Characterising the Inhibitory Actions of Ceramide upon Insulin Signaling in Different Skeletal Muscle Cell Models: A Mechanistic Insight

Ceramides are known to promote insulin resistance in a number of metabolically important tissues including skeletal muscle, the predominant site of insulin-stimulated glucose disposal. Depending on cell type, these lipid intermediates have been shown to inhibit protein kinase B (PKB/Akt), a key medi...

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Vydáno v:	PloS one Ročník 9; číslo 7; s. e101865
Hlavní autoři:	Mahfouz, Rana, Khoury, Rhéa, Blachnio-Zabielska, Agnieszka, Turban, Sophie, Loiseau, Nicolas, Lipina, Christopher, Stretton, Clare, Bourron, Olivier, Ferré, Pascal, Foufelle, Fabienne, Hundal, Harinder S., Hajduch, Eric
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Public Library of Science 24.07.2014 Public Library of Science (PLoS)
Témata:	AKT protein Animal models Animals Biology and Life Sciences Caveolin Caveolins - genetics Caveolins - metabolism Cell culture Cellular signal transduction Ceramide Ceramides Ceramides - pharmacology Composition effects Diabetes mellitus Gene Expression Regulation Glucose Human health and pathology Humans Insulin Insulin - metabolism Insulin - pharmacology Insulin resistance Intermediates Isoforms Kinases Life Sciences Membrane composition Mice Muscle Fibers, Skeletal - cytology Muscle Fibers, Skeletal - drug effects Muscle Fibers, Skeletal - metabolism Muscle, Skeletal - cytology Muscle, Skeletal - drug effects Muscle, Skeletal - metabolism Muscles Myotubes Palmitic acid Phosphoprotein phosphatase Plant lipids Primary Cell Culture Protein kinase C Protein Kinase C - genetics Protein Kinase C - metabolism Protein phosphatase Protein Phosphatase 2 - genetics Protein Phosphatase 2 - metabolism Proto-Oncogene Proteins c-akt - genetics Proto-Oncogene Proteins c-akt - metabolism Rats Rodents Signal transduction Signal Transduction - drug effects Signaling Skeletal muscle Tissues United Kingdom > UK France
ISSN:	1932-6203, 1932-6203
On-line přístup:	Získat plný text
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Popis
Shrnutí:	Ceramides are known to promote insulin resistance in a number of metabolically important tissues including skeletal muscle, the predominant site of insulin-stimulated glucose disposal. Depending on cell type, these lipid intermediates have been shown to inhibit protein kinase B (PKB/Akt), a key mediator of the metabolic actions of insulin, via two distinct pathways: one involving the action of atypical protein kinase C (aPKC) isoforms, and the second dependent on protein phosphatase-2A (PP2A). The main aim of this study was to explore the mechanisms by which ceramide inhibits PKB/Akt in three different skeletal muscle-derived cell culture models; rat L6 myotubes, mouse C2C12 myotubes and primary human skeletal muscle cells. Our findings indicate that the mechanism by which ceramide acts to repress PKB/Akt is related to the myocellular abundance of caveolin-enriched domains (CEM) present at the plasma membrane. Here, we show that ceramide-enriched-CEMs are markedly more abundant in L6 myotubes compared to C2C12 myotubes, consistent with their previously reported role in coordinating aPKC-directed repression of PKB/Akt in L6 muscle cells. In contrast, a PP2A-dependent pathway predominantly mediates ceramide-induced inhibition of PKB/Akt in C2C12 myotubes. In addition, we demonstrate for the first time that ceramide engages an aPKC-dependent pathway to suppress insulin-induced PKB/Akt activation in palmitate-treated cultured human muscle cells as well as in muscle cells from diabetic patients. Collectively, this work identifies key mechanistic differences, which may be linked to variations in plasma membrane composition, underlying the insulin-desensitising effects of ceramide in different skeletal muscle cell models that are extensively used in signal transduction and metabolic studies.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Conceived and designed the experiments: PF FF HSH EH. Performed the experiments: RM RK ST AB-Z NL CL CS. Analyzed the data: PF FF HSH EH. Contributed reagents/materials/analysis tools: OB. Contributed to the writing of the manuscript: CL ST FF EH. Competing Interests: The authors have declared that no competing interests exist.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0101865