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Regulation of Abcg5 and Abcg8 Sterol Transporters in Biliary Cholesterol Elimination, Reverse Cholesterol Transport and Dyslipidemia

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Regulation of Abcg5 and Abcg8 Sterol Transporters in Biliary Cholesterol Elimination, Reverse Cholesterol Transport and Dyslipidemia University of Kentucky UKnowledge University of Kentucky Doctoral Dissertations Graduate School 2011 REGULATION OF ABCG5 AND ABCG8 STEROL TRANSPORTERS IN BILIARY CHOLESTEROL ELIMINATION, REVERSE CHOLESTEROL TRANSPORT AND DYSLIPIDEMIA Nadezhda Steliyanova Sabeva University of Kentucky, [email protected] Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Recommended Citation Sabeva, Nadezhda Steliyanova, "REGULATION OF ABCG5 AND ABCG8 STEROL TRANSPORTERS IN BILIARY CHOLESTEROL ELIMINATION, REVERSE CHOLESTEROL TRANSPORT AND DYSLIPIDEMIA" (2011). University of Kentucky Doctoral Dissertations. 193. https://uknowledge.uky.edu/gradschool_diss/193 This Dissertation is brought to you for free and open access by the Graduate School at UKnowledge. It has been accepted for inclusion in University of Kentucky Doctoral Dissertations by an authorized administrator of UKnowledge. For more information, please contact [email protected]. ABSTRACT OF DISSERTATION Nadezhda Steliyanova Sabeva The GRADUATE SCHOOL UNIVERSITY OF KENTUCKY 2011 REGULATION OF ABCG5 AND ABCG8 STEROL TRANSPORTERS IN BILIARY CHOLESTEROL ELIMINATION, REVERSE CHOLESTEROL TRANSPORT AND DYSLIPIDEMIA ABSTRACT OF DISSERTATION A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Graduate School at the University of Kentucky By Nadezhda Steliyanova Sabeva Lexington, Kentucky Director: Dr. Gregory Graf, Associate Professor, Pharmaceutical Sciences Lexington, Kentucky 2011 ABSTRACT OF DISSERTATION REGULATION OF ABCG5 AND ABCG8 STEROL TRANSPORTERS IN BILIARY CHOLESTEROL ELIMINATION, REVERSE CHOLESTEROL TRANSPORT AND DYSLIPIDEMIA ATP-binding cassette transporters ABCA1 and ABCG1 initiate reverse cholesterol transport generating HDL particles, whereas ABCG5/G8 promote biliary cholesterol secretion thereby facilitating the last step of reverse cholesterol transport. Mutations in the leptin axis result in obesity and dyslipidemia in ob/ob and db/db mice. These mice have defective HDL clearance, increased plasma cholesterol and decreased biliary cholesterol elimination. My studies demonstrate that ABCG5/G8 protein is low in these animals and can be restored with caloric restriction or leptin replacement. To directly test whether ABCG5/G8 alone is able to correct reverse cholesterol transport defect, liver specific ABCG5/G8 expression was achieved in db/db mice by administration of adenoviral ABCG5 and ABCG8. Restoration of biliary cholesterol is able partially to correct dyslipidemia in obese mice, but only in the presence of ezetimibe, an inhibitor of cholesterol absorption. ABCG5/G8 is the body’s primary defense against toxic effects of plant sterols. Plant sterols are used as cholesterol lowering food supplements. However, increased plasma plant sterol concentrations are associated with vascular lesions in dyslipidemic patients and animals. My in vitro studies demonstrate that individual plant sterol alter ABCA1 and ABCG1 abundance, cholesterol efflux and inflammatory cytokine secretion in macrophage foam cells at levels found in humans that consume plant sterol supplements. KEY WORDS: Reverse cholesterol transport, Dyslipidemia, Leptin, ABC-transporters, Macrophage Nadezhda Sabeva June 17, 2011 REGULATION OF ABCG5 AND ABCG8 STEROL TRANSPORTERS IN BILIARY CHOLESTEROL ELIMINATION, REVERSE CHOLESTEROL TRANSPORT AND DYSLIPIDEMIA By Nadezhda Steliyanova Sabeva Dr. Gregory Graf Director of Dissertation Dr. Jim Pauly Director of Graduate Studies June 17, 2011 Date RULES FOR THE USE OF THESES Unpublished theses submitted for the Master’s degree and deposited in the University of Kentucky Library are as a rule open for inspection, but are to be used only with due regard to the rights of the authors. Bibliographical references may be noted, but quotations or summaries of parts may be published only with the permission of the author, and with the usual scholarly acknowledgments. Extensive copying or publication of the thesis in whole or in part also requires the consent of the Dean of the Graduate School of the University of Kentucky. A library that borrows this thesis for use by its patrons is expected to secure the signature of each user. NAME DATE DISSERTATION Nadezhda Steliyanova Sabeva The Graduate School University of Kentucky 2011 REGULATION OF ABCG5 AND ABCG8 STEROL TRANSPORTERS IN BILIARY CHOLESTEROL ELIMINATION, REVERSE CHOLESTEROL TRANSPORT AND DYSLIPIDEMIA DISSERTATION A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Graduate School at the University of Kentucky By Nadezhda Steliyanova Sabeva Lexington, Kentucky Director: Dr. Gregory Graf, Associate Professor, Pharmaceutical Sciences Lexington, Kentucky 2011 TABLE OF CONTENTS LIST OF TABLES ..................................................................................................................... v LIST OF FIGURES .................................................................................................................. vi Chapter 1: GENERAL INTRODUCTION ................................................................................ 1 Cholesterol structure, synthesis and metabolism ............................................ 1 Bile acid synthesis and metabolism .................................................................. 2 Plant sterols structure and metabolism in mammals ....................................... 4 ATP-BINDING CASSETTE (ABC) TRANSPORTERS ..................................................... 7 The ABCA-family ............................................................................................... 7 The ABCB-family ................................................................................................ 8 The ABCG-family ............................................................................................... 9 MOLECULAR REGULATION OF CHOLESTEROL METABOLISM BY NUCLEAR RECEPTORS ....................................................................................................................................... 12 The liver-X-receptors (LXR) ............................................................................. 12 The farnesoid-X-receptors (FXR) ..................................................................... 14 The liver receptor homolog (LRH-1) ............................................................... 15 ADDITIONAL TRANSCRIPTION REGULATORY FACTORS INVOLVED IN CHOLESTEROL METABOLISM ................................................................................................................ 16 Sterol regulatory element binding proteins (SREBPs) .................................... 16 CHOLESTEROL TRAFFICKING IN THE BODY ................................................................... 18 Cholesterol flux in the enterocyte .................................................................. 18 Hepatocytes cholesterol flux .......................................................................... 20 Reverse cholesterol transport (RCT) ............................................................... 22 HARMFUL EFFECTS OF CHOLESTEROL........................................................................... 25 Cholesterol-lowering therapies ...................................................................... 26 Chapter 2: ROLE OF HEPATIC LEPTIN RECEPTOR SIGNALING IN REVERSE CHOLESTEROL TRANSPORT ....................................................................................................................... 30 INTRODUCTION ............................................................................................................. 30 EXPERIMENTAL PROCEDURES ....................................................................................... 32 Reagents and Buffers ...................................................................................... 32 Animals and Treatments ................................................................................. 32 Lipid Analyses .................................................................................................. 33 Membrane proteins analysis .......................................................................... 33 Quantitative Real-time PCR ............................................................................ 34 Statistical Analysis ........................................................................................... 35 RESULTS ......................................................................................................................... 36 DISCUSSION ................................................................................................................... 49 Chapter 3: LIVER SPECIFIC EXPRESSION OF ABCG5/G8 REQUIRES INHIBITION OF CHOLESTEROL ABSORPTION TO REDUCE PLASMA CHOLESTEROL IN DYSLIPIDEMIC DB/DB MICE .................................................................................................................................. 52 INTRODUCTION ............................................................................................................. 52 EXPERIMENTAL PROCEDURE ......................................................................................... 54 iii Reagents and Buffers ...................................................................................... 54 Animals and Treatments ................................................................................. 54 Adenovirus treatment ....................................................................................
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