Iron-frataxin involved in the protective effect of quercetin against alcohol-induced liver mitochondrial dysfunction
Iron-frataxin involved in the protective effect of quercetin against alcohol-induced liver mitochondrial dysfunction
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铁-frataxin参与槲皮素对酒精诱导的肝线粒体功能障碍的保护作用
DOI：
10.1016/j.jnutbio.2022.109258
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发表时间：
2023-02-06
影响因子：
5.6
通讯作者：
Tang，Yuhan
中科院分区：
文献类型：
--
作者：
Liu，Jingjing;Chen，Huimin;Tang，Yuhan
新出现的证据支持了槲皮素对肝脏线粒体疾病的有益作用。然而，槲皮素保护线粒体的分子机制是有限的，特别是在酒精性肝病中。在这项研究中，C57BL/6N小鼠以Lieber de Carli液体饲料(28%乙醇衍生卡路里)和单次狂饮乙醇喂养12周，并用槲皮素(100 mg/kg.bw)进行干预。用乙醇(100 MM)和槲皮素(50µM)刺激细胞，观察线粒体蛋白Frataxin对细胞增殖的影响。结果表明，槲皮素可减轻酒精所致小鼠肝脏的组织病理学改变和线粒体功能紊乱。与PINK1、Parkin、Bnip3和LC3II表达增加、p62、TOM20和VDAC1表达降低一致，乙醇对有丝分裂吞噬的抑制作用可被Quercetin阻断。此外，Quercetin改善了酒精喂养的小鼠肝脏中铁代谢相关蛋白表达的失衡。与乙醇处理的Lv空细胞相比，Frataxin缺乏进一步加重了线粒体功能的抑制。相反，恢复Frataxin的表达可以改善乙醇的效果。此外，Frataxin缺乏降低了Quercetin对乙醇所致线粒体紊乱的保护作用。值得注意的是，柠檬酸铁铵(FAC)和去铁酮分别降低或增加了Frataxin在HepG2CYP2E1+/+细胞中的表达。值得注意的是，我们进一步发现FAC逆转了Quercetin对Frataxin表达的增强作用。最终，沉默NCOA4可减弱Quercetin对LDH释放和线粒体膜电位升高的抑制作用，而加入FAC也有类似的结果。综上所述，这些发现表明，栎素通过调节铁水平增加Frataxin的表达，从而减轻乙醇诱导的线粒体功能障碍。
Emerging evidence supports the beneficial effect of quercetin on liver mitochondrial disorders. However, the molecular mechanism by which quercetin protects mitochondria is limited, especially in alcoholic liver disease. In this study, C57BL/6N mice were fed with Lieber De Carli liquid diet (28% ethanol-derived calories) for 12 weeks plus a single binge ethanol and intervened with quercetin (100 mg/kg.bw). Moreover, HepG2CYP2E1+/+were stimulated with ethanol (100 mM) and quercetin (50 µM) to investigate the effects of mitochondrial protein frataxin. The results indicated that quercetin alleviated alcohol-induced histopathological changes and mitochondrial functional disorders in mice livers. Consistent with increased PINK1, Parkin, Bnip3 and LC3II as well as decreased p62, TOM20 and VDAC1 expression, the inhibition of mitophagy by ethanol was blocked by quercetin. Additionally, quercetin improved the imbalance of iron metabolism-related proteins expression in alcohol-fed mice livers. Compared with ethanol-treated Lv-empty HepG2CYP2E1+/+cells, frataxin deficiency further exacerbated the inhibition of mitochondrial function. Conversely, restoration of frataxin expression ameliorated the effect of ethanol. Furthermore, frataxin deficiency reduced the protective effects of quercetin on mitochondria disordered by ethanol. Attentively, ferric ammonium citrate (FAC) and deferiprone decreased or increased frataxin expression in HepG2CYP2E1+/+, respectively. Notably, we further found FAC reversed the increasing effect of quercetin on frataxin expression. Ultimately, silencing NCOA4 attenuated the inhibition of quercetin on LDH release and mitochondrial membrane potential increase, and similar results were observed by adding FAC. Collectively, these findings demonstrated quercetin increased frataxin expression through regulating iron level, thereby mitigating ethanol-induced mitochondrial dysfunction.