Regulation of hepatic lipin-1 by ethanol: role of AMP-activated protein kinase/sterol regulatory element-binding protein 1 signaling in mice

Hepatology. 2012 Feb;55(2):437-46. doi: 10.1002/hep.24708. Epub 2011 Dec 29.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Animals
  • CCAAT-Binding Factor / metabolism
  • Central Nervous System Depressants / pharmacology*
  • Enzyme Activation
  • Ethanol / pharmacology*
  • Fatty Liver, Alcoholic / etiology*
  • Hepatocytes / metabolism
  • Histones / metabolism
  • Lipid Metabolism
  • Liver / drug effects*
  • Liver / enzymology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nuclear Proteins / metabolism*
  • Phosphatidate Phosphatase / metabolism*
  • Promoter Regions, Genetic
  • Signal Transduction / drug effects
  • Sterol Regulatory Element Binding Protein 1 / metabolism
  • Triglycerides / metabolism
  • Up-Regulation

Substances

  • CCAAT-Binding Factor
  • Central Nervous System Depressants
  • Histones
  • Nuclear Proteins
  • Srebf1 protein, mouse
  • Sterol Regulatory Element Binding Protein 1
  • Triglycerides
  • nuclear factor Y
  • Ethanol
  • AMP-Activated Protein Kinases
  • Lpin1 protein, mouse
  • Phosphatidate Phosphatase