A Membrane-Bound Diacylglycerol Species Induces PKCϵ-Mediated Hepatic Insulin Resistance.

Animals Cell Membrane / chemistry Diglycerides / chemistry Humans Insulin Resistance Liver / metabolism Male Phosphorylation Protein Kinase C-epsilon / metabolism Rats Rats, Sprague-Dawley Receptor, Insulin / metabolism
ceramides dicylglycerols hepatic glucose production hepatic glycogen synthesis hepatic insulin resistance insulin receptor phosphorylation liquid chromatography-tandem mass spectrometry nonalcoholic fatty liver disease protein kinase C-epsilon type 2 diabetes

Journal

Cell metabolism
ISSN: 1932-7420
Titre abrégé: Cell Metab
Pays: United States
ID NLM: 101233170

Informations de publication

Date de publication:
06 10 2020
Historique:
received: 04 01 2020
revised: 22 06 2020
accepted: 03 08 2020
pubmed: 4 9 2020
medline: 9 11 2021
entrez: 4 9 2020
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.cmet.2020.08.001 PMID: 32882164 PMC: PMC7544641
pubmed: 32882164
pii: S1550-4131(20)30414-9
doi: 10.1016/j.cmet.2020.08.001
pmc: PMC7544641
mid: NIHMS1619429
pii:
doi:

Substances chimiques

1,2-diacylglycerol 0
Diglycerides 0
Receptor, Insulin EC 2.7.10.1
Protein Kinase C-epsilon EC 2.7.11.13

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S.

Langues

eng

Sous-ensembles de citation

IM

Pagination

654-664.e5

Subventions

Organisme : NCATS NIH HHS
ID : UL1 TR001863
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK116774
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK119968
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK045735
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK034989
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK113984
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK092661
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK114793
Pays : United States
Organisme : BLRD VA
ID : I01 BX000901
Pays : United States

Informations de copyright

Copyright © 2020 Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Interests The authors declare no competing interests.

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Auteurs

Kun 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.

Ye 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.

Dongyan Zhang (D)

Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA.

Mario Kahn (M)

Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA.

Kasper W Ter Horst (KW)

Department of Endocrinology and Metabolism Amsterdam University Medical Center, 1105AZ Amsterdam, the Netherlands.

Marcos R S 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.

Rafael C 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.

Sandro M 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.

Panu K Luukkonen (PK)

Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA.

Seohyuk Lee (S)

Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA.

Sanjay Bhanot (S)

Ionis Pharmaceuticals, Carlsbad, CA 92008, USA.

Jesse 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.

Niels Blume (N)

CV Research, Novo Nordisk A/S, Novo Nordisk Park, 2760 Maaloev, Denmark.

Morten Grønbech Rasch (MG)

Antibody Technology, Novo Nordisk A/S, Novo Nordisk Park, 2760 Maaloev, Denmark.

Mireille J Serlie (MJ)

Department of Endocrinology and Metabolism Amsterdam University Medical Center, 1105AZ Amsterdam, the Netherlands.

Jonathan S 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.

Gary W Cline (GW)

Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA.

Varman T Samuel (VT)

Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA; VA Connecticut Healthcare System, West Haven, CT 06516, USA.

Gerald I 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.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › A Membrane-Bound Diacylglycerol Species...
questionsmedicales.fr › Cellules › Structures cellulaires › Membrane cellulaire › A Membrane-Bound Diacylglycerol Species...
questionsmedicales.fr › Lipides › Glycérides › Diglycéride › A Membrane-Bound Diacylglycerol Species...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › A Membrane-Bound Diacylglycerol Species...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Résistance aux substances › Insulinorésistance › A Membrane-Bound Diacylglycerol Species...
questionsmedicales.fr › Système digestif › Foie › A Membrane-Bound Diacylglycerol Species...
questionsmedicales.fr › Métabolisme › Phosphorylation › A Membrane-Bound Diacylglycerol Species...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Protéine kinase C › Protein kinase C-epsilon › A Membrane-Bound Diacylglycerol Species...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Rats › A Membrane-Bound Diacylglycerol Species...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Rats › Rat Sprague-Dawley › A Membrane-Bound Diacylglycerol Species...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs peptidiques › Récepteur hormone pancréatique › Récepteur à l'insuline › A Membrane-Bound Diacylglycerol Species...