Regulation of Hepatic Lipin-1 by Ethanol: Role of AMP-Activated Protein Kinase/Sterol Regulatory Element-Binding Protein 1 Signaling in Mice

• DOI: 10.1002/hep.24708
• Publication Date: 2011-09-28T02:58:56Z
• Authors: Ming Hu; Fengming Wang; Xin Li; Christopher Q. Ro...; Xiaomei Liang; Brian N. Finck; Mayurranjan S. Mitra; Ray Zhang; Dave A. Mitchell; Min You
• Keywords: Male; 0301 basic medicine; Ethanol; Phosphatidate Phosphatase; Central Nervous System Depressants; Nuclear Proteins; AMP-Activated Protein Kinases; Lipid Metabolism; 3. Good health; Enzyme Activation; Histones; Mice, Inbred C57BL; Mice; 03 medical and health sciences; CCAAT-Binding Factor; Liver; Hepatocytes; Animals; Promoter Regions, Genetic; Sterol Regulatory Element Binding Protein 1; Triglycerides; Fatty Liver, Alcoholic; Signal Transduction

Abstract

Lipin-1 is a protein that exhibits dual functions as a phosphatidic acid phosphohydrolase enzyme in the triglyceride synthesis pathways and a transcriptional coregulator. Our previous studies have shown that ethanol causes fatty liver by activation of sterol regulatory element-binding protein 1 (SREBP-1) and inhibition of hepatic AMP-activated protein kinase (AMPK) in mice. Here, we tested the hypothesis that AMPK-SREBP-1 signaling may be involved in ethanol-mediated up-regulation of lipin-1 gene expression. The effects of ethanol on lipin-1 were investigated in cultured hepatic cells and in the livers of chronic ethanol-fed mice. Ethanol exposure robustly induced activity of a mouse lipin-1 promoter, promoted cytoplasmic localization of lipin-1, and caused excess lipid accumulation, both in cultured hepatic cells and in mouse livers. Mechanistic studies showed that ethanol-mediated induction of lipin-1 gene expression was inhibited by a known activator of AMPK or overexpression of a constitutively active form of AMPK. Importantly, overexpression of the processed nuclear form of SREBP-1c abolished the ability of 5-aminoimidazole-4-carboxamide ribonucleoside to suppress ethanol-mediated induction of lipin-1 gene-expression level. Chromatin immunoprecipitation assays further revealed that ethanol exposure significantly increased the association of acetylated histone H3 at lysine 9 with the SRE-containing region in the promoter of the lipin-1 gene.

Conclusion:

In conclusion, ethanol-induced up-regulation of lipin-1 gene expression is mediated through inhibition of AMPK and activation of SREBP-1. (Hepatology 2012)