肝细胞HIF-2α通过通过增加细胞外铁来诱导铁,从而加剧NAFLD
Shunkui Luo1, Zhanjin Lu1, Lingling Wang2
1Department of Endocrinology & Metabolism, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China.
American journal of physiology. Endocrinology and metabolism
|December 16, 2024
概括
缺氧诱导因子-2α (HIF-2α) 通过改变铁的分布,增加铁亡的易感性,并促进脂质积累,使非酒精性脂肪性肝病 (NAFLD) 恶化. 通过使用deferoxamine (DFO) 降低细胞外铁可以逆转这些效应.
科学领域:
- 肝病学和代谢疾病
- 分子生物学和遗传学分子生物学和遗传学
- 细胞生理学 细胞生理学
背景情况:
- 缺氧诱导因子-2α (HIF-2α) / Peroxisome Proliferator-activated Receptor Alpha (PPARα) 途径与非酒精性脂肪肝疾病 (NAFLD) 的进展有关.
- HIF-2α在铁调节中的作用及其与肝脂发生的联系表明NAFLD恶化的潜在机制.
研究的目的:
- 为了研究HIF-2α通过影响铁的分布而加剧脂肪肝的假设.
- 阐明HIF-2α在铁流,铁和NAFLD中脂质代谢中的作用.
主要方法:
- 使用肝脏特定的HIF-2α淘汰赛小鼠和具有过度表达HIF-2α的LO2细胞.
- 通过lentiviral感染诱导的HIF-2α过度表达 (OE),随后暴露于自由脂肪酸 (FFAs) 和deferoxamine (DFO).
- 进行了基因和基因组京都百科全书 (KEGG) 途径分析.
主要成果:
- 肝脏HIF-2α淘汰赛减少了肝脏脂质和体重,同时增加了血清铁.
- 在LO2细胞中HIF-2α的过度表达增加了细胞外铁,并且在暴露于FFA时,诱导了铁亡标志物 (减少GSH/GPX4,增加LPO) 和脂质积累.
- DFO治疗逆转了这些影响,减少了铁,增加了GSH/GPX4,降低了LPO,并改善了脂质沉积,可能是通过PI3K/AKT途径.
结论:
- HIF-2α介导的铁流增加了NAFLD细胞对铁亡的敏感性,影响了脂质代谢和积累.
- 向铁调节为NAFLD提供了一个潜在的治疗策略.
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