Decreased expression of endoplasmic reticulum chaperone GRP78 in liver of diabetic mice

Biochem Biophys Res Commun. 2012 Jan 6;417(1):364-70. doi: 10.1016/j.bbrc.2011.11.118. Epub 2011 Dec 1.


To identify molecular targets associated with the development of diabetes, we analyzed the hepatic proteome of obese diabetic db/db mice using electrophoresis on a high-resolution two-dimensional gel combined with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. By comparison between non-diabetic db/+ and diabetic db/db mice, six proteins and one protein were significantly decreased and increased in the diabetic mice, respectively. Among these proteins, two of the decreased proteins are involved in endoplasmic reticulum (ER) stress-related unfolded protein response, GRP78 and protein disulfide isomerase A3, and it was revealed that the decreased GRP78 expression in the liver of diabetic db/db mice is due to the reduction of GRP78 protein synthesis rather than RNA transcription. In addition, we found that the treatment of human hepatocyte HepG2 cells with oleic acid decreased the expression of GRP78, and attenuated the activation of AKT by insulin stimulation. These results suggest that decreased GRP78 expression may induce resistance to insulin by inhibiting the AKT activation, and plays an important role in the development of type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diabetes Mellitus, Type 2 / metabolism*
  • Down-Regulation
  • Endoplasmic Reticulum
  • Heat-Shock Proteins / antagonists & inhibitors
  • Heat-Shock Proteins / biosynthesis*
  • Hep G2 Cells
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism*
  • Humans
  • Insulin / pharmacology
  • Insulin Resistance
  • Liver / metabolism*
  • Male
  • Mice
  • Oleic Acid / pharmacology
  • Protein Disulfide-Isomerases / metabolism
  • Proteomics
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Messenger / genetics
  • Transcription, Genetic


  • Heat-Shock Proteins
  • Insulin
  • RNA, Messenger
  • Oleic Acid
  • Proto-Oncogene Proteins c-akt
  • Protein Disulfide-Isomerases
  • molecular chaperone GRP78