Department of Clinical Laboratory, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, 050000, People's Republic of China.
Department of Electron Microscope Laboratory, Hebei Medical University, Shijiazhuang, 050017, People's Republic of China.
Pflugers Arch. 2023 Nov;475(11):1251-1263. doi: 10.1007/s00424-023-02860-6. Epub 2023 Sep 25.
Studies have confirmed that hepatic iron overload is one of the important factors causing liver damage in the metabolic syndrome (MS). As a special form of autophagy, ferritinophagy is involved in the regulation of iron metabolism. Our previous studies have shown that chronic intermittent hypobaric hypoxia (CIHH) can improve the iron metabolism disorder. The aim of this study was to investigate how CIHH improves liver damage through ferritinophagy in MS rats. Male Sprague-Dawley rats aged 8-10 weeks were randomly divided into four groups: control (CON), CIHH (exposed to hypoxia at a simulated altitude of 5000 m for 28 days, 6 h daily), MS model (induced by a 16-week high-fat diet and 10% fructose water feeding), and MS + CIHH (exposed to CIHH after a 16-week MS inducement) groups. Liver index, liver function, iron content, tissue morphology, oxidative stress, ferritinophagy, ferroptosis, and iron metabolism-related protein expression were measured, and the ferritinophagy flux in the liver was further analyzed. Compared with CON rats, MS rats had an increased liver index, damaged liver tissue and function, increased iron content and iron deposition, disrupted iron metabolism, significantly increased oxidative stress indicators in the liver, significantly upregulated expression of ferroptosis-related proteins, and downregulated expression of nuclear receptor coactivator 4 (NCOA4) and ferritinophagy flux. After CIHH treatment, the degree of liver damage and various abnormal indicators in MS rats were significantly improved. CIHH may improve liver damage by promoting NCOA4-mediated ferritinophagy, reducing iron overload and oxidative stress, and thereby alleviating ferroptosis in MS rats.
研究证实，肝铁过载是代谢综合征（MS）引起肝损伤的重要因素之一。作为自噬的特殊形式，铁蛋白自噬参与铁代谢的调节。我们之前的研究表明，慢性间歇性低氧（CIHH）可改善铁代谢紊乱。本研究旨在探讨 CIHH 如何通过 MS 大鼠的铁蛋白自噬来改善肝损伤。8-10 周龄雄性 Sprague-Dawley 大鼠随机分为 4 组：对照组（CON）、CIHH 组（5000m 模拟海拔缺氧 28 天，每天 6 小时）、MS 模型组（16 周高脂饮食和 10%果糖水喂养）和 MS+CIHH 组（16 周 MS 诱导后暴露于 CIHH）。测量肝指数、肝功能、铁含量、组织形态、氧化应激、铁蛋白自噬、铁死亡、铁代谢相关蛋白表达，并进一步分析肝脏中铁蛋白自噬通量。与 CON 大鼠相比，MS 大鼠肝指数增加，肝组织和功能受损，铁含量和铁沉积增加，铁代谢紊乱，肝氧化应激指标显著增加，铁死亡相关蛋白表达显著上调，核受体共激活因子 4（NCOA4）和铁蛋白自噬通量表达下调。CIHH 治疗后，MS 大鼠的肝损伤程度和各种异常指标均明显改善。CIHH 可能通过促进 NCOA4 介导的铁蛋白自噬，减少铁过载和氧化应激，从而减轻 MS 大鼠的铁死亡，改善肝损伤。
