tumorigenesis. (Doctoral Dissertation). Universiteit Utrecht. Retrieved from http://dspace.library.uu.nl:8080/handle/1874/26874

Chicago Manual of Style (16^th Edition):

van Veelen, W. “Molecular genetics of medullary thyroid carcinoma: multistep tumorigenesis.” 2008. Doctoral Dissertation, Universiteit Utrecht. Accessed April 18, 2021. http://dspace.library.uu.nl:8080/handle/1874/26874.

MLA Handbook (7^th Edition):

van Veelen, W. “Molecular genetics of medullary thyroid carcinoma: multistep tumorigenesis.” 2008. Web. 18 Apr 2021.

Vancouver:

van Veelen W. Molecular genetics of medullary thyroid carcinoma: multistep tumorigenesis. [Internet] [Doctoral dissertation]. Universiteit Utrecht; 2008. [cited 2021 Apr 18]. Available from: http://dspace.library.uu.nl:8080/handle/1874/26874.

Council of Science Editors:

van Veelen W. Molecular genetics of medullary thyroid carcinoma: multistep tumorigenesis. [Doctoral Dissertation]. Universiteit Utrecht; 2008. Available from: http://dspace.library.uu.nl:8080/handle/1874/26874

Universiteit Utrecht

10. Müller, P.A.J. Transcriptomics as a tool to dissect copper homeostasis and COMMD protein function.

Degree: 2008, Universiteit Utrecht

URL: http://dspace.library.uu.nl:8080/handle/1874/27094

► Gene expression profiling offers the possibility to objectively screen the complete genome for variations in gene expression in many different organisms in various defined environments.… (more)

▼ Gene expression profiling offers the possibility to objectively screen the complete genome for variations in gene expression in many different organisms in various defined environments. In the present work we aimed to gain novel insights in copper metabolism and in the function of COMMD (copper metabolism MURR1 domain) proteins by using gene expression profiles. Copper is a trace metal that is essential, but toxic in excess. This is illustrated by the severe phenotypes of the inherited disorders Menkes disease and Wilson disease in which patients suffer from copper deficiency or copper overload, respectively. Information about the transcriptional changes that are induced by copper overload in mammals could help to elucidate the pathophysiological mechanisms that underlie copper overload disorders. We therefore examined the hepatic transcriptional changes after copper exposure by genome-wide gene expression analysis and by a literature-based transcriptomics meta-analysis. Both analyses revealed that, genes involved in defined biological processes, including cholesterol synthesis, were differentially expressed after copper overload. In the second part of the present work, we used transcriptomics to investigate the function of a protein that was previously implicated in the regulation of copper homeostasis; COMMD1. Genome-wide gene expression studies in COMMD1 knockout mice and COMMD1 deficient cell lines revealed that COMMD1 regulates the expression of distinct genes involved in hypoxia and NF-?B (nuclear factor-kappa B) signalling. As COMMD1 is a member of a protein family that shares a homologous COMM domain, we investigated the possibility that this COMMD family of proteins could define transcriptional specificity. We investigated the genome-wide gene expression changes in cell lines deficient for COMMD1, COMMD6 or COMMD9 after incubation with the NF-ΚB stimulus TNF (tumor necrosis factor) and demonstrated COMMD-specific differential expression of TNF target genes compared to control cells. In addition, we identified two nuclear export signals (NESs) in the COMM domain of COMMD1 that were conserved among this COMMD family. The function of many proteins involved in NF-ΚB signaling is regulated though nucleocytoplasmic shuttling that is dominated by NESs and nuclear localization signals. We therefore investigated the functional activity of these NESs by studying COMMD1 localization and COMMD1 function when the COMMD1 NESs were mutated or when nuclear export was blocked with the chemical compound leptomycin B. These studies confirmed that COMMD1 can be actively transported out of the nucleus and that the localization of COMMD1 affects COMMD1 ubiquitination and COMMD1-mediated NF-ΚB signalling. In conclusion, our work has increased our knowledge on copper-dependent transcriptional changes in mammals and has contributed to a better characterization of the function of COMMD proteins and the mechanism of COMMD1-mediated transcriptional regulation in inflammation and hypoxia. Advisors/Committee Members: Wijmenga, C., Berger, R., Klomp, L.W.J..

Subjects/Keywords: Econometric and Statistical Methods: General; Geneeskunde(GENK)

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

APA (6^th Edition):

Müller, P. A. J. (2008). Transcriptomics as a tool to dissect copper homeostasis and COMMD protein function. (Doctoral Dissertation). Universiteit Utrecht. Retrieved from http://dspace.library.uu.nl:8080/handle/1874/27094

Chicago Manual of Style (16^th Edition):

Müller, P A J. “Transcriptomics as a tool to dissect copper homeostasis and COMMD protein function.” 2008. Doctoral Dissertation, Universiteit Utrecht. Accessed April 18, 2021. http://dspace.library.uu.nl:8080/handle/1874/27094.

MLA Handbook (7^th Edition):

Müller, P A J. “Transcriptomics as a tool to dissect copper homeostasis and COMMD protein function.” 2008. Web. 18 Apr 2021.

Vancouver:

Müller PAJ. Transcriptomics as a tool to dissect copper homeostasis and COMMD protein function. [Internet] [Doctoral dissertation]. Universiteit Utrecht; 2008. [cited 2021 Apr 18]. Available from: http://dspace.library.uu.nl:8080/handle/1874/27094.

Council of Science Editors:

Müller PAJ. Transcriptomics as a tool to dissect copper homeostasis and COMMD protein function. [Doctoral Dissertation]. Universiteit Utrecht; 2008. Available from: http://dspace.library.uu.nl:8080/handle/1874/27094

Universiteit Utrecht

11. van Hasselt, P.M. Vitamin K prophylaxis revisited : Focus on risk factors.

Degree: 2009, Universiteit Utrecht

URL: http://dspace.library.uu.nl:8080/handle/1874/33563

► In this thesis the overall efficacy of the Dutch vitamin K prophylaxis regimen in protecting infants against Vitamin K Deficiency Bleeding (VKDB) was investigated by… (more)

▼ In this thesis the overall efficacy of the Dutch vitamin K prophylaxis regimen in protecting infants against Vitamin K Deficiency Bleeding (VKDB) was investigated by focusing on two major risk factors: cholestatic jaundice and feeding type. We first compared the risk of VKDB under different prophylactic regimens in infants with biliary atresia the largest cause of cholestatic jaundice in infancy . The relative risk of a bleeding in breastfed compared with formula-fed infants was 77.5 for the Dutch prophylaxis (consisting of 25 mcg of daily oral prophylaxis), 7.2 for 1 mg of weekly oral prophylaxis, and 9.3 for 2 mg of intramuscular prophylaxis at birth. The risk of VKDB in infants presenting with cholestasis due to A1ATD on the Dutch prophylaxis was similar (~80 percent), despite marked variations in the degree of cholestasis. It was concluded that the Dutch regimen fails to prevent bleedings in apparently healthy infants with unrecognized cholestasis - irrespective of underlying etiology. Discrepant data from Dutch surveillance studies led us to assess changes in breastfeeding rate and the risk of VKDB over time in infants with BA or A1ATD. While the overall incidence of breastfeeding in Dutch newborns changed only marginally, the breastfeeding rate in infants presenting with BA/A1ATD increased from 6/45 (13%) infants in 1991-1994 to 21/44 (47%) in 2003-2006. This increase was paralleled by a quadrupling of the incidence of VKDB in this cohort from 11 to 41%.Thus, the lack of efficacy of the Dutch regimen, previously masked by the high degree of protection offered by formula feeding, was unveiled by a rising breastfeeding rate in infants with (cholestatic) jaundice. Analysis of formula-fed infants with BA or A1ATD suggests that- in contrast with infants on regular formula - the risk of VKD is substantial in infants fed by hydrolysed formula. The high risk of VKDB in cholestatic infants is thought to be due to the poor absorption of vitamin K in the absence of bile. Due to its hydrophobicity, trafficking of Vitamin K to the enterocytes critically depends on micellar incorporation. Therefore, the efficacy of interventions to improve the absorption of vitamin K in the absence of bile was investigated. First we assessed the ability of polymeric micelles to enable gastrointestinal absorption of vitamin K. To that end, vitamin K was encapsulated in micelles composed of mPEG5000-b-p(HPMAm-lac2), a thermosensitive block copolymer. Vitamin K plasma levels rose significantly upon gastric administration of 1 mg vitamin K encapsulated in polymeric micelles in sham operated rats, but not after bile duct ligation (AUC 4543 and 1.64 ng/mL/h respectively, p Advisors/Committee Members: Kimpen, J.L.L., Berger, R., de Koning, T.J., Houwen, RHJ.

Subjects/Keywords: Econometric and Statistical Methods: General; Geneeskunde(GENK)

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

APA (6^th Edition):

van Hasselt, P. M. (2009). Vitamin K prophylaxis revisited : Focus on risk factors. (Doctoral Dissertation). Universiteit Utrecht. Retrieved from http://dspace.library.uu.nl:8080/handle/1874/33563

Chicago Manual of Style (16^th Edition):

van Hasselt, P M. “Vitamin K prophylaxis revisited : Focus on risk factors.” 2009. Doctoral Dissertation, Universiteit Utrecht. Accessed April 18, 2021. http://dspace.library.uu.nl:8080/handle/1874/33563.

MLA Handbook (7^th Edition):

van Hasselt, P M. “Vitamin K prophylaxis revisited : Focus on risk factors.” 2009. Web. 18 Apr 2021.

Vancouver:

van Hasselt PM. Vitamin K prophylaxis revisited : Focus on risk factors. [Internet] [Doctoral dissertation]. Universiteit Utrecht; 2009. [cited 2021 Apr 18]. Available from: http://dspace.library.uu.nl:8080/handle/1874/33563.

Council of Science Editors:

van Hasselt PM. Vitamin K prophylaxis revisited : Focus on risk factors. [Doctoral Dissertation]. Universiteit Utrecht; 2009. Available from: http://dspace.library.uu.nl:8080/handle/1874/33563

Universiteit Utrecht

12. Stapelbroek, J.M. ATP8B1 deficiency; Pathophysiology and treatment of a cholestatic syndrome with extrahepatic symptoms.

Degree: 2009, Universiteit Utrecht

URL: http://dspace.library.uu.nl:8080/handle/1874/36541

► ATP8B1 deficiency is a severe and clinically highly variable hereditary disorder that is primarily characterized by intrahepatic cholestasis. It generally presents as a permanent disorder,… (more)

▼ ATP8B1 deficiency is a severe and clinically highly variable hereditary disorder that is primarily characterized by intrahepatic cholestasis. It generally presents as a permanent disorder, progressive familial intrahepatic cholestasis type 1 (PFIC1), or with intermittent cholestasis (benign recurrent intrahepatic cholestasis type 1 (BRIC1)). Currently there is no effective medical therapy, and most patients need invasive surgery such as partial biliary drainage (PBD) or liver transplantation. The exact pathogenesis of ATP8B1 deficiency remains largely unknown, which complicates the development of effective therapy. ATP8B1 is thought to act as an aminophospholipid flippase, maintaining an asymmetric distribution of aminophospholipids in the plasma membrane. This is essential for the resistance of the canalicular membrane to the detergent effect of bile salts and proper function of the transporters located at this site. While this may explain the cholestasis associated with ATP8B1 deficiency, the function of ATP8B1 in extrahepatic tissues remains enigmatic. Therefore the aim of this thesis was to study the pathophysiology of extrahepatic symptoms of ATP8B1 deficiency and to contribute to the development of non-surgical therapies. In the first part of this thesis we studied the role of ATP8B1 in the intestine and inner ear by using both cellular and animal models. We generated a loss-of-function model through stable transfection of short hairpin-RNA directed against ATP8B1 in the Caco-2 cell line, which resembles intestinal epithelial cells. This resulted in severely compromised bile salt absorption, which was probably due to decreased expression of the bile salt transporter ABST at the apical plasma membrane. Further analysis of this knockdown cell line by cDNA microarray studies, revealed that especially genes encoding plasma membrane proteins were differentially expressed, which points to a general disturbance in apical membrane formation. In addition, we tested hearing capacity in patients and mice with ATP8b1 deficiency using standard audiometry, and found significant hearing loss. The Atp8b1 protein was specifically localized in the stereocilia of the cochlear hair cells and the Atp8b1G308V/G308V mutation was associated with progressive degeneration of these hair cells. Here too a disturbance of the structural integrity of the apical membrane due to ATP8B1 deficiency seems to underlie an extrahepatic symptom. In the second part of the thesis we aimed to further develop effective therapy for ATP8B1 deficiency. We report a complete and long-lasting disappearance of pruritus and normalization of serum bile salt concentrations in cholestatic BRIC1 patients within 24 hours after endoscopic nasobiliary drainage (NBD). In addition, we investigated the molecular consequences of seven disease-causing ATP8B1 mutations in vitro. Five mutations resulted in (partial) retention of ATP8B1 in the endoplasmic reticulum and degradation, indicating protein folding defects. Because protein misfolding can potentially be ameliorated by… Advisors/Committee Members: Berger, R., Kimpen, J.L.L., Houwen, RHJ, Klomp, L.W.J..

Subjects/Keywords: Econometric and Statistical Methods: General; Geneeskunde(GENK)

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

APA (6^th Edition):

Stapelbroek, J. M. (2009). ATP8B1 deficiency; Pathophysiology and treatment of a cholestatic syndrome with extrahepatic symptoms. (Doctoral Dissertation). Universiteit Utrecht. Retrieved from http://dspace.library.uu.nl:8080/handle/1874/36541

Chicago Manual of Style (16^th Edition):

Stapelbroek, J M. “ATP8B1 deficiency; Pathophysiology and treatment of a cholestatic syndrome with extrahepatic symptoms.” 2009. Doctoral Dissertation, Universiteit Utrecht. Accessed April 18, 2021. http://dspace.library.uu.nl:8080/handle/1874/36541.

MLA Handbook (7^th Edition):

Stapelbroek, J M. “ATP8B1 deficiency; Pathophysiology and treatment of a cholestatic syndrome with extrahepatic symptoms.” 2009. Web. 18 Apr 2021.

Vancouver:

Stapelbroek JM. ATP8B1 deficiency; Pathophysiology and treatment of a cholestatic syndrome with extrahepatic symptoms. [Internet] [Doctoral dissertation]. Universiteit Utrecht; 2009. [cited 2021 Apr 18]. Available from: http://dspace.library.uu.nl:8080/handle/1874/36541.

Council of Science Editors:

Stapelbroek JM. ATP8B1 deficiency; Pathophysiology and treatment of a cholestatic syndrome with extrahepatic symptoms. [Doctoral Dissertation]. Universiteit Utrecht; 2009. Available from: http://dspace.library.uu.nl:8080/handle/1874/36541

Universiteit Utrecht

13. Fuchs, S.A. D-serine in health and disease.

Degree: 2010, Universiteit Utrecht

URL: http://dspace.library.uu.nl:8080/handle/1874/183170

► Amino acids are among the most important molecules for living beings, since they are used to build peptides and proteins. Depending on their spatial positioning,… (more)

▼ Amino acids are among the most important molecules for living beings, since they are used to build peptides and proteins. Depending on their spatial positioning, amino acids can occur as D- or L-amino acids. This determines the function of peptides and proteins in the human body. It was long thought that only L-amino acids occurred in nature. In this respect, identification of the D-amino acid D-serine in the human brain was revolutionary. Moreover, D-serine appeared to function as a neurotransmitter by binding to the NMDA-receptor, similar to glycine. We developed two different analysis techniques to determine concentrations of D-serine (and glycine and other D- and L-amino acids) in biological fluids and determined reference ranges in cerebrospinal fluid from apparently healthy subjects. We observed very high D-serine concentrations directly after birth, both absolutely and relative to glycine and L-serine, followed by a rapid decline over the first 3 years to low adult values. Patients with the rare metabolic disorder 3-phosphoglycerate dehydrogenase deficiency fail to reach these high D-serine concentrations after birth and display severe neurological symptoms, including microcephaly, seizures and mental retardation. The one patient identified and treated pre- and postnatally did achieve high D-serine concentrations after birth and was born with a normal head circumference, no epilepsy and she develops well. The NMDA-receptor plays an important role in central nervous system development and we hypothesized that D-serine, as an NMDA-receptor agonist, might be essential in this respect. In fact, we demonstrate preliminary evidence for a role for D-serine in synaptogenesis in a P19 cell model for neuronal differentiation. The NMDA-receptor has also been implicated in numerous pathological conditions and we hypothesized that D-serine might play a role in these disorders, including perinatal asphyxia, one of the greatest causes of neonatal mortality and morbidity worldwide. We therefore investigated D-serine concentrations in rat glioma cells and in cerebrospinal fluid from piglets and human newborns after (simulated) hypoxia-ischemia. We observed significant increases in concentrations of both endogenous NMDAr co-agonists D-serine and glycine after hypoxia-ischemia, which in combination with the known elevated glutamate concentrations upon global ischemia are bound to lead to massive NMDAr activation, excitotoxicity and neuronal damage. Influencing these NMDAr co-agonist concentrations provides an interesting treatment target for this common, devastating and currently untreatable condition. Schizophrenia is another disease strongly associated with NMDAr dysfunction and potentially with altered D-serine concentrations. However, we found no differences in D-serine or glycine concentrations between cerebrospinal fluid from male patients with schizophrenia and controls before and after treatment with the antipsychotic drug olanzapine. This implies that cerebrospinal fluid D-serine and glycine concentrations do not… Advisors/Committee Members: Berger, R., Kimpen, J.L.L., de Koning, T.J., Klomp, L.W.J..

Subjects/Keywords: Econometric and Statistical Methods: General; Geneeskunde (GENK); Geneeskunde(GENK)

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

APA (6^th Edition):

Fuchs, S. A. (2010). D-serine in health and disease. (Doctoral Dissertation). Universiteit Utrecht. Retrieved from http://dspace.library.uu.nl:8080/handle/1874/183170

Chicago Manual of Style (16^th Edition):

Fuchs, S A. “D-serine in health and disease.” 2010. Doctoral Dissertation, Universiteit Utrecht. Accessed April 18, 2021. http://dspace.library.uu.nl:8080/handle/1874/183170.

MLA Handbook (7^th Edition):

Fuchs, S A. “D-serine in health and disease.” 2010. Web. 18 Apr 2021.

Vancouver:

Fuchs SA. D-serine in health and disease. [Internet] [Doctoral dissertation]. Universiteit Utrecht; 2010. [cited 2021 Apr 18]. Available from: http://dspace.library.uu.nl:8080/handle/1874/183170.

Council of Science Editors:

Fuchs SA. D-serine in health and disease. [Doctoral Dissertation]. Universiteit Utrecht; 2010. Available from: http://dspace.library.uu.nl:8080/handle/1874/183170

Universiteit Utrecht

14. Vonk, W.I.M. Understanding COMMD1 function: Novel perspectives from in vitro and in vivo studies.

Degree: 2011, Universiteit Utrecht

URL: http://dspace.library.uu.nl:8080/handle/1874/202399

► The transition metal copper is essential for all aerobic organisms as it is required as cofactor in a diversity of cellular processes, including mitochondrial respiration,… (more)

▼ The transition metal copper is essential for all aerobic organisms as it is required as cofactor in a diversity of cellular processes, including mitochondrial respiration, pigmentation, and iron homeostasis. Controversially, copper can be extremely toxic due to the formation of reactive oxygen species. Therefore, a homeostatic control of intracellular copper concentrations is needed, regulated by processes mediating copper import, distribution, storage and excretion. When one of these processes is distorted, copper-related diseases, characterized by either copper deficiency or accumulation, can develop. However, the exact mechanism of cellular copper excretion is at present incompletely understood. This is illustrated by a range of copper storage disorders with unknown etiology, in which patients are highly sensitive to hepatic copper accumulation when the dietary copper intake is enhanced. We focused primarily on the copper overload disorder copper toxicosis. In dogs, an exon 2 deletion of the COMMD1 gene is associated with this disease. In this thesis, we aimed to provide more insight into the role of COMMD1 in copper homeostasis. Since Commd1 knockout mice are embryonic lethal, and thus an appropriate genetic mouse model to study the role of Commd1 in copper toxicosis was lacking, we generated a hepatocyte-specific Commd1-deficient mouse model. Similar to a diversity of human copper overload disorders, Commd1 deficiency only resulted in a progressive copper accumulation (10- to 20-fold relative to controls) when the mice were fed a copper-rich diet. This suggests that Commd1 is a rate-limiting factor in hepatic copper excretion and genetically underlines the importance of Commd1 in normal hepatic copper excretion. Using a biochemical screen to identify novel protein interactions of COMMD1, we established an interaction between COMMD1 and ATP7A. ATP7A is a copper transporting P-type ATPase involved in copper transport along the gastro-intestinal tract and across the blood-brain barrier. Mutations in ATP7A are associated with the copper deficiency disorder of Menkes disease. COMMD1 was demonstrated to partially restore the impaired copper transporting function of ATP7A mutant proteins, and thus might be considered as a potential modifier of Menkes disease pathogenesis. In this same biochemical screen, we also identified an interaction between COMMD1 and the antioxidant SOD1. Mutations in SOD1 are associated with the neurodegenerative disorder Amyotrophic Lateral Sclerosis (ALS). COMMD1 was shown to impair the SOD1 scavenging function as result of abrogated SOD1 maturation. COMMD1 interfered with the process of SOD1 homodimerization resulting in enhanced cytotoxicity. Subsequently, we examined the effect of COMMD1 on ALS pathogenesis. A pathophysiological hallmark of ALS is the formation of large protein aggregates in the spinal cords of patients, leading to motoneuron damage. Strikingly, binding of COMMD1 to SOD1 mutants resulted in induced aggregate formation of mutant SOD1 proteins. This was accompanied by a… Advisors/Committee Members: Wijmenga, C., Berger, R., Klomp, L.W.J., van de Sluis, A.J.A.

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

APA (6^th Edition):

Vonk, W. I. M. (2011). Understanding COMMD1 function: Novel perspectives from in vitro and in vivo studies. (Doctoral Dissertation). Universiteit Utrecht. Retrieved from http://dspace.library.uu.nl:8080/handle/1874/202399

Chicago Manual of Style (16^th Edition):

Vonk, W I M. “Understanding COMMD1 function: Novel perspectives from in vitro and in vivo studies.” 2011. Doctoral Dissertation, Universiteit Utrecht. Accessed April 18, 2021. http://dspace.library.uu.nl:8080/handle/1874/202399.

MLA Handbook (7^th Edition):

Vonk, W I M. “Understanding COMMD1 function: Novel perspectives from in vitro and in vivo studies.” 2011. Web. 18 Apr 2021.

Vancouver:

Vonk WIM. Understanding COMMD1 function: Novel perspectives from in vitro and in vivo studies. [Internet] [Doctoral dissertation]. Universiteit Utrecht; 2011. [cited 2021 Apr 18]. Available from: http://dspace.library.uu.nl:8080/handle/1874/202399.

Council of Science Editors:

Vonk WIM. Understanding COMMD1 function: Novel perspectives from in vitro and in vivo studies. [Doctoral Dissertation]. Universiteit Utrecht; 2011. Available from: http://dspace.library.uu.nl:8080/handle/1874/202399

Universiteit Utrecht

15. Gadaleta, R.M.G. Farnesoid X Receptor activation protects against intestinal inflammation: potential mechanisms and therapeutic implications.

Degree: 2011, Universiteit Utrecht

URL: http://dspace.library.uu.nl:8080/handle/1874/204958

► Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory disorder, characterized by dysregulation of the mucosal immune system and compromised intestinal epithelial barrier. In IBD… (more)

▼ Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory disorder, characterized by dysregulation of the mucosal immune system and compromised intestinal epithelial barrier. In IBD the immunological balance between pro-inflammatory and anti-inflammatory mediators is severely impaired and shifted towards the pro-inflammatory side. The nuclear transcription factor kappa B is a key regulator in this shift. The bile salt nuclear Farnesoid X Receptor (FXR) is a member of the nuclear receptors (NRs) superfamily, mainly expressed in the ileum and liver. Once activated by bile salts, it regulates transcription of genes involved in bile salt homeostasis. Moreover it is also implicated in liver regeneration, carcinogenesis, energy expenditure, as well as lipid and glucose homeostasis. In this thesis, we aimed to explore the role of FXR in maintaining a healthy gut and the potential therapeutic implications of FXR pharmacological activation for IBD. Functional cross-talk between NF-?B and several NRs exists. NRs were shown to have anti-inflammatory properties, by interfering with NF-?B function and activated NF-?B is described to inhibit several NRs activity. We have recently found that pharmacological FXR activation decreases the severity of inflammation and preserves the intestinal barrier integrity in two murine colitis models. Moreover, it decreases mRNA expression of pro-inflammatory genes and increases expression of antibacterial defense genes. Moreover FXR activation inhibits inflammatory signalling in various primary human immune cell types and in lamina propria mononuclear cells from IBD patients. In another study we show that there is mutual crosstalk between FXR and NF-?B in different model systems. Firstly, the pro-inflammatory cytokine TNF? decreases FXR target gene expression in enterocyte-like cells. This finding was confirmed in ileal specimens of WT mice cultured ex vivo, and in vivo in mice with severe intestinal inflammation. Finally, ileal expression of the FXR target gene SHP is 50% lower in patients with one of the IBD phenotype, Crohn’s disease. Taken together, these findings show that FXR is not only an active player in inhibition of inflammation, but also is a target of the inflammatory response itself. The classical mechanism by which FXR regulates gene transcription is via transactivation. Beside that, we provide evidence for a novel FXR role in transrepressing NF-?B signaling. We started dissecting the mechanisms for classical transactivation and transrepression of FXR, by identification and characterization of a novel phosphorylation site on FXR-S224. Disruption of this site revealed that it is essential for FXR target gene transactivation, but not for transrepression of NF-?B signalling. These findings potentially advance drug design for FXR, since selective FXR ligands which do not result in S224 phosphorylation may be useful to treat hepatic/intestinal inflammation without interfering with metabolism, finally reducing potential side effects. The results described in this thesis… Advisors/Committee Members: Siersema, PD, Berger, R., van Mil, Saskia, van Erpecum, KJ.

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APA (6^th Edition):

Gadaleta, R. M. G. (2011). Farnesoid X Receptor activation protects against intestinal inflammation: potential mechanisms and therapeutic implications. (Doctoral Dissertation). Universiteit Utrecht. Retrieved from http://dspace.library.uu.nl:8080/handle/1874/204958

Chicago Manual of Style (16^th Edition):

Gadaleta, R M G. “Farnesoid X Receptor activation protects against intestinal inflammation: potential mechanisms and therapeutic implications.” 2011. Doctoral Dissertation, Universiteit Utrecht. Accessed April 18, 2021. http://dspace.library.uu.nl:8080/handle/1874/204958.

MLA Handbook (7^th Edition):

Gadaleta, R M G. “Farnesoid X Receptor activation protects against intestinal inflammation: potential mechanisms and therapeutic implications.” 2011. Web. 18 Apr 2021.

Vancouver:

Gadaleta RMG. Farnesoid X Receptor activation protects against intestinal inflammation: potential mechanisms and therapeutic implications. [Internet] [Doctoral dissertation]. Universiteit Utrecht; 2011. [cited 2021 Apr 18]. Available from: http://dspace.library.uu.nl:8080/handle/1874/204958.

Council of Science Editors:

Gadaleta RMG. Farnesoid X Receptor activation protects against intestinal inflammation: potential mechanisms and therapeutic implications. [Doctoral Dissertation]. Universiteit Utrecht; 2011. Available from: http://dspace.library.uu.nl:8080/handle/1874/204958

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