title: Ablation of C/EBPbeta alleviates ER stress and pancreatic beta cell failure through the GRP78 chaperone in mice.
abstract: Pancreatic beta cell failure is thought to underlie the progression from glucose intolerance to overt diabetes, and ER stress is implicated in such beta cell dysfunction. We have now shown that the transcription factor CCAAT/enhancer-binding protein beta (C/EBPbeta) accumulated in the islets of diabetic animal models as a result of ER stress before the onset of hyperglycemia. Transgenic overexpression of C/EBPbeta specifically in beta cells of mice reduced beta cell mass and lowered plasma insulin levels, resulting in the development of diabetes. Conversely, genetic ablation of C/EBPbeta in the beta cells of mouse models of diabetes, including Akita mice, which harbor a heterozygous mutation in Ins2 (Ins2WT/C96Y), and leptin receptor-deficient (Lepr-/-) mice, resulted in an increase in beta cell mass and ameliorated hyperglycemia. The accumulation of C/EBPbeta in pancreatic beta cells reduced the abundance of the molecular chaperone glucose-regulated protein of 78 kDa (GRP78) as a result of suppression of the transactivation activity of the transcription factor ATF6alpha, thereby increasing the vulnerability of these cells to excess ER stress. Our results thus indicate that the accumulation of C/EBPbeta in pancreatic beta cells contributes to beta cell failure in mice by enhancing susceptibility to ER stress.
authors: Department of Internal Medicine, Division of Diabetes, Metabolism, and Endocrinology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors: Tomokazu
authors: T
authors: Matsuda
authors: Yoshiaki
authors: Y
authors: Kido
authors: Shun-ichiro
authors: S
authors: Asahara
authors: Tsuneyasu
authors: T
authors: Kaisho
authors: Takashi
authors: T
authors: Tanaka
authors: Naoko
authors: N
authors: Hashimoto
authors: Yutaka
authors: Y
authors: Shigeyama
authors: Akihiko
authors: A
authors: Takeda
authors: Tae
authors: T
authors: Inoue
authors: Yuki
authors: Y
authors: Shibutani
authors: Maki
authors: M
authors: Koyanagi
authors: Tetsuya
authors: T
authors: Hosooka
authors: Michihiro
authors: M
authors: Matsumoto
authors: Hiroshi
authors: H
authors: Inoue
authors: Tohru
authors: T
authors: Uchida
authors: Masato
authors: M
authors: Koike
authors: Yasuo
authors: Y
authors: Uchiyama
authors: Shizuo
authors: S
authors: Akira
authors: Masato
authors: M
authors: Kasuga
mesh_terms: D051702:Activating Transcription Factor 6; D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000235:genetics / Q000502:physiology*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D054411:Receptors, Leptin / Q000502:physiology; D015534:Trans-Activators / Q000502:physiology
chemical_list: D051702:Activating Transcription Factor 6; C497112:Atf6 protein, mouse; D022782:CCAAT-Enhancer-Binding Protein-beta; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D007328:Insulin; D008565:Membrane Proteins; D054411:Receptors, Leptin; D015534:Trans-Activators; C515447:leptin receptor, mouse