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A Membrane-Bound Diacylglycerol Species Induces PKCϵ-Mediated Hepatic Insulin Resistance.
Cell Metabolism ( IF 27.7 ) Pub Date : 2020-09-02 , DOI: 10.1016/j.cmet.2020.08.001
Kun Lyu 1 , Ye Zhang 2 , Dongyan Zhang 3 , Mario Kahn 3 , Kasper W Ter Horst 4 , Marcos R S Rodrigues 5 , Rafael C Gaspar 6 , Sandro M Hirabara 7 , Panu K Luukkonen 3 , Seohyuk Lee 3 , Sanjay Bhanot 8 , Jesse Rinehart 9 , Niels Blume 10 , Morten Grønbech Rasch 11 , Mireille J Serlie 4 , Jonathan S Bogan 12 , Gary W Cline 3 , Varman T Samuel 13 , Gerald I Shulman 1
Affiliation  

Nonalcoholic fatty liver disease is strongly associated with hepatic insulin resistance (HIR); however, the key lipid species and molecular mechanisms linking these conditions are widely debated. We developed a subcellular fractionation method to quantify diacylglycerol (DAG) stereoisomers and ceramides in the endoplasmic reticulum (ER), mitochondria, plasma membrane (PM), lipid droplets, and cytosol. Acute knockdown (KD) of diacylglycerol acyltransferase-2 in liver induced HIR in rats. This was due to PM sn-1,2-DAG accumulation, which promoted PKCϵ activation and insulin receptor kinase (IRK)-T1160 phosphorylation, resulting in decreased IRK-Y1162 phosphorylation. Liver PM sn-1,2-DAG content and IRK-T1160 phosphorylation were also higher in humans with HIR. In rats, liver-specific PKCϵ KD ameliorated high-fat diet-induced HIR by lowering IRK-T1160 phosphorylation, while liver-specific overexpression of constitutively active PKCϵ-induced HIR by promoting IRK-T1160 phosphorylation. These data identify PM sn-1,2-DAGs as the key pool of lipids that activate PKCϵ and that hepatic PKCϵ is both necessary and sufficient in mediating HIR.



中文翻译:

膜结合的二酰基甘油物种诱导 PKCϵ 介导的肝胰岛素抵抗。

非酒精性脂肪肝与肝胰岛素抵抗 (HIR) 密切相关;然而,连接这些条件的关键脂质种类和分子机制存在广泛争议。我们开发了一种亚细胞分馏方法来量化内质网 (ER)、线粒体、质膜 (PM)、脂滴和细胞质中的二酰基甘油 (DAG) 立体异构体和神经酰胺。肝脏中二酰基甘油酰基转移酶-2 的急性敲低 (KD) 诱导大鼠 HIR。这是由于 PM sn -1,2-DAG 积累,促进 PKCϵ 活化和胰岛素受体激酶 (IRK)-T1160 磷酸化,导致 IRK-Y1162 磷酸化降低。肝PM SN-1,2-DAG 含量和 IRK-T1160 磷酸化在患有 HIR 的人中也更高。在大鼠中,肝脏特异性 PKCϵ KD 通过降低 IRK-T1160 磷酸化改善高脂肪饮食诱导的 HIR,而肝脏特异性过表达组成型活性 PKCϵ 诱导的 HIR 通过促进 IRK-T1160 磷酸化。这些数据表明 PM sn -1,2-DAGs 是激活 PKCϵ 的关键脂质池,肝脏 PKCϵ 在介导 HIR 中既是必要的又是充分的。

更新日期:2020-10-06
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