| Aryl hydrocarbon receptor-mediated induction of Stearoyl-CoA desaturase 1 alters hepatic fatty acid composition in TCDD-elicited steatosis. | |
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MedLine Citation:
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PMID: 21890736 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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2,3,7,8-tetrachlorodibenzo-ρ-dioxin (TCDD) induces hepatic dyslipidemia mediated by the aryl hydrocarbon receptor (AhR). Stearoyl-CoA desaturase 1 (Scd1) performs the rate-limiting step in monounsaturated fatty acid (MUFA) synthesis, desaturating 16:0 and 18:0 into 16:1n7 and 18:1n9, respectively. To further examine the role of Scd1 in TCDD-induced hepatotoxicity, comparative studies were performed in Scd1(+/+) and Scd1(-/-) mice treated with 30 μg/kg TCDD. TCDD induced Scd1 activity, protein, and messenger RNA (mRNA) levels approximately twofold. In Scd1(+/+) mice, hepatic effects were marked by increased vacuolization and inflammation and a 3.5-fold increase in serum alanine aminotransferase (ALT) levels. Hepatic triglycerides (TRGs) were induced 3.9-fold and lipid profiling by gas chromatography-mass spectroscopy measured a 1.9-fold increase in fatty acid (FA) levels, consistent with the induction of lipid transport genes. Induction of Scd1 altered FA composition by decreasing saturated fatty acid (SFA) molar ratios 8% and increasing MUFA molar ratios 9%. Furthermore, ChIP-chip analysis revealed AhR enrichment (up to 5.7-fold), and computational analysis identified 16 putative functional dioxin response elements (DREs) within Scd1 genomic loci. Band shift assays confirmed AhR binding with select DREs. In Scd1(-/-) mice, TCDD induced minimal hepatic vacuolization and inflammation, while serum ALT levels remained unchanged. Although Scd1 deficiency attenuated TCDD-induced TRG accumulation, overall FA levels remained unchanged compared with Scd1(+/+) mice. In Scd1(-/-) mice, TCDD induced SFA ratios 8%, reduced MUFA ratios 13%, and induced polyunsaturated fatty acid ratios 5% relative to treated Scd1(+/+) mice. Collectively, these results suggest that AhR regulation of Scd1 not only alters lipid composition but also contributes to the hepatotoxicity of TCDD. |
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Authors:
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Michelle M Angrish; A D Jones; Jack R Harkema; Timothy R Zacharewski |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2011-09-02 |
Journal Detail:
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Title: Toxicological sciences : an official journal of the Society of Toxicology Volume: 124 ISSN: 1096-0929 ISO Abbreviation: Toxicol. Sci. Publication Date: 2011 Dec |
Date Detail:
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Created Date: 2011-11-17 Completed Date: 2012-05-16 Revised Date: 2012-05-24 |
Medline Journal Info:
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Nlm Unique ID: 9805461 Medline TA: Toxicol Sci Country: United States |
Other Details:
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Languages: eng Pagination: 299-310 Citation Subset: IM |
Affiliation:
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Genetics Program, Michigan State University, East Lansing, Michigan 48824, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Blotting, Western Drug-Induced Liver Injury / genetics, metabolism Fatty Acids / metabolism* Fatty Liver / genetics, metabolism* Gas Chromatography-Mass Spectrometry Liver / drug effects*, metabolism Mice Mice, Knockout Principal Component Analysis Real-Time Polymerase Chain Reaction Receptors, Aryl Hydrocarbon / metabolism* Response Elements / genetics Stearoyl-CoA Desaturase / biosynthesis*, genetics Tetrachlorodibenzodioxin / toxicity* Triglycerides / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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P42ES04911/ES/NIEHS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Fatty Acids; 0/Receptors, Aryl Hydrocarbon; 0/Triglycerides; 1746-01-6/Tetrachlorodibenzodioxin; EC 1.14.19.1/Scd1 protein, mouse; EC 1.14.19.1/Stearoyl-CoA Desaturase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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