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Role of TMEM141 in Cholesterol Metabolism

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Role of TMEM141 in Cholesterol Metabolism Role of TMEM141 in Cholesterol Metabolism A thesis submitted To Kent State University in partial Fulfillment of the requirements for the Degree of Master of Science By Wrood S. Al-Khfajy December, 2014 Thesis written by Wrood S. Al-Khfajy B.S., Al-Mustansiriya University, 2007 M.S., Kent State University, 2014 Approved by Yanqiao Zhang, Associate Professor, M.D., Masters Advisor. Yoonkwang Lee, Assistant Professor, Ph.D., Committee member. Werner Geldenhuys, Assistant Professor, Ph.D., Committee member. Eric Mintz, Professor, Ph.D., Director, School of Biomedical Sciences. James L. Blank, Ph.D., Dean, College of Arts & Sciences II Table of Contents List of Figures.................................................................................................................viii List of abbreviations.........................................................................................................xi Acknowledgments.......................................................................................................... xv Dedication……………………………………….……………………………………………..xvi Chapter One: Introduction 1-1 The Nuclear receptor..................................................................................................1 1-2 Farnesoid X receptor (FXR) is a nuclear receptor. ....................................................2 1-2-1 FXR Ligands………………………..…………………………………………………… 3 1-2-2 FXR DNA binding motifs………………………………………………………………...3 1-2-3 Function of FXR…………………………………………………………….………….…4 1-2-4 Role of FXR in bile acid metabolism………………………………………………..….5 1-2-5 FXR and lipid metabolism……………………………………………………………… 5 1-2-6 FXR and cholesterol metabolism……………………………………………………… 6 1-2-6-1 FXR and the cholesterol absorption……….………………..….……6 1-2-6-2 FXR and de novo cholesterol synthesis……………………….…....6 1-2-6-3 FXR and reverse cholesterol transport………………………………6 1-2-7 FXR and triglyceride metabolism………….…...……………...……….………………7 1-2-8 FXR and glucose metabolism…………………………………..………………………7 1-3 Cholesterol homeostasis…………………….…………………………………………….8 III 1-3-1 Cholesterol synthesis…………...……………...…………………..……….…….…….8 1-3-2 Cholesterol absorption and transport……….……………….…..………...…10 1-3-3 Role of High density lipoprotein (HDL) in cholesterol homeostasis……….11 1-3-4 HDL and reverse cholesterol transport…………………………………….…12 1-3-5 The anti-inflammatory and antioxidant activity of HDL……………......……13 1-4 ABCA1-mediated the regulation of cholesterol efflux…………………………………14 1-4-1 ABCA1 and HDL biogenesis…………………………………………………..14 1-4-2 Mechanism of ABCA1-mediated cholesterol efflux…………………………16 1-4-3 Sub-cellular localization of ABCA1……………………….…........................17 1-4-4 Regulation of ABCA1 transcription………………………………….…..……18 a) Pre-transcriptional regulation………………...……………………………18 b) Transcriptional regulation………………………………..........................19 c) Post-translational regulation of ABCA1 activity……………………….…20 1- Regulation of ABCA1 degradation pathways……………….......20 a) Calpain mediated ABCA1 degradation……..……………………23 b) Ubiquitin– mediated ABCA1 degradation pathway……………..20 2- Regulation of ABCA1 by microRNAs……………………………..22 1-5 Transmembrane protein141 and cholesterol homeostasis …..…………………..….23 Chapter Two: Materials and methods 2-1 Mice, Diets and Ligands …………………………………………………………………26 2-2 Adenovirus…………………………………………………………………………………26 IV 2-3 Real-Time PCR……………………………………………………………………………27 2-4 Western Blot Assay……………………………………………………………………….28 2-5 Reporter Plasmids………………………………………………………………………...28 2-6 Transient Transfection……………………………………………………………………29 2-7 Lipid and Lipoprotein Analysis…………………………………………………………...29 2-8 VLDL Secretion……………………………………………………………………………30 2-9 Co-immunoprecipitation…………………………………………………………………..30 2-10 Immuno-flourascence……………...........................................................................30 2-11 Cholesterol efflux in RAW-264.7 macrophages………………….…………………..31 2-12 Isolation of the primary Hepatocytes …………………………….……………………32 2-13 Statistical analysis……….………………………………………………………………32 Chapter Three: Results 3-1 Tmem141 expression is induced by GW4064 in wild-type but not FXR-deficient mice………………………………………………….........................................................33 3-2 Tmem141 expression is induced by INT747 in wild-type but not FXR-deficient mice………………………………………………….........................................................35 3-3 Identification of the FXR response element in the Tmem141 gene….………...….36 3-4 Knockdown of hepatic Tmem141 markedly reduces Plasma Cholesterol………..38 3-5 Hepatic Tmem141 deficiency results in down-regulation of multiple genes involved in lipid metabolism………………..…………………….………..…………………….…….42 3-6 Knockdown of Tmem141 in the liver decreases the expression of hepatic ATP – binding cassette Transporter sub-family A1 (ABCA1) protein level by 80 %...............44 V 3-7 Over-expression of hepatic Tmem141 had no effect on lipid metabolism………….48 3-8 Over-expression of hepatic Tmem141 has no effect on the expression of ABCA1, ApoA1 or lipogenic genes:…………………………………………………...…….…….…..49 3-9 Over-expression of Tmem141 has no impact on Hepatic ATP-binding cassette transporter sub-Family A1 (ABCA1) expression..........…………………………….….......50 3-10 Knockdown of hepatic Tmem141 does not affect Very-Low-Density Lipoprotein (VLDL) secretion……………..……………………………….……………………….……....51 3-11 Knockdown of Tmem141 in the liver partially reduces plasma cholesterol levels in Ldlr -/-mic………………………………..…………………………….………………………...52 3-12 Hepatic over-expression of Tmem141 has no effect on plasma cholesterol or Triglyceride levels in Ldlr -/- mice ………………….…………………………………….…..54 3-13 Hepatic knockdown of Tmem141 has no effect on plasma cholesterol or Triglyceride levels in apoe -/- mice ………………….…………………….……….………..55 3-14 Hepatic over-expression of Tmem141 has no effect on plasma cholesterol or Triglyceride levels in apoe -/- mice …..…………..………………………………………....57 3-15 Tmem141 deficiency impairs cholesterol efflux from primary hepatocytes…...….59 3-16 Knockdown of Tmem141 decreases the expression of ABCA1 protein level in RAW macrophages cells…………………………………………….…………………..…...60 3-17 Tmem141 deficiency impairs cholesterol efflux from macrophages ……………....61 3-18 Liver X receptor, a key regulator of HDL and cholesterol metabolism, does not regulate Tmem141 expression …………………………………………………………..….63 3-19 Tmem141 over expression dose not improves ABCA1 stability……......................64 3-20 Tmem141 interacts with ABCA1 in vitro………….……………………………..........65 VI 3-21 Tmem141 mRNA and protein distribution patterns………………………………….66 3-22 TMEM141 is localized in late endosome/ lysosome compartments.......................67 3-23 Tmem141 expression is reduced in db/db mice ………………………………….….69 3-24 High-Fat diet selectively reduces Tmem141 expression in mice liver ………….....71 3-25 Tmem141 regulates ABCA1 expression in human…………………………………..73 Chapter Four: Discussion 4- Discussion ………………………………………………………………………….……….82 References ……………………………………………………………………………………92 VII List of Figures Figure 1-1 Structure and DNA binding of nuclear receptors……..…………………………1 Figure 1-2 FXR regulate a large number of target genes involved in bile acid, lipoprotein and glucose metabolism ……………………………………………………………………….4 Figure 1-3 Major steps of cholesterol biosynthesis…………….…….....…………….…….9 Figure 1-4 Metabolism of chylomicron, VLDL, IDL and LDL…………………………...…11 Figure1-5 ABCA1 and reverse cholesterol transport……………………….…….………..15 Figure 1-6: HDL formation by ABCA1.....................................................................…...17 Figure 1-7 Tmem141A NMR spectroscopy structure…….……………………………..…23 Figure 1-8 Tmem141 isoforms…………………………………………………..………......24 Figure 3-1: Hepatic Tmem141 is induced by synthetic FXR agonist GW4064 in wild-type but not in FXR-/- mice by FXR.................................................................................…...34 Figure 3-2: Hepatic Tmem141 is induced by synthetic FXR agonist INT747 in wild-type but not in FXR-/- mice by FXR................................................................................…....36 Figure 3-3: Identification of an FXRE in the Tmem141 gene……..……………...……….37 Figure 3-4 Knockdown of Tmem141 in the liver reduce plasma cholesterol level mainly in the HDL fraction…………………………………………………………………………..…41 Figure 3-5 Hepatic Tmem141 deficiency down regulates the expression of multiple genes involved in lipid metabolism …………………………….…………………...……….43 Figure 3-6 Hepatic Tmem141 deficiency reduces the liver expression of ATP –binding cassette transporter sub-family A1 and ApoA-1…………….…………………...……..…45 VIII Figure 3-7 Over-expression of Tmem141 in the liver of wild-type mice……………....…48 Figure: 3-8 Hepatic over- expression of Tmem141 has no Effect on genes implicated in lipid metabolism……………………………………………….……………………….....……49 Figure 3-9 Hepatic Tmem141 over expression had no effect on the liver expression of ATP –binding cassette transporter sub-family A1 and ApoA-1 ……………..….….…..50 Figure 3-10 Loss of hepatic Tmem141 has no effect on VLDL secretion..…….……..…52 Figure 3-11 Tmem141 deficiency reduces plasma cholesterol level, partially through LDL receptor lipids ……………….……….………………………..…………………………53 Figure 3-12 Over- expression of hepatic Tmem141 reduces plasma glucose of LDLR-/- mice………………….………………………..…………………...…………………..……….54 Figure 3-13 Knockdown of hepatic Tmem141 had no effect on plasma lipids of ApoE-/- mice……………………………………………………………………….………………...…..56 Figure 3-14 Over- expression of hepatic Tmem141 had no effect on plasma lipids of ApoE-/- mice…………………………………...………………………………………...….…58
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