PMID- 33242093 OWN - NLM STAT- MEDLINE DCOM- 20210617 LR - 20210617 IS - 1745-7270 (Electronic) IS - 1672-9145 (Linking) VI - 53 IP - 1 DP - 2021 Jan 12 TI - 1,25-(OH)2D3 protects pancreatic beta cells against H2O2-induced apoptosis through inhibiting the PERK-ATF4-CHOP pathway. PG - 46-53 LID - 10.1093/abbs/gmaa138 [doi] AB - Endoplasmic reticulum (ER) stress plays a critical role in pancreatic beta cell destruction which leads to the pathogenesis of type 1 diabetes mellitus (T1DM). Vitamin D (VD) has been reported to reduce the risk of T1DM; however, it remains unknown whether VD affects ER stress in pancreatic beta cells. In this study, we investigated the role of the active form of VD, 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3], in ER stress-induced beta cell apoptosis and explored its potential mechanism in mouse insulinoma cell line mouse insulinoma 6 (MIN6). The results of cell counting kit-8 (CCK8) and flow cytometric analyses showed that 1,25-(OH)2D3 caused a significant increase in the viability of MIN6 cells injured by H2O2. The protein kinase like ER kinase (PERK) signal pathway, one of the most conserved branches of ER stress, was found to be involved in this process. H2O2 activated the phosphorylation of PERK, upregulated the activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP) expression, and subsequently initiated cell apoptosis, which were significantly reversed by 1,25-(OH)2D3 pretreatment. In addition, GSK2606414, a specific inhibitor of PERK, suppressed PERK phosphorylation and reduced the expressions of ATF4 and CHOP, leading to a significant decrease in beta cell apoptosis induced by H2O2. Taken together, the present findings firstly demonstrated that 1,25-(OH)2D3 could prevent MIN6 cells against ER stress-associated apoptosis by inhibiting the PERK-ATF4-CHOP pathway. Therefore, our results suggested that 1,25-(OH)2D3 might serve as a potential therapeutic target for preventing pancreatic beta cell destruction in T1DM. CI - (c) The Author(s) 2021. Published by Oxford University Press on behalf of the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. FAU - Hu, Xiaobo AU - Hu X AD - The Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, Department of Biochemistry, Hengyang Medical School, University of South China, Hengyang 421001, China. AD - Department of Biochemistry, Hengyang Medical School, University of South China, Hengyang 421001, China. AD - The Key Laboratory of Typical Environmental Pollution and Health Hazards, University of South China, Hengyang 421001, China. FAU - Hu, Cong AU - Hu C AD - The Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, Department of Biochemistry, Hengyang Medical School, University of South China, Hengyang 421001, China. AD - Department of Biochemistry, Hengyang Medical School, University of South China, Hengyang 421001, China. AD - The Key Laboratory of Typical Environmental Pollution and Health Hazards, University of South China, Hengyang 421001, China. FAU - Liu, Jun AU - Liu J AD - The Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, Department of Biochemistry, Hengyang Medical School, University of South China, Hengyang 421001, China. AD - Department of Biochemistry, Hengyang Medical School, University of South China, Hengyang 421001, China. FAU - Wu, Zhuan AU - Wu Z AD - The Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, Department of Biochemistry, Hengyang Medical School, University of South China, Hengyang 421001, China. AD - Department of Biochemistry, Hengyang Medical School, University of South China, Hengyang 421001, China. AD - The Key Laboratory of Typical Environmental Pollution and Health Hazards, University of South China, Hengyang 421001, China. FAU - Duan, Tingting AU - Duan T AD - The Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, Department of Biochemistry, Hengyang Medical School, University of South China, Hengyang 421001, China. AD - Department of Biochemistry, Hengyang Medical School, University of South China, Hengyang 421001, China. AD - The Key Laboratory of Typical Environmental Pollution and Health Hazards, University of South China, Hengyang 421001, China. FAU - Cao, Zhaohui AU - Cao Z AD - The Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, Department of Biochemistry, Hengyang Medical School, University of South China, Hengyang 421001, China. AD - Department of Biochemistry, Hengyang Medical School, University of South China, Hengyang 421001, China. AD - The Key Laboratory of Typical Environmental Pollution and Health Hazards, University of South China, Hengyang 421001, China. LA - eng PT - Journal Article PL - China TA - Acta Biochim Biophys Sin (Shanghai) JT - Acta biochimica et biophysica Sinica JID - 101206716 RN - 0 (7-methyl-5-(1-((3-(trifluoromethyl)phenyl)acetyl)-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo(2,3-d)pyrimidin-4-amine) RN - 0 (Atf4 protein, mouse) RN - 0 (Ddit3 protein, mouse) RN - 0 (Indoles) RN - 0 (Protective Agents) RN - 145891-90-3 (Activating Transcription Factor 4) RN - 147336-12-7 (Transcription Factor CHOP) RN - BBX060AN9V (Hydrogen Peroxide) RN - EC 2.7.11.1 (PERK kinase) RN - EC 2.7.11.1 (eIF-2 Kinase) RN - FXC9231JVH (Calcitriol) RN - JAC85A2161 (Adenine) SB - IM MH - Activating Transcription Factor 4/*antagonists & inhibitors MH - Adenine/analogs & derivatives/pharmacology MH - Animals MH - Apoptosis/drug effects MH - Calcitriol/*pharmacology MH - Cell Line MH - Cell Survival/drug effects MH - Diabetes Mellitus, Type 1/drug therapy/metabolism MH - Endoplasmic Reticulum Stress/drug effects MH - Hydrogen Peroxide/toxicity MH - Indoles/pharmacology MH - Insulin-Secreting Cells/cytology/*drug effects MH - Mice MH - Protective Agents/*pharmacology MH - Signal Transduction/*drug effects MH - Transcription Factor CHOP/*antagonists & inhibitors MH - eIF-2 Kinase/*antagonists & inhibitors OTO - NOTNLM OT - 1,25-(OH)2D3 OT - MIN6 cells OT - PERK OT - diabetes OT - endoplasmic reticulum stress EDAT- 2020/11/27 06:00 MHDA- 2021/06/22 06:00 CRDT- 2020/11/26 12:08 PHST- 2020/04/29 00:00 [received] PHST- 2020/11/27 06:00 [pubmed] PHST- 2021/06/22 06:00 [medline] PHST- 2020/11/26 12:08 [entrez] AID - 6006719 [pii] AID - 10.1093/abbs/gmaa138 [doi] PST - ppublish SO - Acta Biochim Biophys Sin (Shanghai). 2021 Jan 12;53(1):46-53. doi: 10.1093/abbs/gmaa138.