Involvement of mammalian sirtuin 1 in the action of ethanol in the liver.
Chronic ethanol feeding causes liver steatosis in animal models by upregulating the sterol regulatory element-binding protein 1 (SREBP-1), which subsequently increases the synthesis of hepatic lipid. SREBP-1 activity is regulated by reversible acetylation at specific lysine residues. The present study tests the hypothesis that activation of SREBP-1 by ethanol may be mediated by mammalian sirtuin 1 (SIRT1), a NAD(+)-dependent class III protein deacetylase. The effects of ethanol on SIRT1 were determined in cultured rat hepatoma cells and in the livers of ethanol-fed mice. In rat H4IIEC3 cells, we observed that ethanol exposure induced SREBP-1c lysine acetylation and SREBP-1c transcriptional activity. The effect of ethanol was abolished by expression of wild-type SIRT1 or by treatment with resveratrol, a known potent SIRT1 agonist. Conversely, knocking down SIRT1 by the small silencing SIRT1 plasmid SIRT1shRNA or expression of a SIRT1 mutant, SIRT1(H363Y), did not negate the ethanol effect. These findings suggest that the effect of ethanol on SREBP-1 is mediated, at least in part, through SIRT1 inhibition. Consistent with the in vitro findings, chronic ethanol feeding substantially downregulated hepatic SIRT1 in mice. Inhibition of hepatic SIRT1 activity was associated with an increase in the acetylated active nuclear form of SREBP-1c in the livers of ethanol-fed mice. Our results indicate an essential role for SIRT1 in mediating the effects of ethanol on SREBP-1 and hepatic lipid metabolism, as well as the development of alcoholic fatty liver. Hence, SIRT1 may represent a novel therapeutic target for treatment of human alcoholic fatty liver disease.
You
Min
M
Dept. of Molecular Pharmacology and Physiology, School of Basic Biomedical Sciences, College of Medicine, Box 8, Univ. of South Florida, 12901 Bruce B. Downs Blvd, Tampa, FL 33612, USA. myou@health.usf.edu
Liang
Xiaomei
X
Ajmo
Joanne M
JM
Ness
Gene C
GC
D000107:Acetylation; D000428:Alcohol Drinking / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015536:Down-Regulation; D020536:Enzyme Activators / Q000494:pharmacology; D000431:Ethanol / Q000008:administration & dosage / Q000633:toxicity*; D005235:Fatty Liver, Alcoholic / Q000209:etiology / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005992:Glycerol-3-Phosphate O-Acyltransferase / Q000235:genetics / Q000378:metabolism; D050155:Lipogenesis / Q000187:drug effects / Q000235:genetics; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D000077185:Resveratrol; D056564:Sirtuin 1; D037761:Sirtuins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013230:Stearoyl-CoA Desaturase / Q000235:genetics / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
D020536:Enzyme Activators; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D034741:RNA, Small Interfering; D051780:Sterol Regulatory Element Binding Protein 1; D013267:Stilbenes; D015534:Trans-Activators; D014157:Transcription Factors; D000431:Ethanol; D013230:Stearoyl-CoA Desaturase; D005992:Glycerol-3-Phosphate O-Acyltransferase; C470545:Sirt1 protein, mouse; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; D037761:Sirtuins; D000077185:Resveratrol