Premium
Regulation of hepatic lipin‐1 by ethanol: Role of AMP‐activated protein kinase/sterol regulatory element‐binding protein 1 signaling in mice
Author(s) -
Hu Ming,
Wang Fengming,
Li Xin,
Rogers Christopher Q.,
Liang Xiaomei,
Finck Brian N.,
Mitra Mayurranjan S.,
Zhang Ray,
Mitchell Dave A.,
You Min
Publication year - 2012
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.24708
Subject(s) - sterol regulatory element binding protein , protein kinase a , microbiology and biotechnology , chemistry , amp activated protein kinase , kinase , signal transduction , biochemistry , sterol , medicine , biology , ampk , cholesterol
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. (H epatology 2012)