Involvement of mammalian sirtuin 1 in the action of ethanol in the liver

• DOI: 10.1152/ajpgi.00575.2007
• Publication Date: 2008-01-31T20:59:03Z
• Authors: Min You; Xiaomei Liang; Joanne M. Ajmo; Gene C. Ness
• Keywords: Sirtuin 1; Steatosis

Chronic ethanol feeding causes liver steatosis in animal models by upregulating the sterol regulatory element-binding protein 1 (SREBP-1), which subsequently increases synthesis of hepatic lipid. SREBP-1 activity is regulated reversible acetylation at specific lysine residues. The present study tests hypothesis that activation may be mediated mammalian sirtuin (SIRT1), a NAD(+)-dependent class III deacetylase. effects on SIRT1 were determined cultured rat hepatoma cells and livers ethanol-fed mice. In H4IIEC3 cells, we observed exposure induced SREBP-1c transcriptional activity. effect was abolished expression wild-type or treatment with resveratrol, known potent agonist. Conversely, knocking down small silencing plasmid SIRT1shRNA mutant, SIRT1(H363Y), did not negate effect. These findings suggest mediated, least part, through inhibition. Consistent vitro findings, chronic substantially downregulated Inhibition associated an increase acetylated active nuclear form Our results indicate essential role for mediating lipid metabolism, as well development alcoholic fatty liver. Hence, represent novel therapeutic target human disease.