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Saturated Fatty Acids Induce c-Src Clustering within Membrane Subdomains, Leading to JNK Activation

Journal article
Authors Ryan G. Holzer
Eek-Joong Park
Ning Li
Helen Tran
Monica Chen
Crystal Choi
Giovanni Solinas
Michael Karin
Published in Cell
Volume 147
Issue 1
Pages 173–184
ISSN 0092-8674
Publication year 2011
Published at Institute of Medicine, Department of Molecular and Clinical Medicine
Pages 173–184
Language en
Links www.sciencedirect.com/science/artic...
Keywords Lipotoxicity, obesity, insulin resistance, JNK, c-Src
Subject categories Basic Medicine

Abstract

Saturated fatty acids (FA) exert adverse health effects and are more likely to cause insulin resistance and type 2 diabetes than unsaturated FA, some of which exert protective and beneficial effects. Saturated FA, but not unsaturated FA, activate Jun N-terminal kinase (JNK), which has been linked to obesity and insulin resistance in mice and humans. However, it is unknown how saturated and unsaturated FA are discriminated. We now demonstrate that saturated FA activate JNK and inhibit insulin signaling through c-Src activation. FA alter the membrane distribution of c-Src, causing it to partition into intracellular membrane subdomains, where it likely becomes activated. Conversely, unsaturated FA with known beneficial effects on glucose metabolism prevent c-Src membrane partitioning and activation, which are dependent on its myristoylation, and block JNK activation. Consumption of a diabetogenic high-fat diet causes the partitioning and activation of c-Src within detergent insoluble membrane subdomains of murine adipocytes.

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