학술논문
A Membrane-Bound Diacylglycerol Species Induces PKCϵ-Mediated Hepatic Insulin Resistance.
Document Type
Academic Journal
Author
Lyu K; Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA; Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT 06510, USA.; Zhang Y; Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA; Department of Endocrinology & Metabolism, First Hospital of Jilin University, Changchun, Jilin 130021, China.; Zhang D; Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA.; Kahn M; Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA.; Ter Horst KW; Department of Endocrinology and Metabolism Amsterdam University Medical Center, 1105AZ Amsterdam, the Netherlands.; Rodrigues MRS; Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA; School of Medicine, State University of Ponta Grossa, Avenida General Carlos Cavalcanti, Ponta Grossa, PR 84030-900, Brazil.; Gaspar RC; Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA; Laboratory of Molecular Biology of Exercise, School of Applied Science, University of Campinas, Limeira, SP 13484-350, Brazil.; Hirabara SM; Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA; Postgraduate Interdisciplinary Program of Health Sciences, Cruzeiro do Sul University, Sao Paulo, SP 01506-000, Brazil.; Luukkonen PK; Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA.; Lee S; Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA.; Bhanot S; Ionis Pharmaceuticals, Carlsbad, CA 92008, USA.; Rinehart J; Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT 06510, USA; Systems Biology Institute, Yale University, West Haven, CT 06516, USA.; Blume N; CV Research, Novo Nordisk A/S, Novo Nordisk Park, 2760 Maaloev, Denmark.; Rasch MG; Antibody Technology, Novo Nordisk A/S, Novo Nordisk Park, 2760 Maaloev, Denmark.; Serlie MJ; Department of Endocrinology and Metabolism Amsterdam University Medical Center, 1105AZ Amsterdam, the Netherlands.; Bogan JS; Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA; Department of Cell Biology, Yale School of Medicine, New Haven, CT 06510, USA.; Cline GW; Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA.; Samuel VT; Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA; VA Connecticut Healthcare System, West Haven, CT 06516, USA.; Shulman GI; Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA; Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT 06510, USA. Electronic address: gerald.shulman@yale.edu.
Source
Publisher: Cell Press Country of Publication: United States NLM ID: 101233170 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1932-7420 (Electronic) Linking ISSN: 15504131 NLM ISO Abbreviation: Cell Metab Subsets: MEDLINE
Subject
Language
English
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.
Competing Interests: Declaration of Interests The authors declare no competing interests.
(Copyright © 2020 Elsevier Inc. All rights reserved.)
Competing Interests: Declaration of Interests The authors declare no competing interests.
(Copyright © 2020 Elsevier Inc. All rights reserved.)