Abstract
Pancreatic β cells death is a major factor driving the deterioration of glucose control in type 2 diabetes mellitus (T2DM). Ferroptosis is a non-apoptotic form of lipid peroxidation-induced cell death. The long-chain acyl-CoA synthetase 4 (ACSL4) contributes significantly to lipid metabolism and determines ferroptosis sensitivity. Accounting for still limited understanding of lipotoxicity-related ferroptosis in β cells, we aim to identify pancreatic β cells ferroptosis in lipotoxicity-induced diabetes and the role of ACSL4 plays in this process. In this study, we found that fatty acids could induce apoptosis in pancreatic β cells, along with a new form of death called ferroptosis. Pancreatic islets of 16-week HFD-fed mice showed reduced mitochondrial cristae, decreased mitochondrial cristae, and increased bilayer membrane density compared to LFD-fed mice. Iron fluorescence staining showed increased intracellular Fe2+ levels in pancreatic islets. Ferroptosis inhibitor fer-1 had a specific protective effect of on HFD-induced β-cell ferroptosis. Through using the Cre-LoxP system, we performed a ACSL4 knockout model of the HFD-induced metabolic diseases, we found that lipid metabolism dictates ferroptosis in pancreatic β cells through ACSL4, which appear to be related to pancreatic β cells dysfunction. ACSL4 knockdown attenuated fatty acids-induced ferroptosis in pancreatic β cells in vivo and in vitro. ACSL4 overexpression induces ferroptosis in MIN6 cells. Moreover, we observed that troglitazone attenuated AA, DHA, PA and erastin induced ferroptosis in MIN6 cells. These results together provide definitive evidence linking β cells with lipotoxicity-induced ferroptosis and suggest the anti-ferroptosis effect of ACSL4 may be a new therapeutic target for the targeted therapy of T2DM. Disclosure M. Zhang: None. L. Qin: None. Y. Qin: None. Q. Wei: None. X. Chen: None. Funding National Natural Science Foundation of China (81974103)
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