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Saturated fatty acids induce c-Src clustering within membrane subdomains, leading to JNK activation

Ryan G Holzer1, Eek-Joong Park, Ning Li

  • 1Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.

Cell
|October 4, 2011
PubMed

Insights

Saturated fatty acids activate Jun N-terminal kinase (JNK) and impair insulin signaling by altering c-Src protein distribution. Unsaturated fatty acids prevent this, offering a potential mechanism for their beneficial effects on glucose metabolism.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Metabolic Diseases

Background:

  • Saturated fatty acids (FA) are linked to insulin resistance and type 2 diabetes.
  • Jun N-terminal kinase (JNK) activation by saturated FA is implicated in obesity and insulin resistance.
  • The mechanism distinguishing saturated from unsaturated FA in cellular signaling remains unclear.

Purpose of the Study:

  • To elucidate how saturated and unsaturated fatty acids are discriminated by cellular signaling pathways.
  • To investigate the role of c-Src activation in mediating the effects of saturated FA on insulin signaling.
  • To identify the molecular mechanisms underlying the differential effects of FA on JNK activation.

Main Methods:

  • Investigated the effects of saturated and unsaturated FA on c-Src membrane distribution and activation in adipocytes.
  • Assessed the impact of FA-induced c-Src activation on JNK signaling and insulin signaling pathways.
  • Utilized myristoylation inhibition to determine its role in FA-mediated c-Src and JNK activation.

Main Results:

  • Saturated FA, but not unsaturated FA, promote the partitioning of c-Src into intracellular membrane subdomains, leading to its activation.
  • Activated c-Src mediates the activation of JNK and inhibition of insulin signaling by saturated FA.
  • Unsaturated FA prevent c-Src membrane partitioning and activation, thereby blocking JNK activation.
  • Myristoylation of c-Src is crucial for its membrane partitioning and subsequent activation by saturated FA.
  • A high-fat diet induced c-Src partitioning and activation in murine adipocytes.

Conclusions:

  • Cellular discrimination between saturated and unsaturated FA involves the regulation of c-Src membrane distribution and activation.
  • Saturated FA promote insulin resistance and JNK activation via c-Src pathway.
  • Unsaturated FA exert protective effects by preventing c-Src activation and downstream signaling.

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