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Type: Artigo
Title: A membrane-bound diacylglycerol species induces PKCϵ-mediated hepatic insulin resistance
Author: Lyu, Kun
Zhang, Ye
Zhang, Dongyan
Kahn, Mario
Horst, Kasper W. ter
Rodrigues, Marcos R.S.
Gaspar, Rafael C.
Hirabara, Sandro M.
Luukkonen, Panu K.
Lee, Seohyuk
Bhanot, Sanjay
Rinehart, Jesse
Blume, Niels
Rasch, Morten Grønbech
Serlie, Mireille J.
Bogan, Jonathan S.
Cline, Gary W.
Samuel, Varman T.
Shulman, Gerald I.
Abstract: 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
Subject: Proteina quinase C
Country: Países Baixos
Editor: Elsevier
Rights: Fechado
Identifier DOI: 10.1016/j.cmet.2020.08.001
Date Issue: 2020
Appears in Collections:FCA - Artigos e Outros Documentos

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