Geriatric Department of Endocrinology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
Department of Nephrology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
Cell Biochem Biophys. 2024 Sep;82(3):2079-2094. doi: 10.1007/s12013-024-01315-8. Epub 2024 May 27.
Recent studies showed that patients with iron overload had increased risk of insulin resistance or diabetes. Ferroptosis is a new type of cell death mainly caused by iron-dependent oxidative damage. In the present study, we investigated potential mechanisms of iron overload induced hepatic ferroptosis and insulin resistance through in vivo and in vitro experiments. In vivo, the mice models of iron overload were established by intraperitoneal injection of iron dextran. The changes of body weight, serum ferritin and blood glucose were measured. Hematoxylin-eosin (HE) and Perl's stainings were used to observe the pathological changes and iron deposition in the liver of mice. In vitro, HepG2 cells were treated with ferric ammonium citrate (FAC, 9 mmol/L, 24 h) to establish the cell models of iron overload. The labile iron pool, cell viability, glucose consumption and glycogen contents were measured. The ultrastructure of mitochondria was observed by transmission electron microscope (TEM). The malondialdehyde (MDA) and glutathione (GSH) kits were used to detect lipid peroxidation in liver tissues of mice and HepG2 cells. RT-PCR and Western blot were used to detect the mRNA and protein expression levels of ferroptosis factors and JAK2/STAT3 signaling pathway. In this study, we used the iron chelator deferasirox in mice and HepG2 cells. Iron overload caused weight loss, elevated serum ferritin, fasting blood glucose, fasting insulin, HOMA-IR, impaired glucose tolerance, and decreased insulin sensitivity in mice. HE staining and Perls staining showed clumps of iron deposition in the liver of iron overload mice. Iron overload could reduce the glucose consumption, increase MDA contents of HepG2 cells, while reduce glycogen and GSH contents in liver tissues of mice and HepG2 cells. TEM showed deletion of mitochondrial ridge and rupture of outer membrane in HepG2 cells with iron overload. Iron chelator deferasirox could significantly improve the above indicators, which might be related to the activation of JAK2/STAT3/SLC7A11 signaling pathway and hepatic ferroptosis. Iron overload could induce hepatic ferroptosis and insulin resistance by inhibiting the JAK2/STAT3/SLC7A11 signaling pathway, and the iron chelator deferasirox might improve hepatic insulin resistance induced by iron overload.
最近的研究表明，铁过载患者发生胰岛素抵抗或糖尿病的风险增加。铁死亡是一种主要由铁依赖性氧化损伤引起的新型细胞死亡。本研究通过体内和体外实验研究铁过载诱导的肝铁死亡和胰岛素抵抗的潜在机制。在体内，通过腹腔注射右旋糖酐铁建立铁过载小鼠模型。测量体重、血清铁蛋白和血糖的变化。苏木精-伊红（HE）和 Perl 染色观察小鼠肝脏的病理变化和铁沉积。在体外，用三氯化铁铵（FAC，9mmol/L，24h）处理 HepG2 细胞建立铁过载细胞模型。测量不稳定铁池、细胞活力、葡萄糖消耗和肝糖原含量。用透射电子显微镜（TEM）观察线粒体超微结构。用丙二醛（MDA）和谷胱甘肽（GSH）试剂盒检测小鼠肝组织和 HepG2 细胞的脂质过氧化。用 RT-PCR 和 Western blot 检测铁死亡相关因子和 JAK2/STAT3 信号通路的 mRNA 和蛋白表达水平。本研究在小鼠和 HepG2 细胞中使用铁螯合剂地拉罗司。铁过载导致小鼠体重减轻、血清铁蛋白、空腹血糖、空腹胰岛素、HOMA-IR 升高、糖耐量受损和胰岛素敏感性降低。HE 染色和 Perls 染色显示铁过载小鼠肝脏铁沉积呈团块状。铁过载可降低 HepG2 细胞葡萄糖消耗，增加 MDA 含量，同时降低小鼠肝组织和 HepG2 细胞中糖原和 GSH 含量。TEM 显示铁过载 HepG2 细胞中线粒体嵴缺失和外膜破裂。铁螯合剂地拉罗司可显著改善上述指标，这可能与 JAK2/STAT3/SLC7A11 信号通路的激活和肝铁死亡有关。铁过载可能通过抑制 JAK2/STAT3/SLC7A11 信号通路诱导肝铁死亡和胰岛素抵抗，铁螯合剂地拉罗司可能改善铁过载引起的肝胰岛素抵抗。
