MicroRNA-217 promotes ethanol-induced fat accumulation in hepatocytes by down-regulating SIRT1.
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.
Departments of Molecular Pharmacology and Physiology, University of South Florida Health Sciences Center, Tampa, Florida 33612.
Huquan
H
Yin
Departments of Molecular Pharmacology and Physiology, University of South Florida Health Sciences Center, Tampa, Florida 33612.
Ming
M
Hu
Departments of Molecular Pharmacology and Physiology, University of South Florida Health Sciences Center, Tampa, Florida 33612.
Ray
R
Zhang
Departments of Molecular Pharmacology and Physiology, University of South Florida Health Sciences Center, Tampa, Florida 33612.
Zheng
Z
Shen
Departments of Molecular Pharmacology and Physiology, University of South Florida Health Sciences Center, Tampa, Florida 33612.
Laura
L
Flatow
Departments of Molecular Pharmacology and Physiology, University of South Florida Health Sciences Center, Tampa, Florida 33612. Electronic address: myou@health.usf.edu.
Min
M
You
D000818:Animals; D002460:Cell Line; D002492:Central Nervous System Depressants / Q000009:adverse effects* / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D000431:Ethanol / Q000009:adverse effects* / Q000494:pharmacology; D005227:Fatty Acids / Q000235:genetics / Q000378:metabolism*; D005235:Fatty Liver, Alcoholic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000235:genetics; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D010711:Phosphatidate Phosphatase / Q000235:genetics / Q000378:metabolism; D056564:Sirtuin 1 / Q000096:biosynthesis* / Q000235:genetics
D002492:Central Nervous System Depressants; D005227:Fatty Acids; C553315:MIRN217 microRNA, human; D035683:MicroRNAs; D009687:Nuclear Proteins; D000431:Ethanol; C485999:LPIN1 protein, human; C418978:Lpin1 protein, mouse; D010711:Phosphatidate Phosphatase; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1