Nfe2l1 deficiency mitigates streptozotocin-induced pancreatic β-cell destruction and development of diabetes in male mice. (December 2021)

• Record Type: Journal Article
• Authors: Bao, Simeng; Zheng, Hongzhi; Chen, Chengjie; Zhang, Yuhang; Bao, Lina; Yang, Bei; Hou, Yongyong; Chen, Yanyan; Zhang, Qiang; Pi, Jingbo; Fu, Jingqi
• Is Part Of: Food and chemical toxicology. Volume 158(2021)
• Publication Date: 2021-12
• Subjects: NFE2L1 -- Streptozotocin -- Pancreatic β-cell damage -- Islets -- Glycolysis; Toxicology -- Periodicals; Food poisoning -- Periodicals; Food Poisoning -- Periodicals; Toxicology -- Periodicals; Toxicologie -- Périodiques; Intoxications alimentaires -- Périodiques; Food poisoning; Toxicology; Periodicals; Electronic journals; 615.9
• DOI: 10.1016/j.fct.2021.112633
• Languages: English
• ISSNs: 0278-6915

Abstract

Abstract: Streptozotocin (STZ) is a pancreatic β cell-specific toxicant that is widely used to generate models of diabetes in rodents as well as in the treatment of tumors derived from pancreatic β cells. DNA alkylation, oxidative stress and mitochondrial toxicity have been recognized as the mechanisms for STZ-induced pancreatic β cell damage. Here, we found that pancreatic β cell-specific deficiency of nuclear factor erythroid-derived factor 2-related factor 1 (NFE2L1), a master regulator of the cellular adaptive response to a variety of stresses, in mice led to a dramatic resistance to STZ-induced hyperglycemia. Indeed, fifteen days subsequent to last dosage of STZ, the pancreatic β cell specific Nfe2l1 knockout [ Nfe2l1 (β)-KO] mice showed reduced hyperglycemia, improved glucose tolerance, higher plasma insulin and more intact islets surrounded by exocrine acini compared to the Nfe2l1 -Flox control mice with the same treatment. Immunohistochemistry staining revealed a greater amount of insulin-positive cells in the pancreas of Nfe2l1 (β)-KO mice than those in Nfe2l1 -Flox mice 15 days after the last STZ injection. In line with this observation, both isolated Nfe2l1 (β)-KO islets and Nfe2l1 -deficient MIN6 ( Nfe2l1 -KD) cells were resistant to STZ-induced toxicity and apoptosis. Furthermore, pretreatment of the MIN6 cells with glycolysis inhibitor 2-Deoxyglucose sensitized Nfe2l1 -KD cells to STZ-induced toxicity. These findings demonstrated that loss of Nfe2l1 attenuates pancreatic β cells damage and dysfunction caused by STZ exposure, partially due to Nfe2l1 deficiency-induced metabolic switch to enhanced glycolysis.