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Fatty acid represses insulin receptor gene expression by impairing HMGA1 through protein kinase Cepsilon

Debleena Dey1, Anirban Bhattacharya, Sibsankar Roy

  • 1Molecular Endocrinology Laboratory, Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Kolkata 700032, India.

Biochemical and Biophysical Research Communications
|April 17, 2007
PubMed

Insights

Free fatty acids like palmitate impair insulin signaling by inhibiting PDK1 and promoting PKCepsilon translocation to the nucleus. This disrupts insulin receptor gene transcription, reducing insulin sensitivity and contributing to type 2 diabetes.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Endocrinology

Background:

  • Free fatty acids (FFAs) are implicated in insulin resistance and type 2 diabetes.
  • The precise molecular mechanisms underlying FFA-induced insulin resistance remain incompletely understood.

Purpose of the Study:

  • To elucidate the mechanism by which palmitate, a common FFA, induces insulin resistance.
  • To investigate the role of protein kinase C epsilon (PKCepsilon) in palmitate's effects on insulin signaling.

Main Methods:

  • Studied the effect of palmitate on insulin-stimulated phosphorylation of key signaling molecules like PDK1 and PKCepsilon.
  • Investigated the subcellular localization of PKCepsilon using a translocation inhibitor peptide (epsilonV1).
  • Assessed the impact of palmitate and PKCepsilon translocation on insulin receptor (IR) gene transcription and expression.

Main Results:

  • Palmitate significantly inhibited insulin-stimulated phosphorylation of PDK1 and plasma membrane-bound PKCepsilon.
  • Palmitate stimulated cytosolic PKCepsilon phosphorylation and its translocation to the nucleus.
  • Nuclear translocation of phospho-PKCepsilon was associated with inhibition of IR gene transcription, mediated partly through HMGA1, leading to reduced cell surface IR and compromised insulin sensitivity.

Conclusions:

  • Palmitate induces insulin resistance through a novel pathway involving nuclear translocation of phospho-PKCepsilon.
  • This translocation disrupts insulin receptor gene expression, highlighting a critical mechanism in FFA-induced insulin resistance.
  • Targeting PKCepsilon translocation may offer a therapeutic strategy for managing insulin resistance and type 2 diabetes.

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