Document Detail


A novel role for the dioxin receptor in fatty acid metabolism and hepatic steatosis.
MedLine Citation:
PMID:  20303349     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND & AIMS: The aryl hydrocarbon receptor (AhR) also known as the dioxin receptor or xenobiotic receptor is a member of the basic helix-loop-helix/period AhR nuclear translocator single minded family. The goal of this study was to determine the endobiotic role of AhR in hepatic steatosis.
METHODS: Wild-type, constitutively activated AhR transgenic, AhR null and CD36/fatty acid translocase null mice were used to investigate the role of AhR in steatosis and the involvement of CD36 in the steatotic effect of AhR. The promoters of the mouse and human CD36 genes were cloned and their regulation by AhR was analyzed.
RESULTS: Activation of AhR induced spontaneous hepatic steatosis characterized by the accumulation of triglycerides. The steatotic effect of AhR likely is owing to the combined up-regulation of CD36 and fatty acid transport proteins, suppression of fatty acid oxidation, inhibition of hepatic export of triglycerides, increase in peripheral fat mobilization, and increased hepatic oxidative stress. Promoter analysis established CD36 as a novel transcriptional target of AhR. Activation of AhR in liver cells induced CD36 gene expression and enhanced fatty acid uptake. The steatotic effect of an AhR agonist was inhibited in CD36-/- mice.
CONCLUSIONS: Our study reveals a novel link between AhR-induced steatosis and the expression of CD36. Industrial or military exposures to dioxin and related compounds have been linked to increased prevalence of fatty liver in human beings. Results from this study may help to establish AhR and its target CD36 as novel therapeutic and preventive targets for fatty liver disease.
Authors:
Jung Hoon Lee; Taira Wada; Maria Febbraio; Jinhan He; Tsutomu Matsubara; Min Jae Lee; Frank J Gonzalez; Wen Xie
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-03-17
Journal Detail:
Title:  Gastroenterology     Volume:  139     ISSN:  1528-0012     ISO Abbreviation:  Gastroenterology     Publication Date:  2010 Aug 
Date Detail:
Created Date:  2010-07-27     Completed Date:  2010-08-12     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  0374630     Medline TA:  Gastroenterology     Country:  United States    
Other Details:
Languages:  eng     Pagination:  653-63     Citation Subset:  AIM; IM    
Copyright Information:
Copyright (c) 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
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MeSH Terms
Descriptor/Qualifier:
Adiposity
Animals
Antigens, CD36 / genetics,  metabolism*
Basic Helix-Loop-Helix Transcription Factors
Body Weight
Cell Line
Fatty Acid Transport Proteins / metabolism
Fatty Acids / metabolism*
Fatty Liver / chemically induced,  genetics,  metabolism*,  physiopathology
Female
Humans
Liver / drug effects,  metabolism*
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Oxidation-Reduction
Oxidative Stress
Promoter Regions, Genetic
Receptors, Aryl Hydrocarbon / agonists,  deficiency,  genetics,  metabolism*
Tetrachlorodibenzodioxin / toxicity
Transfection
Triglycerides / metabolism
Grant Support
ID/Acronym/Agency:
DK076962/DK/NIDDK NIH HHS; DK083952/DK/NIDDK NIH HHS; N01-DK-7-0004/HHSN267200700004C/DK/NIDDK NIH HHS; R01 DK076962/DK/NIDDK NIH HHS; R01 DK076962-01A2/DK/NIDDK NIH HHS; R01 DK083952/DK/NIDDK NIH HHS; R01 ES014626/ES/NIEHS NIH HHS; R01 ES014626-04/ES/NIEHS NIH HHS
Chemical
Reg. No./Substance:
0/Ahr protein, mouse; 0/Antigens, CD36; 0/Basic Helix-Loop-Helix Transcription Factors; 0/Fatty Acid Transport Proteins; 0/Fatty Acids; 0/Receptors, Aryl Hydrocarbon; 0/Triglycerides; DO80M48B6O/Tetrachlorodibenzodioxin
Comments/Corrections

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