A Raft to Insulin Resistance?

Sci. Signal.  11 Oct 2011:
Vol. 4, Issue 194, pp. ec283
DOI: 10.1126/scisignal.4194ec283

Saturated fatty acids (FAs) can promote insulin resistance and diabetes, effects that have been linked to their activation of Jun N-terminal kinase (JNK). Unsaturated fatty acids, which can inhibit JNK activation by saturated FAs, can have beneficial effects; indeed, some polyunsaturated FAs protect against insulin resistance. Noting that FAs incorporate into cell membranes, and that saturated and polyunsaturated FAs have opposing effects on membrane fluidity, Holzer et al. explored the possibility that membrane alterations leading to activation of a membrane kinase could mediate the effects of FAs on JNK. The saturated fatty acids stearic acid (SA; C18:0) and palmitic acid (PA; C16:0) failed to activate JNK in fibroblasts lacking c-Src; similarly, c-Src knockdown in NIH 3T3 or HEK293T cells decreased JNK activation by PA, whereas reconstitution with c-Src restored JNK activation. PA or SA promoted redistribution of c-Src, and c-Src phosphorylated on Tyr418 (phospho-Tyr418c-Src, presumably an activated form) into detergent-resistant membrane (DRM) fractions corresponding to lipid rafts (membrane microdomains enriched in cholesterol, sphingolipids, and other lipids with saturated acyl chains and thought to act as signaling platforms). Immunofluorescence analysis showed aggregates of phospho-Tyr418c-Src associated with perinuclear and vesicular membranes after PA treatment, where it colocalized with the DRM marker flotillin-1 and the lysosomal marker LAMP-1. Pretreatment with mono [palmitoleic acid (POA; C16:1, n-7) or oleic acid (OA; C18:1, n-9)]– or polyunsaturated FAs [eicosapentaenoic acid (EPA; C20:5, n-3)] inhibited PA-dependent redistribution of c-Src and phospho-Tyr418c-Src into DRM and JNK activation. Similarly, POA inhibited PA-dependent colocalization of phospho-Tyr418c-Src with flotillin-1 and LAMP-1. In vivo studies showed that consumption of a high-fat diet promoted accumulation of total c-Src and phospho-Tyr418c-Src in DRM fractions of mouse adipose tissue and increased c-Src catalytic activity in this fraction. The authors thus propose that the cell membrane—through FA incorporation—acts as the sensor of saturated or unsaturated FAs so that consumption of a diabetogenic high-fat diet changes the membrane distribution of c-Src and promotes its activation, thereby stimulating JNK activation.

R. G. Holzer, E.-J. Park, N. Li, H. Tran, M. Chen, C. Choi, G. Solinas, M. Karin, Saturated fatty acids induce c-Src clustering within membrane subdomains, leading to JNK activation. Cell 147, 173–184 (2011). [PubMed]