Iron overload induces islet β cell ferroptosis by activating ASK1/P-P38/CHOP signaling pathway

PeerJ

article

Ling Deng¹  Man-Qiu Mo²  Jinling Zhong¹  Zhengming Li³  Guoqiao Li¹  Yuzhen Liang¹ 

[1] Department of Endocrinology, The Second Affiliated Hospital of Guangxi Medical University;Department of Geriatric Endocrinology and Metabolism, The First Affiliated Hospital of Guangxi Medical University;Department of Endocrinology, People’s Hospital of Guangxi Zhuang Autonomous Region

关键词: Iron overload;    Ferroptosis;    Type 2 diabetes;    Deferasirox;    Pancreatic β-cell function;    Lipid peroxidation;    Endoplasmic reticulum stress;   

DOI  :  10.7717/peerj.15206

学科分类：社会科学、人文和艺术（综合）

来源: Inra

【 摘 要 】

Background Recent studies have shown that the accumulation of free iron and lipid peroxides will trigger a new form of cell death—ferroptosis. This form of cell death is associated with a variety of diseases, including type 2 diabetes. We hypothesize that iron overload may play a role in driving glucose metabolism abnormalities by inducing endoplasmic reticulum stress that mediates ferroptosis in islet β cells. In this study, we tested this conjecture from in vivo and in vitro experiments. Methods We established a mouse iron overload model by intraperitoneal injection of iron dextrose (50 mg/kg) and an iron overload cell model by treating MIN6 cells with ferric ammonium citrate (640 μmol/L, 48 h) in vitro. The iron deposition in pancreatic tissue was observed by Prussian blue staining, and the pathological changes in pancreatic tissues by HE staining and the protein expression level by pancreatic immunohistochemistry. In the cellular experiments, we detected the cell viability by CCK8 and observed the cellular ultrastructure by transmission electron microscopy. We also used MDA and ROS kits to detect the level of oxidative stress and lipid peroxidation in cells. Western blotting was performed to detect the expression levels of target proteins. Results Iron overload induces MIN6 cell dysfunction, leading to increased fasting blood glucose, impaired glucose tolerance, and significantly decreased insulin sensitivity in mice. This process may be related to the ferroptosis of islet β cells and the activation of ASK1/P-P38/CHOP signaling pathway.

【 授权许可】

CC BY