MicroRNA-217 Promotes Ethanol-induced Fat Accumulation in Hepatocytes by Down-regulating SIRT1*
- From the Departments of Molecular Pharmacology and Physiology, University of South Florida Health Sciences Center, Tampa, Florida 33612
- ↵1 To whom correspondence should be addressed: Dept. of Molecular Pharmacology and Physiology, School of Basic Biomedical Sciences, College of Medicine, Box 8, University of South Florida, 12901 Bruce B. Downs Blvd., Tampa, FL 33612. Tel.: 813-396-9107; Fax: 813-974-3079; E-mail: myou{at}health.usf.edu.
Abstract
Ethanol-mediated inhibition of hepatic sirtuin 1 (SIRT1) plays a crucial role in the pathogenesis of alcoholic fatty liver disease. Here, we investigated the underlying mechanisms of this inhibition by identifying a new hepatic target of ethanol action, microRNA-217 (miR-217). The role of miR-217 in the regulation of the effects of ethanol was investigated in cultured mouse AML-12 hepatocytes and in the livers of chronically ethanol-fed mice. In AML-12 hepatocytes and in mouse livers, chronic ethanol exposure drastically and specifically induced miR-217 levels and caused excess fat accumulation. Further studies revealed that overexpression of miR-217 in AML-12 cells promoted ethanol-mediated impairments of SIRT1 and SIRT1-regulated genes encoding lipogenic or fatty acid oxidation enzymes. More importantly, miR-217 impairs functions of lipin-1, a vital lipid regulator, in hepatocytes. Taken together, our novel findings suggest that miR-217 is a specific target of ethanol action in the liver and may present as a potential therapeutic target for treating human alcoholic fatty liver disease.
Footnotes
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↵* This work was supported, in whole or in part, by National Institutes of Health, National Institute on Alcoholism and Alcohol Abuse, Grants AA-015951 and AA-013623 (to M. Y.).
- Received December 14, 2011.
- Revision received January 25, 2012.
- © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.
