Endoplasmic Reticulum Stress-Induced Activation of Activating Transcription Factor 6 Decreases Insulin Gene Expression via Up-Regulation of Orphan Nuclear Receptor Small Heterodimer Partner

Abstract

The highly developed endoplasmic reticulum (ER) structure of pancreatic beta-cells is a key factor in beta-cell function. Here we examined whether ER stress-induced activation of activating transcription factor (ATF)-6 impairs insulin gene expression via up-regulation of the orphan nuclear receptor small heterodimer partner (SHP; NR0B2), which has been shown to play a role in beta-cell dysfunction. We examined whether ER stress decreases insulin gene expression, and this process is mediated by ATF6. A small interfering RNA that targeted SHP was used to determine whether the effect of ATF6 on insulin gene expression is mediated by SHP. We also measured the expression level of ATF6 in pancreatic islets in Otsuka Long Evans Tokushima Fatty rats, a rodent model of type 2 diabetes. High glucose concentration (30 mmol/liter glucose) increased ER stress in INS-1 cells. ER stress induced by tunicamycin, thapsigargin, or dithiotreitol decreased insulin gene transcription. ATF6 inhibited insulin promoter activity, whereas X-box binding protein-1 and ATF4 did not. Adenovirus-mediated overexpression of active form of ATF6 in INS-1 cells impaired insulin gene expression and secretion. ATF6 also down-regulated pancreatic duodenal homeobox factor-1 and RIPE3b1/MafA gene expression and repressed the cooperative action of pancreatic duodenal homeobox factor-1, RIPE3b1/MafA, and beta-cell E box transactivator 2 in stimulating insulin transcription. The ATF6-induced suppression of insulin gene expression was associated with up-regulation of SHP gene expression. Finally, we found that expression of ATF6 was increased in the pancreatic islets of diabetic Otsuka Long Evans Tokushima Fatty rats, compared with their lean, nondiabetic counterparts, Long-Evans Tokushima Otsuka rats. Collectively, this study shows that ER stress-induced activation of ATF6 plays an important role in the development of beta-cell dysfunction.

Sustained production of spliced X-box binding protein 1 (XBP1) induces pancreatic beta cell dysfunction and apoptosis

“…Accumulating evidence suggests that a cross-talk exists between the ATF6α and IRE1α-XBP1s pathways to achieve maximal induction of their downstream target genes [5,6,48]. A recent study revealed deleterious effects of ATF6α overexpression on beta cell function and expression of insulin, PDX1 and MAFA in INS-1 cells [49]. Together with our data in primary cells, this suggests that the ATF6α and XBP1 pathways may have redundant roles in the regulation of insulin expression and secretion.…”

“…However, due to the deleterious effects of prolonged increased XBP1s level, this mechanism has to be closely regulated in beta cells, resulting in a limited XPB1 splicing as shown by previous studies [2,12] and the present data. These observations, together with other studies showing detrimental effects of prolonged eukaryotic translation initiation factor 2 alpha (eIF2α) or ATF6α activation in beta cells [24,49], suggest that tight control of ER homeostasis is crucial to maintain beta cell function and survival.…”

Stress hypERactivation in the β-cell

“…Under ER stress, ATF6 is activated, leading to a decrease in insulin gene expression. 34 This suggests that ATF6 may have dual functions: positive regulation of chaperones and negative regulation of insulin promoter activity. The involvement of the UPR triad (i.e., IRE1, PERK and ATF6) in b-cell proteostasis and insulin biosynthesis illustrates translation of UPR target mRNAs, such as activating transcription factor 4 (ATF4).…”

Activating transcription factor 6 protects insulin receptor from ER stress-stimulated desensitization via p42/44 ERK pathway

“…Contrary to the opinion that the ATF6 family contributes to alleviating cellular stress [9,16,24] , the studies by Seo et al suggest that ATF6 plays an important role in the development of β-cell dysfunction [49] . Although ATF6 was shown to suppress insulin gene expression in INS-1 cells, this process might be a feedback to prevent hyperinsulinmia in vivo.…”