9-cis-retinoic acid elevates MRP3 expression by inhibiting sumoylation of RXR alpha to alleviate cholestatic liver injury
9-cis-retinoic acid elevates MRP3 expression by inhibiting sumoylation of RXR alpha to alleviate cholestatic liver injury
复制标题
9-顺式视黄酸通过抑制 RXR α 的苏酰化来提高 MRP3 表达，减轻胆汁淤积性肝损伤
DOI：
10.1016/j.bbrc.2018.06.001
复制
发表时间：
2018
影响因子：
3.1
通讯作者：
Li Kewei
中科院分区：
文献类型：
--
作者：
Yuan Zhiqing;Wang Guiyang;Qu Junwen;Wang Xiaopeng;Li Kewei
维生素A及其代谢产物已被发现对胆汁淤积性肝损伤具有保护作用，但胆汁淤积性肝损伤的确切机制尚不清楚。本研究旨在探讨维生素A代谢产物9-顺式维甲酸（9-cis-retinoic acid，9-cis-retinoic acid）在胆汁淤积性肝损伤中的作用及其机制。对照组和实验组进行肝功能和组织学检查。通过qRT-PCR、Western blotting和IHC检测肝组织中MRP 3的表达。在细胞水平上研究RXRα类小泛素化对MRP 3表达的影响。结果9-cis-维甲酸可显著降低BDL-小鼠血清ALT和AST水平，减轻肝细胞坏死。我们还发现，MRP 3，一个重要的保护性肝胆转运胆汁淤积，提高9-顺式维甲酸在体内和体外。9-顺式维甲酸减弱了RXRα的SUMO化，促进了RXRα的胞浆定位，减轻了RXRα与RARα的相互作用。结论9-顺式维甲酸可能通过抑制RXRα的SUMO化，提高MRP 3的表达，从而减轻胆汁淤积性肝损伤。
AimsVitamin A and its metabolites has been found to be protective against cholestatic liver injury, but the exact underlying mechanisms involved in cholestatic liver injury remain unclear. The objective of this study was to determine the function and mechanisms of 9-cis-retinoic acid, the metabolite of vitamin A, in cholestatic liver injury.MethodsThe bile duct ligated (BDL) mice were treated with 9-cis-retinoic acid by intravenous injection through the tail for 10 days. The liver function and histology were assessed in the matched group and experimental group. The expression of MRP3 in liver tissue was tested by qRT-PCR, Western blotting, and IHC. Effect of RXRα sumoylation on MRP3 expression was investigated at a cellular level. Influence of 9-cis-retinoic acid on RXRα sumoylation was also tested in cells.ResultsOur findings showed that 9-cis-retinoic acid significantly decreases the serum ALT and AST level, alleviates hepatic necrosis of the BDL-mice. We also identified MRP3, an important protective hepatobiliary transporter in cholestasis, was elevated by 9-cis-retinoic acidin vivoandin vitro. 9-cis-retinoic acid weakened the sumoylation of RXRα, which promotes the cytoplasmic location of RXRα and lightens the interaction of RXRα and RARα. Inhibition of RXRα and RARα interaction increased MRP3 expression.Conclusions9-cis-retinoic acid alleviates cholestatic liver injury by elevating MRP3 expression through its mechanism of inhibiting sumoylation of RXRα.