Improving Lipophagy by Restoring Rab7 Cycle: Protective Effects of Quercetin on Ethanol-Induced Liver Steatosis.
Improving Lipophagy by Restoring Rab7 Cycle: Protective Effects of Quercetin on Ethanol-Induced Liver Steatosis.
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通过恢复 Rab7 循环改善脂肪吞噬：槲皮素对乙醇诱导的肝脏脂肪变性的保护作用
DOI：
10.3390/nu14030658
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发表时间：
2022-02-04
期刊：
影响因子：
5.9
通讯作者：
Yao P
中科院分区：
文献类型：
--
作者：
Lin H;Guo X;Liu J;Liu P;Mei G;Li H;Li D;Chen H;Chen L;Zhao Y;Jiang C;Yu Y;Liu W;Yao P
长期饮酒阻碍了脂肪吞噬，这有助于肝脂肪变性的发病机制。脂肪吞噬相关的Rab 7被认为是酒精性肝病进展的关键调节因子，尽管其机制尚不明确。更重要的是，保肝槲皮素是否靶向Rab 7相关的脂肪吞噬障碍尚不清楚。在此，酒精性脂肪肝诱导慢性加单暴饮乙醇喂养雄性C57 BL/6 J小鼠表现为阻碍自噬体形成与脂滴和融合与溶酶体相比，正常对照，这是正常化的部分槲皮素。Rab 7的GST-RILP下拉试验表明，GTP-Rab 7作为乙醇喂养小鼠的槲皮素治疗得到改善。当暴露于乙醇时，转染CYP 2 E1的HepG 2细胞表现出类似的噬脂功能障碍，当预先用siRNA-Rab 7转染细胞时，该功能被阻断。乙醇诱导的脂肪变性和自噬通量破坏被Rab 7特异性抑制剂CID 1067700加重，而被Rab 7 Wt质粒转染减轻，这通过免疫荧光共定位分析和mCherry-GFP-LC 3转染来观察。此外，TBC 1D 5，一个Rab GTP酶激活蛋白，为随后的正常循环Rab 7，下调后，酒精管理，但恢复槲皮素。Rab 7循环被乙醇阻滞并被槲皮素校正，通过光漂白后的荧光恢复（FRAP）进一步揭示。总而言之，槲皮素通过使乙醇引起的Rab 7周转障碍和随后的脂肪吞噬障碍正常化来减弱肝脂肪变性，突出了槲皮素样植物化学物质对抗酒精的关键第一击的新机制和有希望的前景。
Chronic alcohol consumption retards lipophagy, which contributes to the pathogenesis of liver steatosis. Lipophagy-related Rab7 has been presumed as a crucial regulator in the progression of alcohol liver disease despite elusive mechanisms. More importantly, whether or not hepatoprotective quercetin targets Rab7-associated lipophagy disorder is unknown. Herein, alcoholic fatty liver induced by chronic-plus-single-binge ethanol feeding to male C57BL/6J mice was manifested by hampering autophagosomes formation with lipid droplets and fusion with lysosomes compared with the normal control, which was normalized partially by quercetin. The GST-RILP pulldown assay of Rab7 indicated an improved GTP-Rab7 as the quercetin treatment for ethanol-feeding mice. HepG2 cells transfected with CYP2E1 showed similar lipophagy dysfunction when exposed to ethanol, which was blocked when cells were transfected with siRNA-Rab7 in advance. Ethanol-induced steatosis and autophagic flux disruption were aggravated by the Rab7-specific inhibitor CID1067700 while alleviated by transfecting with the Rab7Wt plasmid, which was visualized by immunofluorescence co-localization analysis and mCherry-GFP-LC3 transfection. Furthermore, TBC1D5, a Rab GTPase-activating protein for the subsequent normal circulation of Rab7, was downregulated after alcohol administration but regained by quercetin. Rab7 circulation retarded by ethanol and corrected by quercetin was further revealed by fluorescence recovery after photobleaching (FRAP). Altogether, quercetin attenuates hepatic steatosis by normalizing ethanol-imposed Rab7 turnover disorders and subsequent lipophagy disturbances, highlighting a novel mechanism and the promising prospect of quercetin-like phytochemicals against the crucial first hit from alcohol.
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影响因子：
5.9
作者：
Kim SN;Kwon HJ;Akindehin S;Jeong HW;Lee YH
通讯作者：
Lee YH
DOI：
10.1016/j.cgh.2017.11.045
发表时间：
2018-08
期刊：
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association
影响因子：
--
作者：
Cholankeril G;Ahmed A
通讯作者：
Ahmed A
影响因子：
--
作者：
Costa LG;Garrick JM;Roquè PJ;Pellacani C
通讯作者：
Pellacani C
DOI：
10.1111/j.1530-0277.2012.01742.x
发表时间：
2012-08
期刊：
Alcoholism, clinical and experimental research
影响因子：
--
作者：
Dolganiuc A;Thomes PG;Ding WX;Lemasters JJ;Donohue TM Jr
通讯作者：
Donohue TM Jr
影响因子：
6
作者：
Guerra F;Bucci C
通讯作者：
Bucci C