Pigment epithelium-derived factor (PEDF) ameliorates advanced glycation end product (AGE)-induced hepatic insulin resistance in vitro by suppressing Rac-1 activation

Horm Metab Res. 2008 Sep;40(9):620-5. doi: 10.1055/s-0028-1083785. Epub 2008 Sep 15.


Advanced glycation end products (AGEs) could be implicated in insulin resistance. However, the molecular mechanisms underlying this are not fully understood. Since pigment epithelium-derived factor (PEDF) blocks the AGE-signaling pathways, we examined here whether and how PEDF improves insulin resistance in AGE-exposed hepatoma cells, Hep3B cells. Proteins were extracted from Hep3B cells, immunoprecipitated with or without insulin receptor substrate-1 (IRS-1) antibodies, and subjected to Western blot analysis. Glycogen synthesis was measured using [ (14)C]-d-glucose. AGE induced Rac-1 activation and increased phosphorylation of IRS-1 at serine-307 residues, JNK, c-JUN, and IkappaB kinase in association with decreased IkappaB levels in Hep3B cells. PEDF or overexpression of dominant negative Rac-1 blocked these effects of AGE on Hep3B cells. Further, AGEs decreased tyrosine phosphorylation of IRS-1, and subsequently reduced the association of p85 subunit of phosphatidylinositol 3-kinase with IRS-1 and glycogen synthesis in insulin-exposed Hep3B cells, all of which were inhibited by PEDF. Our present study suggests that PEDF could improve the AGE-elicited insulin resistance in Hep3B cells by inhibiting JNK- and IkappaB kinase-dependent serine phosphorylation of IRS-1 via suppression of Rac-1 activation. PEDF may play a protective role against hepatic insulin resistance in diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Cell Line, Tumor
  • Enzyme Activation / drug effects
  • Eye Proteins / pharmacology*
  • Genes, Dominant
  • Glycation End Products, Advanced / pharmacology*
  • Glycogen / biosynthesis
  • Hepatocytes / drug effects
  • Hepatocytes / enzymology*
  • Hepatocytes / metabolism*
  • Humans
  • I-kappa B Kinase / metabolism
  • I-kappa B Proteins / metabolism
  • Insulin / metabolism
  • Insulin Receptor Substrate Proteins
  • Insulin Resistance*
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Models, Biological
  • NF-KappaB Inhibitor alpha
  • Nerve Growth Factors / pharmacology*
  • Phosphoproteins / metabolism
  • Phosphotyrosine / metabolism
  • Serpins / pharmacology*
  • Signal Transduction / drug effects
  • rac1 GTP-Binding Protein / metabolism*


  • Adaptor Proteins, Signal Transducing
  • Eye Proteins
  • Glycation End Products, Advanced
  • I-kappa B Proteins
  • IRS1 protein, human
  • Insulin
  • Insulin Receptor Substrate Proteins
  • NFKBIA protein, human
  • Nerve Growth Factors
  • Phosphoproteins
  • Serpins
  • pigment epithelium-derived factor
  • NF-KappaB Inhibitor alpha
  • Phosphotyrosine
  • Glycogen
  • I-kappa B Kinase
  • JNK Mitogen-Activated Protein Kinases
  • rac1 GTP-Binding Protein