ATF4-mediated transcriptional regulation protects against β-cell loss during endoplasmic reticulum stress in a mouse model

Molecular Metabolism

Jun Zhang¹  Mai Inagaki²  Miho Oyadomari³  Kazuhito Tsuboi⁴  Yoshio Fujitani⁴  Seiichi Oyadomari⁵  Yasuo Okamoto⁵  Keisuke Kitakaze⁶  Yasuhiro Takenouchi⁶  Masanori Tachikawa⁶  Yoshimasa Hamada⁶ 

[1] Corresponding author. Department of Pharmacology, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan.;Department of Molecular Research, Diabetes Therapeutics and Research Center, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, 770-8503, Japan;Department of Pharmacology, Kawasaki Medical School, Kurashiki, Okayama, 701-0192, Japan;Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, 770-8503, Japan;Department of Pharmacology, Kawasaki Medical School, Kurashiki, Okayama, 701-0192, Japan;Division of Molecular Biology, Institute for Genome Research, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, 770-8503, Japan;

关键词: Diabetes;    Beta cell;    Endoplasmic reticulum stress;    Unfolded protein response;    Integrated stress response;    Activating transcription factor 4;   

DOI  :  

来源: DOAJ

【 摘 要 】

Objective: Activating transcription factor 4 (ATF4) is a transcriptional regulator of the unfolded protein response and integrated stress response (ISR) that promote the restoration of normal endoplasmic reticulum (ER) function. Previous reports demonstrated that dysregulation of the ISR led to development of severe diabetes. However, the contribution of ATF4 to pancreatic β-cells remains poorly understood. In this study, we aimed to analyze the effect of ISR enhancer Sephin1 and ATF4-deficient β-cells to clarify the role of ATF4 in β-cells under ER stress conditions. Methods: To examine the role of ATF4 in vivo, ISR enhancer Sephin1 (5 mg/kg body weight, p.o.) was administered daily for 21 days to Akita mice. We also established β-cell–specific Atf4 knockout (βAtf4-KO) mice that were further crossed with Akita mice. These mice were analyzed for characteristics of diabetes, β-cell function, and morphology of the islets. To identify the downstream factors of ATF4 in β-cells, the islets of βAtf4-KO mice were subjected to cDNA microarray analyses. To examine the transcriptional regulation by ATF4, we also performed in situ PCR analysis of pancreatic sections from mice and ChIP-qPCR analysis of CT215 β-cells. Results: Administration of the ISR enhancer Sephin1 improved glucose metabolism in Akita mice. Sephin1 also increased the insulin-immunopositive area and ATF4 expression in the pancreatic islets. Akita/βAtf4-KO mice exhibited dramatically exacerbated diabetes, shown by hyperglycemia at an early age, as well as a remarkably short lifespan owing to diabetic ketoacidosis. Moreover, the islets of Akita/βAtf4-KO mice presented increased numbers of cells stained for glucagon, somatostatin, and pancreatic polypeptide and increased expression of aldehyde dehydrogenase 1 family member 3, a marker of dedifferentiation. Using microarray analysis, we identified atonal BHLH transcription factor 8 (ATOH8) as a downstream factor of ATF4. Deletion of ATF4 in β-cells showed reduced Atoh8 expression and increased expression of undifferentiated markers, Nanog and Pou5f1. Atoh8 expression was also abolished in the islets of Akita/βAtf4-KO mice. Conclusions: We conclude that transcriptional regulation by ATF4 maintains β-cell identity via ISR modulation. This mechanism provides a promising target for the treatment of diabetes.

【 授权许可】

Unknown