Hepatic Activating Transcription Factor 3 (ATF3) in Lipid Metabolism

Bibliographic Details
Main Author:	Jadhav, Kavita, Jadhav
Language:	English
Published:	Kent State University / OhioLINK 2017
Subjects:	Biology
Online Access:	http://rave.ohiolink.edu/etdc/view?acc_num=kent1511806289848847

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spelling	ndltd-OhioLink-oai-etd.ohiolink.edu-kent15118062898488472021-08-03T07:04:45Z Hepatic Activating Transcription Factor 3 (ATF3) in Lipid Metabolism Jadhav, Kavita, Jadhav Biology Activating Transcription Factor (ATF) 3 is a member of the cAMP response element-binding protein (CREB) family of proteins wherein it binds to a consensus sequence TGACGTCA on the promoters of its downstream targets. So far, the role of hepatic ATF3 in lipid metabolism is completely unknown. In this project, we have utilized both gain- and loss-of-function approaches to address the role of hepatic ATF3 in regulating triglyceride and cholesterol homeostasis. For gain-of-function studies, we used adenoviruses or adeno-associated adenovirus (AAV)-mediated ATF3 expression in the liver. For loss of function studies, we used adenoviruses-mediated expression of ATF3 shRNA, global Atf3¿¿¿ mice or liver-specific Atf3¿¿¿ mice. Our data show that over-expression of hepatic ATF3 reduces hepatic triglyceride (TG) levels and plasma cholesterol levels in chow or high fat diet (HFD)-fed wild-type mice, db/db mice, and atherosclerosis-prone Apoe¿¿¿ mice or Ldlr¿¿¿ mice. Conversely, loss of hepatic ATF3 increases hepatic TG and plasma cholesterol levels. Global analysis of hepatic ATF3-regulated genes by RNA-Seq shows that hepatic ATF3 may regulate genes involved in bile acid metabolism, very low-density lipoprotein (VLDL) secretion, fatty acid oxidation (FAO), lipoprotein uptake, lipolysis, lipogenesis and inflammation. We have therefore performed qRT-PCR, Western blotting and functional assays to confirm the RNA-Seq data. In addition, we investigated the role of hepatic ATF3 in diet-induced non-alcoholic fatty liver disease (NAFLD) or atherosclerosis. Our data indicate that ATF3 induces FAO and lipolysis and reverse cholesterol transport by increasing hepatic lipoprotein uptake and inhibiting intestinal cholesterol absorption via altering bile acid composition. ATF3 has no effect on VLDL secretion, lipogenesis or intestinal fat absorption. As a result, gain-of hepatic ATF3 functions protects against NAFLD and atherosclerosis in Apoe¿¿¿ mice. Our data suggest that hepatic ATF3 may be targeted for treatment of both NAFLD and atherosclerosis. 2017-12-01 English text Kent State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=kent1511806289848847 http://rave.ohiolink.edu/etdc/view?acc_num=kent1511806289848847 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection	NDLTD
language	English
sources	NDLTD
topic	Biology
spellingShingle	Biology Jadhav, Kavita, Jadhav Hepatic Activating Transcription Factor 3 (ATF3) in Lipid Metabolism
author	Jadhav, Kavita, Jadhav
author_facet	Jadhav, Kavita, Jadhav
author_sort	Jadhav, Kavita, Jadhav
title	Hepatic Activating Transcription Factor 3 (ATF3) in Lipid Metabolism
title_short	Hepatic Activating Transcription Factor 3 (ATF3) in Lipid Metabolism
title_full	Hepatic Activating Transcription Factor 3 (ATF3) in Lipid Metabolism
title_fullStr	Hepatic Activating Transcription Factor 3 (ATF3) in Lipid Metabolism
title_full_unstemmed	Hepatic Activating Transcription Factor 3 (ATF3) in Lipid Metabolism
title_sort	hepatic activating transcription factor 3 (atf3) in lipid metabolism
publisher	Kent State University / OhioLINK
publishDate	2017
url	http://rave.ohiolink.edu/etdc/view?acc_num=kent1511806289848847
work_keys_str_mv	AT jadhavkavitajadhav hepaticactivatingtranscriptionfactor3atf3inlipidmetabolism
_version_	1719453070428995584

Hepatic Activating Transcription Factor 3 (ATF3) in Lipid Metabolism

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