Regulation of hepatic lipin-1 by ethanol: role of AMP-activated protein kinase/sterol regulatory element-binding protein 1 signaling in mice.
Hepatology
; 55(2): 437-46, 2012 Feb.
Article
em En
| MEDLINE
| ID: mdl-21953514
ABSTRACT
UNLABELLED 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.
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Base de dados:
MEDLINE
Assunto principal:
Fosfatidato Fosfatase
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Proteínas Nucleares
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Depressores do Sistema Nervoso Central
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Etanol
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Fígado Gorduroso Alcoólico
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Fígado
Limite:
Animals
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article