Ablation of C/EBPβ alleviates ER stress and pancreatic β cell failure through the GRP78 chaperone in mice

Abstract

Pancreatic β cell failure is thought to underlie the progression from glucose intolerance to overt diabetes, and ER stress is implicated in such β cell dysfunction. We have now shown that the transcription factor CCAAT/ enhancer-binding protein β (C/EBPβ) accumulated in the islets of diabetic animal models as a result of ER stress before the onset of hyperglycemia. Transgenic overexpression of C/EBPβ specifically in β cells of mice reduced β cell mass and lowered plasma insulin levels, resulting in the development of diabetes. Conversely, genetic ablation of C/EBPβ in the β cells of mouse models of diabetes, including Akita mice, which harbor a heterozygous mutation in Ins2 (Ins2 WT/C96Y ), and leptin receptor-deficient (Lepr -/-) mice, resulted in an increase in β cell mass and ameliorated hyperglycemia. The accumulation of C/EBPβ in pancreatic β 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 ATF6α, thereby increasing the vulnerability of these cells to excess ER stress. Our results thus indicate that the accumulation of C/EBPβ in pancreatic β cells contributes to β cell failure in mice by enhancing susceptibility to ER stress.

Insulin demand regulates β cell number via the unfolded protein response

“…We first studied leptin-receptor-deficient db/db mice on the C57BLKS genetic background. These mice are a well-established β cell ER stress model, due to a combination of elevated insulin demand from insulin resistance and the C57BLKS genetic influence, which is predisposed to β cell ER stress and failure (29)(30)(31)(32). At 4 weeks of age, db/db mice still had near-normal body weight and blood glucose, but they showed UPR activation as determined by BiP immunostaining ( Figure 5, A-D).…”

“…To determine whether ER stress applied directly to the β cell increases β cell proliferation in vivo, we studied heterozygous Ins2 C96Y/+ (herein referred to as Akita) mice, in which a mutant proinsulin (1 of 4 insulin alleles) causes β cell ER stress due to improper disulfide formation (32,33). These mice are born with normal glucose tolerance but become diabetic by adulthood due to ER stress-induced β cell failure (34,35).…”

A Reevaluation of the Role of the Unfolded Protein Response in Islet Dysfunction: Maladaptation or a Failure to Adapt?

“…For example, the overexpression of the ER chaperone BiP in b-cells protects mice against HFD-induced diabetes (39). Conversely a reduction in BiP expression as a result of C/EBPb-mediated downregulation of ATF6 is associated with diabetes (43). Moreover, administration of pharmacological chaperones such as tauroursodeoxycholic acid, 4-phenylbutyrate (PBA), and the more recently discovered azoramide can restore rodent islet function both in vitro and in vivo (32,36,40,(44)(45)(46).…”

Dual and opposing roles of the unfolded protein response regulated by IRE1α and XBP1 in proinsulin processing and insulin secretion

“…It has been suggested that the UPR plays a protective role in the adaptation of the β-cell to increased insulin production (12,13). UPR pathways mediated by IRE1/XBP1 and ATF6 have been implicated in insulin secretion and β-cell survival, but their in vivo functions in β-cells are not fully understood (14)(15)(16)(17)(18).…”