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

Ming Hu, Fengming Wang, Xin Li, Christopher Q. Rogers, Xiaomei Liang, Brian N. Finck, Mayurranjan S. Mitra, Ray Zhang, Dave A. Mitchell, Min You

Research output: Contribution to journalArticlepeer-review

87 Scopus citations

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.

Original languageEnglish
Pages (from-to)437-446
Number of pages10
JournalHepatology
Volume55
Issue number2
DOIs
StatePublished - Feb 2012

Fingerprint

Dive into the research topics of 'Regulation of hepatic lipin-1 by ethanol: Role of AMP-activated protein kinase/sterol regulatory element-binding protein 1 signaling in mice'. Together they form a unique fingerprint.

Cite this