Document Detail


Role of the Ah receptor in homeostatic control of fatty acid synthesis in the liver.
MedLine Citation:
PMID:  22696238     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
We have previously demonstrated a role for the aryl hydrocarbon receptor (AHR) in the attenuation of the cholesterol biosynthesis pathway. This regulation did not require that the AHR binds to its cognate response element. Based on these observations and other reports depicting a role for AHR in lipid metabolism, we chose to investigate the involvement of the receptor in the regulation of the fatty acid synthesis pathway in mice and humans. For this purpose, C57BL/6J, liver-specific transgenic DRE-binding mutant AhR (A78D-AhrTtr CreAlb Ahrfx/fx) and CreAlb Ahrfx/fx mice were treated with an AHR ligand, and hepatic mRNA expression levels of key fatty acid genes (e.g., Acaca, Fasn, Scd1) were measured. The basal levels of those genes were also compared between C57BL6/J and hepatic AHR-deficient mice, as well as between Ahb and Ahd congenic mice. To extend these results to humans, fatty acid gene expression in human cells were compared with AHR-silenced cells. In addition, primary human hepatocytes were treated with an AHR ligand to assess alterations in gene expression and fatty acid synthesis. These studies indicated that the AHR constitutively attenuates the expression of key fatty acid synthesis genes in the absence of binding to its cognate response element. In addition, activation of AHR led to further repression of the expression of these genes and a decrease in overall fatty acid synthesis and secretion in human hepatocytes. Based on our results, we can conclude that increased AHR activity represses fatty acid synthesis, suggesting it may be a future therapeutic target.
Authors:
Rachel Tanos; Iain A Murray; Philip B Smith; Andrew Patterson; Gary H Perdew
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-06-13
Journal Detail:
Title:  Toxicological sciences : an official journal of the Society of Toxicology     Volume:  129     ISSN:  1096-0929     ISO Abbreviation:  Toxicol. Sci.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-09-18     Completed Date:  2013-02-14     Revised Date:  2013-10-11    
Medline Journal Info:
Nlm Unique ID:  9805461     Medline TA:  Toxicol Sci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  372-9     Citation Subset:  IM    
Affiliation:
Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Line
Fatty Acids / biosynthesis*
Gas Chromatography-Mass Spectrometry
Homeostasis / physiology*
Humans
Liver / metabolism*
Mice
Mice, Inbred C57BL
Mice, Transgenic
Receptors, Aryl Hydrocarbon / physiology*
Reverse Transcriptase Polymerase Chain Reaction
Grant Support
ID/Acronym/Agency:
ES004869/ES/NIEHS NIH HHS; ES019964/ES/NIEHS NIH HHS; R01 ES004869/ES/NIEHS NIH HHS; R01 ES019964/ES/NIEHS NIH HHS
Chemical
Reg. No./Substance:
0/Fatty Acids; 0/Receptors, Aryl Hydrocarbon
Comments/Corrections

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