AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice.
AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice.
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DOI：
10.1016/j.cmet.2011.03.009
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发表时间：
2011-04-06
期刊：
影响因子：
29
通讯作者：
Zang M
中科院分区：
文献类型：
--
作者：
Li Y;Xu S;Mihaylova MM;Zheng B;Hou X;Jiang B;Park O;Luo Z;Lefai E;Shyy JY;Gao B;Wierzbicki M;Verbeuren TJ;Shaw RJ;Cohen RA;Zang M
AMPK已成为多酚对1型和2型糖尿病脂质代谢紊乱有益作用的关键机制。我们证明AMPK与固醇调节元件结合蛋白（SREBP-1c和−2）相互作用并直接磷酸化。AMPK对SREBP-1c的Ser 372磷酸化对于抑制多酚和二甲双胍对SREBP-1c的蛋白水解加工和转录活性是充分和必要的。AMPK刺激Ser 372磷酸化，抑制SREBP-1c裂解和核转位，并抑制暴露于高糖的肝细胞中SREBP-1c靶基因表达，导致脂肪生成和脂质蓄积减少。合成多酚S17834对AMPK的肝脏激活可部分通过SREBP-1c Ser 372的磷酸化和抑制SREBP-1c和−2依赖性脂肪生成来保护饮食诱导的胰岛素抵抗LDL受体缺陷小鼠的肝脏脂肪变性、高脂血症和加速动脉粥样硬化。AMPK依赖的SREBP磷酸化可能为对抗胰岛素抵抗、血脂异常和动脉粥样硬化提供新的治疗策略。
AMPK has emerged as a critical mechanism for salutary effects of polyphenols on lipid metabolic disorders in type 1 and type 2 diabetes. We demonstrate that AMPK interacts with and directly phosphorylates sterol regulatory element binding proteins (SREBP-1c and −2). Ser372 phosphorylation of SREBP-1c by AMPK is sufficient and necessary for inhibition of proteolytic processing and transcriptional activity of SREBP-1c in response to polyphenols and metformin. AMPK stimulates Ser372 phosphorylation, suppresses SREBP-1c cleavage and nuclear translocation, and represses SREBP-1c target gene expression in hepatocytes exposed to high glucose, leading to reduced lipogenesis and lipid accumulation. Hepatic activation of AMPK by the synthetic polyphenol S17834 protects against hepatic steatosis, hyperlipidemia, and accelerated atherosclerosis in diet-induced insulin resistant LDL receptor deficient mice in part through phosphorylation of SREBP-1c Ser372 and suppression of SREBP-1c and −2-dependent lipogenesis. AMPK-dependent phosphorylation of SREBP may offer novel therapeutic strategies to combat insulin resistance, dyslipidemia, and atherosclerosis.
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影响因子：
29
作者：
Sundqvist, A;Bengoechea-Alonso, MT;Ericsson, J
通讯作者：
Ericsson, J
DOI：
10.1073/pnas.0914798107
发表时间：
2010-02-23
影响因子：
11.1
作者：
Li, Shijie;Brown, Michael S.;Goldstein, Joseph L.
通讯作者：
Goldstein, Joseph L.
影响因子：
10.5
作者：
Walker, Amy K.;Yang, Fajun;Naar, Anders M.
通讯作者：
Naar, Anders M.
影响因子：
7.7
作者：
Foretz, M;Ancellin, N;Viollet, B
通讯作者：
Viollet, B
影响因子：
4
作者：
Yang, Jian;Craddock, Lauren;Liu, Zhi-Mei
通讯作者：
Liu, Zhi-Mei