| The role of AMP-activated protein kinase in the action of ethanol in the liver. | |
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MedLine Citation:
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PMID: 15578517 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND & AIMS: Our previous work has shown that ethanol induces the fatty acid synthesis pathway by activation of sterol regulatory element-binding protein 1 (SREBP-1). In the present study, we studied the mechanisms of this activation by identifying a new target of ethanol, AMP-activated protein kinase (AMPK). METHODS: The effects of ethanol on AMPK, acetyl-CoA carboxylase (ACC), and SREBP-1 were assessed in rat hepatic cells and in the livers of ethanol-fed mice. RESULTS: In rat hepatoma H4IIEC3 or McA-RH 7777 cell lines, ethanol-induced transcription of an SREBP-regulated promoter was suppressed by the presence of 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) or metformin, 2 known AMPK activators. Consistent with this, over expression of a constitutively active form of AMPK blocked the effect of ethanol, whereas coexpression of a dominant-negative form of AMPK augmented the effect. Moreover, activation of AMPK by metformin or AICAR largely blocked the ability of ethanol to increase levels of mature SREBP-1 protein. These findings suggest that the effect of ethanol on SREBP-regulated promoter activation was partially mediated through AMPK inhibition. We further demonstrated that AMPK was inhibited by ethanol in hepatic cells. In parallel, ethanol increased the activity of ACC and suppressed the rate of palmitic acid oxidation. Finally, feeding mice a low-fat diet with ethanol resulted in significantly reduced hepatic AMPK activity, increased ACC activity, and enhanced malonyl CoA content. CONCLUSIONS: Taken together, our findings suggest that AMPK may play a key role in regulating the effects of ethanol on SREBP-1 activation, fatty acid metabolism, and development of alcoholic fatty liver. |
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Authors:
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Min You; Michinaga Matsumoto; Christine M Pacold; Won Kyoo Cho; David W Crabb |
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Publication Detail:
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Type: Journal Article; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Gastroenterology Volume: 127 ISSN: 0016-5085 ISO Abbreviation: Gastroenterology Publication Date: 2004 Dec |
Date Detail:
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Created Date: 2004-12-03 Completed Date: 2005-01-04 Revised Date: 2008-11-21 |
Medline Journal Info:
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Nlm Unique ID: 0374630 Medline TA: Gastroenterology Country: United States |
Other Details:
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Languages: eng Pagination: 1798-808 Citation Subset: AIM; IM |
Affiliation:
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Depatment of Medicine, Indiana University School of Medicine, Richard Roudebush Veteran's Affairs Medical Center, Indianapolis, Indiana 46202, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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AMP-Activated Protein Kinases Animals CCAAT-Enhancer-Binding Proteins / pharmacology* Cell Culture Techniques Cell Line, Tumor Central Nervous System Depressants / adverse effects* DNA-Binding Proteins / pharmacology* Ethanol / adverse effects* Fatty Acids / metabolism Fatty Liver, Alcoholic / physiopathology Gene Expression Regulation Helix-Loop-Helix Motifs Hepatocytes / enzymology* Humans Leucine Zippers Liver Neoplasms, Experimental / enzymology, physiopathology Mice Multienzyme Complexes / physiology* Oxidation-Reduction Promoter Regions, Genetic Protein-Serine-Threonine Kinases / physiology* Rats Sterol Regulatory Element Binding Protein 1 Transcription Factors / pharmacology* |
| Grant Support | |
ID/Acronym/Agency:
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AA103623/AA/NIAAA NIH HHS; AA15070/AA/NIAAA NIH HHS; P50-AA07611/AA/NIAAA NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/CCAAT-Enhancer-Binding Proteins; 0/Central Nervous System Depressants; 0/DNA-Binding Proteins; 0/Fatty Acids; 0/Multienzyme Complexes; 0/SREBF1 protein, human; 0/Srebf1 protein, mouse; 0/Srebf1 protein, rat; 0/Sterol Regulatory Element Binding Protein 1; 0/Transcription Factors; 64-17-5/Ethanol; EC 2.7.11.1/AMP-Activated Protein Kinases; EC 2.7.11.1/Protein-Serine-Threonine Kinases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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