+publisher:"University of Kansas" +contributor:("Guo, Grace L.")

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1. Thomas, Ann M. THE ROLE OF EPIGENETICS IN TRANSCRIPTIONAL REGULATION OF FXR AND SILENCING FXR EXPRESSION IN HUMAN COLON CANCER.

Degree: PhD, Pharmacology, Toxicology & Therapeutics, 2011, University of Kansas

URL: http://hdl.handle.net/1808/8386

Farnesoid X receptor (FXR) is a ligand activated transcription factor belonging to the nuclear receptor superfamily and bile acids are its endogenous ligands. FXR is a critical regulator of the enterohepatic circulation of bile acids, lipid homeostasis, glucose metabolism, and tumor suppression in liver and intestine. Consequently, FXR has become a very promising therapeutic target for the prevention and/or treatment of cholestasis, hyperlipidemic disorders, metabolic syndrome, and liver and colon cancer. Studies suggest epigenetic mechanisms are critical for proper transcriptional induction of nuclear receptors. Likewise, evidence shows epigenetic mechanisms are responsible for modulating the tissue/cell-specific FXR expression in human colon cancer. However, how epigenetic mechanisms are involved in FXR induced transcription or tissue-specific FXR expression remains elusive. Understanding these mechanisms is crucial for future development of pharmacological modulators of FXR as well as understanding the full physiological roles of FXR. This dissertation was designed to elucidate epigenetic mechanisms involved in tissue-specific FXR induced gene transcription, orphan nuclear receptors critical for regulating FXR function, and epigenetic mechanisms responsible for FXR silencing in colon cancer. In specific aim 1, a genome-wide FXR binding assay was done in mouse liver and intestine. Specific aim 2 focuses on the role of the orphan nuclear receptor hepatocyte nuclear factor 4fnalpha (HNF4&alpha) in regulating liver-specific functions of FXR. And finally, in specific aim 3, DNA methylation of FXR promoter was investigated as the mechanism responsible for FXR silencing in human colon cancer. In conclusion, genome-wide binding of FXR implicates novel epigenetic mechanisms and orphan nuclear receptors in regulating FXR function. Furthermore, this study indicates that HNF4&alpha is at least one orphan nuclear receptor capable of regulating FXR function in the liver. Findings from these first two aims succeeded in progressing drug development fields aimed at finding new FXR modulators for the treatment of multiple metabolic disorders by elucidating novel epigenetic mechanisms that may be investigated as therapeutic targets. Finally, FXR is at least partially down-regulated by DNA methylation in human colon cancer, suggesting a potential mechanism to be targeted for the prevention, treatment, and/or diagnosis of colon cancer. Advisors/Committee Members: Guo, Grace L. (advisor), Apte, Udayan (cmtemember), Hagenbuch, Bruno (cmtemember), Petroff, Brian K. (cmtemember), Zhong, Xiao-bo (cmtemember).

Subjects/Keywords: Cellular biology; Colon cancer; DNA methylation; Epigenetics; Farnesoid x receptor; Nuclear receptors

…Toxicology & Therapeutics at the University of Kansas Medical Center, particularly members of the…

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

APA (6^th Edition):

Thomas, A. M. (2011). THE ROLE OF EPIGENETICS IN TRANSCRIPTIONAL REGULATION OF FXR AND SILENCING FXR EXPRESSION IN HUMAN COLON CANCER. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/8386

Chicago Manual of Style (16^th Edition):

Thomas, Ann M. “THE ROLE OF EPIGENETICS IN TRANSCRIPTIONAL REGULATION OF FXR AND SILENCING FXR EXPRESSION IN HUMAN COLON CANCER.” 2011. Doctoral Dissertation, University of Kansas. Accessed January 19, 2021. http://hdl.handle.net/1808/8386.

MLA Handbook (7^th Edition):

Thomas, Ann M. “THE ROLE OF EPIGENETICS IN TRANSCRIPTIONAL REGULATION OF FXR AND SILENCING FXR EXPRESSION IN HUMAN COLON CANCER.” 2011. Web. 19 Jan 2021.

Vancouver:

Thomas AM. THE ROLE OF EPIGENETICS IN TRANSCRIPTIONAL REGULATION OF FXR AND SILENCING FXR EXPRESSION IN HUMAN COLON CANCER. [Internet] [Doctoral dissertation]. University of Kansas; 2011. [cited 2021 Jan 19]. Available from: http://hdl.handle.net/1808/8386.

Council of Science Editors:

Thomas AM. THE ROLE OF EPIGENETICS IN TRANSCRIPTIONAL REGULATION OF FXR AND SILENCING FXR EXPRESSION IN HUMAN COLON CANCER. [Doctoral Dissertation]. University of Kansas; 2011. Available from: http://hdl.handle.net/1808/8386

2. Zhan, Le. STUDY OF FXR IN PRIMARY HUMAN HEPATOCYTES AND FXR REGULATED BA HOMEOSTASIS IN PARENTERAL NUTRITION ASSOCIATED LIVER DISEASES.

Degree: PhD, Pharmacology, Toxicology & Therapeutics, 2014, University of Kansas

URL: http://hdl.handle.net/1808/19570

Farnesoid X receptor (FXR, NR1H4) is a ligand activated transcription factor belonging to the nuclear receptor (NR) superfamily, and is highly expressed in the liver, intestine, and kidney, in both humans and rodents. Bile acids (BAs) are the endogenous ligands of FXR. FXR mainly functions as the BA sensor by regulating genes that are critically involved in BA homeostasis. FXR has also been shown to play important roles in lipid, cholesterol and glucose metabolism, as well as inflammation, tumorigenesis, and liver regeneration. FXR deficiency is implicated in numerous liver diseases and mice with modulation of FXR have been used as animal models to study liver physiology and pathology. Genome-wide studies in mouse livers and intestines suggest FXR's diverse and broadly tissue specific functions. In the first aim, we studied the genome-wide FXR binding and transcriptome profiles upon FXR activation in primary human hepatocytes (PHHs) and HepG2 cells. Chromatin immunoprecipitation followed by massive parallel sequencing (ChIP-seq) was performed in PHHs and HepG2 cells, treated with a synthetic FXR agonist, GW4064 or DMSO control. In parallel, RNA deep sequencing (RNA-seq) and RNA microarray were performed for GW4064 or control treated PHHs and wild type (WT) mouse livers, respectively. ChIP-seq showed similar profiles of genome-wide FXR binding in humans and mice in terms of motif analysis and pathway prediction. However, RNA-seq and microarray showed more different transcriptome profiles between PHHs and mouse livers upon GW4064 treatment. In summary, we have established genome-wide human FXR binding and transcriptome profiles. These results will aid in determining the human FXR functions, as well as judging to what level the mouse models could be used to study human FXR functions in future studies. Recent studies in the field of parenteral nutrition (PN) suggest that down-regulation of FXR signaling is critically involved in the pathogenesis of PN associated liver diseases (PNALD), especially PN associated cholestasis (PNAC) in preterm infants. PN is a life-saving therapy for patients who cannot tolerate enteral food intake. However, long-term PN can lead to a spectrum of liver diseases, summarized as PNALD. PNAC is predominately found in preterm infants and neonates, and has high rate of progression into liver failure. Options for clinical management of PNALD are still limited. While it is suggested that multiple risk factors are contributing to the development of PNALD, the pathogenesis of PNALD remains poorly understood. Animal studies obtained from preterm piglets and several mouse models have shed light on the mechanisms underlined. To date, whether FXR and BAs are involved in the development and progression of PNALD is not well studied. In the second aim, we established a valid mouse PN model in our laboratory. Using RNA microarray profiling and serum BA profiling, we identified novel signatures involved in BA homeostasis in adult PN mice. We detected significantly increased gene expression of cytochrome P450,… Advisors/Committee Members: Guo, Grace L (advisor), Ding, Wen-Xing (cmtemember), Apte, Udayan (cmtemember), Li, Tiangang (cmtemember), Zhu, Hao (cmtemember).

Subjects/Keywords: Pharmacology; Toxicology; BA; ChIP-seq; FXR; humans versus mice; liver; PNALD

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

APA (6^th Edition):

Zhan, L. (2014). STUDY OF FXR IN PRIMARY HUMAN HEPATOCYTES AND FXR REGULATED BA HOMEOSTASIS IN PARENTERAL NUTRITION ASSOCIATED LIVER DISEASES. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/19570

Chicago Manual of Style (16^th Edition):

Zhan, Le. “STUDY OF FXR IN PRIMARY HUMAN HEPATOCYTES AND FXR REGULATED BA HOMEOSTASIS IN PARENTERAL NUTRITION ASSOCIATED LIVER DISEASES.” 2014. Doctoral Dissertation, University of Kansas. Accessed January 19, 2021. http://hdl.handle.net/1808/19570.

MLA Handbook (7^th Edition):

Zhan, Le. “STUDY OF FXR IN PRIMARY HUMAN HEPATOCYTES AND FXR REGULATED BA HOMEOSTASIS IN PARENTERAL NUTRITION ASSOCIATED LIVER DISEASES.” 2014. Web. 19 Jan 2021.

Vancouver:

Zhan L. STUDY OF FXR IN PRIMARY HUMAN HEPATOCYTES AND FXR REGULATED BA HOMEOSTASIS IN PARENTERAL NUTRITION ASSOCIATED LIVER DISEASES. [Internet] [Doctoral dissertation]. University of Kansas; 2014. [cited 2021 Jan 19]. Available from: http://hdl.handle.net/1808/19570.

Council of Science Editors:

Zhan L. STUDY OF FXR IN PRIMARY HUMAN HEPATOCYTES AND FXR REGULATED BA HOMEOSTASIS IN PARENTERAL NUTRITION ASSOCIATED LIVER DISEASES. [Doctoral Dissertation]. University of Kansas; 2014. Available from: http://hdl.handle.net/1808/19570

University of Kansas

3. Pacyniak, Erik Kristofer. Molecular Mechanism of Polybrominated Diphenyl Ether Disposition in the Liver.

Degree: PhD, Pharmacology, Toxicology & Therapeutics, 2010, University of Kansas

URL: http://hdl.handle.net/1808/7717

Polybrominated diphenyl ethers (PBDEs) were introduced in the late 1970's as additive flame retardants incorporated into textiles, electronics, plastics and furniture. Although 2,2',3,3',4,4',5,5',6,6'-decabromodiphenyl ether (BDE209) is the only congener currently on the market, 2,2`,4,4`-tetrabromodiphenyl ether (BDE47), 2,2`,4,4`,5-pentabromodiphenyl ether (BDE99), and 2,2`,4,4`,5,5`-hexabromodiphenyl ether (BDE153) are the predominant congeners detected in human and wildlife samples. Upon exposure, PBDEs enter the liver where they are biotransformed to potentially toxic metabolites. Although the human liver burden of PBDEs is not clear, the presence of PBDEs in human liver is particularly alarming because it has been demonstrated in rodents that hydroxylated metabolites may play a pivotal role in PBDE-mediated toxicity. The mechanism by which PBDEs enter the liver was not known. However, due to their large molecular weights (MWs ~485 to 1000 Da), they were not likely to enter hepatocytes by simple diffusion. Organic anion transporting polypeptides (OATPs: human; Oatps: rodents) are responsible for hepatic uptake of a variety of amphipathic compounds of MWs larger than 350 Da. Therefore, I tested the hypothesis that OATPs/Oatps expressed in human and mouse hepatocytes are responsible for the uptake of PBDE congeners 47, 99, and 153 by using Chinese hamster ovary (CHO) cell lines expressing OATP1B1, OATP1B3, or OATP2B1 and Human Embryonic Kidney 293 (HEK293) cells transiently expressing Oatp1a1, Oatp1a4, Oatp1b2, or Oatp2b1. Direct uptake studies illustrated that PBDE congeners are substrates of human and mouse hepatic OATPs/Oatps, except for Oatp1a1. Detailed kinetic analysis revealed that OATP1B1, OATP1B3, Oatp1a4, and Oatp1b2 transport BDE47 with the highest affinity followed by BDE99 and BDE153. However, both OATP2B1 and Oatp2b1 transported all three congeners with similar affinities. The importance of hepatic Oatps for the accumulation of BDE47 in liver was confirmed using Oatp1a4- and Oatp1b2-null mice. These results clearly suggest that uptake of PBDEs via these OATPs/Oatps are responsible for liver-specific accumulation of PBDEs. In mouse liver, PBDEs induce drug metabolizing enzymes, namely cytochrome P450s (Cyps). However, the molecular mechanisms underlying this induction was unknown. Cyp2b10 and 3a11 are target genes of the xenobiotic nuclear receptors, the constitutive androstane receptor (CAR) and pregnane X receptor (PXR), both of which are responsible for mediating induction of Cyp2b10 and Cyp3a11, respectively. I hypothesized that PBDE congeners are CAR and/or PXR activators. Using reporter-gene luciferase assays I showed that BDE47, BDE99 and BDE209 activate human and mouse CAR and PXR in a concentration-dependent manner. Furthermore, induction of Cyp2b10 and Cyp3a11 was markedly suppressed in CAR- and PXR-null mice, respectively, indicating that PBDE congeners activate these receptors in vivo. BDE47 and BDE99, the primary congeners detected in humans in the United States, are capable of inducing… Advisors/Committee Members: Guo, Grace L. (advisor), Hagenbuch, Bruno (cmtemember), Klaassen, Curtis D. (cmtemember), Reed, Gregory A. (cmtemember), Petroff, Brian K. (cmtemember).

Subjects/Keywords: Toxicology; Constitutive androstane receptor; Nuclear receptors; Organic anion transporting polypeptide; Polybrominated diphenyl ethers; Pregnane x receptor

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

APA (6^th Edition):

Pacyniak, E. K. (2010). Molecular Mechanism of Polybrominated Diphenyl Ether Disposition in the Liver. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/7717

Chicago Manual of Style (16^th Edition):

Pacyniak, Erik Kristofer. “Molecular Mechanism of Polybrominated Diphenyl Ether Disposition in the Liver.” 2010. Doctoral Dissertation, University of Kansas. Accessed January 19, 2021. http://hdl.handle.net/1808/7717.

MLA Handbook (7^th Edition):

Pacyniak, Erik Kristofer. “Molecular Mechanism of Polybrominated Diphenyl Ether Disposition in the Liver.” 2010. Web. 19 Jan 2021.

Vancouver:

Pacyniak EK. Molecular Mechanism of Polybrominated Diphenyl Ether Disposition in the Liver. [Internet] [Doctoral dissertation]. University of Kansas; 2010. [cited 2021 Jan 19]. Available from: http://hdl.handle.net/1808/7717.

Council of Science Editors:

Pacyniak EK. Molecular Mechanism of Polybrominated Diphenyl Ether Disposition in the Liver. [Doctoral Dissertation]. University of Kansas; 2010. Available from: http://hdl.handle.net/1808/7717

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