title: Regulation of hepatic lipin-1 by ethanol: role of AMP-activated protein kinase/sterol regulatory element-binding protein 1 signaling in mice.
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.
  
  
  CONCLUSIONS
  In conclusion, ethanol-induced up-regulation of lipin-1 gene expression is mediated through inhibition of AMPK and activation of SREBP-1.
authors.affiliation: Departments of Molecular Pharmacology and Physiology, University of South Florida Health Sciences Center, Tampa, FL, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Hu
authors.forename: Fengming
authors.initials: F
authors.lastname: Wang
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.forename: Christopher Q
authors.initials: CQ
authors.lastname: Rogers
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Liang
authors.forename: Brian N
authors.initials: BN
authors.lastname: Finck
authors.forename: Mayurranjan S
authors.initials: MS
authors.lastname: Mitra
authors.forename: Ray
authors.initials: R
authors.lastname: Zhang
authors.forename: Dave A
authors.initials: DA
authors.lastname: Mitchell
authors.forename: Min
authors.initials: M
authors.lastname: You
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D023081:CCAAT-Binding Factor / Q000378:metabolism; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D004789:Enzyme Activation; D000431:Ethanol / Q000494:pharmacology*; D005235:Fatty Liver, Alcoholic / Q000209:etiology*; D022781:Hepatocytes / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D050356:Lipid Metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000378:metabolism*; D010711:Phosphatidate Phosphatase / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D015398:Signal Transduction / Q000187:drug effects; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D023081:CCAAT-Binding Factor; D002492:Central Nervous System Depressants; D006657:Histones; D009687:Nuclear Proteins; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; C402244:nuclear factor Y; D000431:Ethanol; D055372:AMP-Activated Protein Kinases; C418978:Lpin1 protein, mouse; D010711:Phosphatidate Phosphatase