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

Abstract

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.

• Authors: T Yoshida, S Yamagishi, K Nakamura, T Matsui, T Imaizumi, M Takeuchi, H Koga, T Ueno, M Sata
• Journal: Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme (Horm Metab Res) Vol. 40 Issue 9 Pg. 620-5 (Sep 2008) ISSN: 0018-5043 [Print] Germany
• PMID: 18792873 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• 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, enzymology, 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)