Regulation of hepatic lipin-1 by ethanol: role of AMP-activated protein kinase/sterol regulatory element-binding protein 1 signaling in mice.
Regulation of hepatic lipin-1 by ethanol: role of AMP-activated protein kinase/sterol regulatory element-binding protein 1 signaling in mice.
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DOI：
10.1002/hep.24708
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发表时间：
2012-02
期刊：
影响因子：
13.5
通讯作者：
You, Min
中科院分区：
文献类型：
--
作者：
Hu, Ming;Wang, Fengming;Li, Xin;Rogers, Christopher Q.;Liang, Xiaomei;Finck, Brian N.;Mitra, Mayurranjan S.;Zhang, Ray;Mitchell, Dave A.;You, Min
Lipin-1是一种具有双重功能的蛋白质，在甘油三酯合成途径中作为磷脂酸磷酸水解酶（PAP）酶和转录共调节剂。我们之前的研究表明，乙醇通过激活小鼠的固醇调节元件结合蛋白1 （SREBP-1）和抑制肝脏amp活化激酶（AMPK）导致脂肪肝。在这里，我们验证了AMPK-SREBP-1信号可能参与乙醇介导的脂素-1基因表达上调的假设。在培养肝细胞和慢性酒精喂养小鼠肝脏中研究了乙醇对脂素-1的影响。乙醇暴露强烈诱导小鼠脂质-1启动子的活性，促进脂质-1的细胞质定位，并在培养的肝细胞和小鼠肝脏中引起过量的脂质积累。机制研究表明，乙醇介导的脂素-1基因表达的诱导被已知的AMPK激活因子或AMPK组成活性形式的过表达抑制。重要的是，SREBP-1c加工核形式（nSREBP-1c）的过表达会破坏AICAR抑制乙醇介导的脂素-1基因表达水平的能力。染色质免疫沉淀（ChIP）实验进一步显示，乙醇暴露显著增加了乙酰化组蛋白H3在赖氨酸9 （Lys9）上与脂素-1基因启动子中含有sre区域的关联。综上所述，乙醇诱导的lipin-1基因表达上调是通过抑制AMPK和激活SREBP-1介导的。
Lipin-1 is a protein that exhibits dual functions as a phosphatidic acid phosphohydrolase (PAP) enzyme in the triglyceride synthesis pathways and a transcriptional co-regulator. 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 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 processed nuclear form of SREBP-1c (nSREBP-1c) abolished the ability of AICAR to suppress ethanol-mediated induction of lipin-1 gene expression level. Chromatin immunoprecipitation (ChIP) assays further revealed that ethanol exposure significantly increased association of acetylated Histone H3 at lysine 9 (Lys9) with the SRE-containing region in the promoter of the lipin-1 gene. 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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DOI：
10.1152/ajpgi.00456.2009
发表时间：
2010-03-01
影响因子：
4.5
作者：
Shen, Zheng;Liang, Xiaomei;You, Min
通讯作者：
You, Min
影响因子：
12.4
作者：
Campagna, M.;Herranz, D.;Rivas, C.
通讯作者：
Rivas, C.
DOI：
10.1152/ajpgi.00091.2005
发表时间：
2005-12-01
影响因子：
4.5
作者：
Park, PH;Lim, RW;Shukla, SD
通讯作者：
Shukla, SD
影响因子：
4.8
作者：
Barroso, Emma;Rodriguez-Calvo, Ricardo;Vazquez-Carrera, Manuel
通讯作者：
Vazquez-Carrera, Manuel
影响因子：
6.5
作者：
Manmontri, Boripant;Sariahmetoglu, Meltem;Brindley, David N.
通讯作者：
Brindley, David N.