論文 - 詳細
| RRC ID | 28593 |
|---|---|
| 著者 | Nishiyama Y, Goda N, Kanai M, Niwa D, Osanai K, Yamamoto Y, Senoo-Matsuda N, Johnson RS, Miura S, Kabe Y, Suematsu M. |
| タイトル | HIF-1α induction suppresses excessive lipid accumulation in alcoholic fatty liver in mice. |
| ジャーナル | J Hepatol |
| Abstract |
BACKGROUND & AIMS:Chronic alcohol intake stimulates hepatic oxygen consumption and subsequently causes liver hypoxia, leading to activation of hypoxia inducible factor-1 (HIF-1). Although HIF-1 plays a crucial role in the metabolic switch from aerobic to anaerobic metabolism in response to hypoxia, its roles in the regulation of lipid metabolism in alcoholic fatty liver remain unknown. METHODS:Wild-type and hepatocyte-specific HIF-1α-null mice were subjected to a 6% ethanol-containing liquid diet for 4 weeks, and functional effects of loss of the HIF-1α gene on lipid metabolism were examined in the liver. RESULTS:Hepatocyte-specific HIF-1α-null mice developed severe hypertriglyceridemia with enhanced accumulation of lipids in the liver of mice exposed to a 6% ethanol-containing liquid diet for 4 weeks. Sterol regulatory element-binding protein 1c (SREBP-1c) and its downstream target acetyl-CoA carboxylase were greatly activated as the hepatic steatosis progressed, and these alterations were inversely correlated with the expression of the HIF-1-regulated gene DEC1. Overexpression of DEC1 in the mutant liver abrogated the detrimental effects of loss of HIF-1α gene on ethanol-induced fatty liver with reduced SREBP-1c expression. Conversely, co-administration of the HIF hydroxylase inhibitor dimethyloxalylglycine for the last 2 weeks improved markedly the ethanol-induced fatty liver in mice. CONCLUSIONS:The current results provide direct evidence for protective roles of HIF-1 induction in the development of ethanol-induced fatty liver via activation of the HIF-1-regulated transcriptional repressor DEC1. |
| 巻・号 | 56(2) |
| ページ | 441-7 |
| 公開日 | 2012-2-1 |
| DOI | 10.1016/j.jhep.2011.07.024 |
| PII | S0168-8278(11)00659-3 |
| PMID | 21896344 |
| MeSH | Acetyl-CoA Carboxylase / metabolism Amino Acids, Dicarboxylic / pharmacology Animals Basic Helix-Loop-Helix Transcription Factors / metabolism Disease Susceptibility Ethanol / administration & dosage Fatty Liver, Alcoholic / genetics Fatty Liver, Alcoholic / metabolism* Fatty Liver, Alcoholic / prevention & control* Gene Expression / drug effects Homeodomain Proteins / metabolism Hypoxia-Inducible Factor 1, alpha Subunit / biosynthesis* Hypoxia-Inducible Factor 1, alpha Subunit / deficiency Hypoxia-Inducible Factor 1, alpha Subunit / genetics Lipid Metabolism* Liver / drug effects Liver / metabolism Male Mice Mice, Knockout Sterol Regulatory Element Binding Protein 1 / genetics Sterol Regulatory Element Binding Protein 1 / metabolism |
| IF | 20.582 |
| 引用数 | 57 |
| WOS 分野 | GASTROENTEROLOGY & HEPATOLOGY |
| リソース情報 | |
| 遺伝子材料 | mDEC1-FLAG in pCAGGS (RDB08473) |