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

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 men. However, it is unknown how saturated and unsaturated FA are discriminated. We now demonstrate that saturated FA activate JNK and induce insulin resistance by altering the membrane distribution of c-Src, causing it to partition into intracellular membrane subdomains where it may become 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 adipocytes.

Palmitate Contributes to Insulin Resistance through Downregulation of the Src-Mediated Phosphorylation of Akt in C2C12 Myotubes

“…PP2 not only decreased insulin-stimulated glucose uptake, but also inhibited the phosphorylation of Src at Tyr416 and, Akt at Thr308 and Ser473, in agreement with previous reports. 26,27) Recently, Holzer and colleagues reported 36) that saturated fatty acids such as palmitate and stearic acid result in insulin resistance by inducing Akt inactivation involving Src phosphorylation, consistently with our results. In their study, however, saturated fatty acids regulated the phosphorylation of Src at Tyr418 but not at Tyr416, leading to JNK activation suppressing Akt phosphorylation.…”

“…Additionally, some saturated fatty acids such as stearic acid have been found to induce insulin resistance by inhibiting Akt phosphorylation. 13,36,38) They are similar to palmitate. It is likely that other saturated fatty acids also have negative effects on the Src-mediated Akt phosphorylation.…”

Free Fatty Acids Shift Insulin-induced Hepatocyte Proliferation towards CD95-dependent Apoptosis

“…Activation of the insulin receptor leads to tyrosine phosphorylation of the insulin receptor substrate (IRS)-1, thereby triggering downstream signaling pathways such as the phosphatidylinositide 3-kinase/Akt pathway, which mediate metabolic actions of insulin (39) and insulin-induced hepatocyte swelling (40). JNK can induce insulin resistance through serine/threonine phosphorylation of the IRS-1 and Ϫ2 and thereby attenuate downstream insulin signaling (41)(42)(43)(44). This is also reflected by the attenuation of insulin-induced EGFR activation in presence of FFA.…”

Degradation of Keap1 activates BH3-only proteins Bim and PUMA during hepatocyte lipoapoptosis

“…5,8 JNK activation during lipoapoptosis is likely multifactorial and could result from saturated FFA-induced ER stress 42,43 and/or from reduction in cell membrane fluidity by saturated FFA. 44 Here we observe that degradation of Keap1 protein by PA correlates temporally with increased phosphorylation of JNK; and shRNA-targeted knockdown of Keap1 in liver cells is sufficient to promote JNK activation. The precise mechanisms by which Keap1 suppresses JNK activation is presently unclear but merits further investigation.…”

“…The precise mechanisms by which Keap1 suppresses JNK activation is presently unclear but merits further investigation. Two main kinases, glycogen synthase kinase-3b 42 and mixed lineage kinase (MLK)-3, 44,45 have been implicated in JNK activation in the metabolic syndrome accompanying NAFLD or in cellular apoptosis by saturated FFA. During hepatocyte lipoapoptosis, MLK3-dependent activation of JNK is mediated by GTP-binding protein cell division cycle protein (Cdc)42 and Ras-related C3 botulinum toxin substrate 1 (Rac1).…”