安普克
肠道菌群
瓜氨酸
化学
新陈代谢
细胞生物学
生物
生物化学
精氨酸
酶
蛋白激酶A
氨基酸
作者
Donglin Zhao,Yuan Gao,Yiqin Chen,Yingsi Zhang,Yian Deng,Sai Niu,Hui Dai
标识
DOI:10.1002/mnfr.202300723
摘要
Scope Oxidative stress caused by iron overload tends to result in intestinal mucosal barrier dysfunction and intestinal microbiota imbalance. As a neutral and nonprotein amino acid, L‐Citrulline (L‐cit) has been implicated in antioxidant and mitochondrial amelioration properties. This study investigates whether L‐cit can alleviate iron overload‐induced intestinal injury and explores the underlying mechanisms. Methods and results C57BL/6J mice are intraperitoneally injected with iron dextran, then gavaged with different dose of L‐cit for 2 weeks. L‐cit treatment significantly alleviates intestine pathological injury, oxidative stress, ATP level, and mitochondrial respiratory chain complex activities, accompanied by ameliorating mitochondrial quality control. L‐cit‐mediated protection is associated with the upregulation of Glutathione Peroxidase 4 (GPX4) expression, inhibition Nuclear Receptor Coactivator 4 (NCOA4)‐mediated ferritinophagy and ferroptosis, and improvement of gut microbiota. To investigate the underlying molecular mechanisms, Intestinal Porcine Epithelial Cell line‐J2 (IPEC‐J2) cells are treated with L‐cit or AMP‐activated Protein Kinase (AMPK) inhibitor. AMPK signaling has been activated by L‐cit. Notably, Compound C abolishes L‐cit's protection on intestinal barrier, mitochondrial function, and antioxidative capacity in IPEC‐J2 cells. Conclusion L‐cit may restrain ferritinophagy and ferroptosis to regulate iron metabolism, and induce AMPK pathway activation, which contributes to exert antioxidation, ameliorate iron metabolism and mitochondrial quality control, and improve intestinal microbiota. L‐cit is a promising therapeutic strategy for iron overload‐induced intestinal injury.
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