title: Decreased expression of endoplasmic reticulum chaperone GRP78 in liver of diabetic mice.
abstract: 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.
authors.affiliation: Department of Biochemistry & Molecular Biology, Division of Biological Sciences, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Yamagishi
authors.forename: Takashi
authors.initials: T
authors.lastname: Ueda
authors.forename: Akinori
authors.initials: A
authors.lastname: Mori
authors.forename: Youhei
authors.initials: Y
authors.lastname: Saito
authors.forename: Takumi
authors.initials: T
authors.lastname: Hatayama
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D015536:Down-Regulation; D004721:Endoplasmic Reticulum; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D019301:Oleic Acid / Q000494:pharmacology; D019704:Protein Disulfide-Isomerases / Q000378:metabolism; D040901:Proteomics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D007328:Insulin; D012333:RNA, Messenger; D019301:Oleic Acid; D051057:Proto-Oncogene Proteins c-akt; D019704:Protein Disulfide-Isomerases