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Nerve growth factor induced farnesoid X receptor upregulation modulates autophagy flux and protects hepatocytes in cholestatic livers.
Archives of Biochemistry and Biophysics ( IF 3.9 ) Pub Date : 2020-01-27 , DOI: 10.1016/j.abb.2020.108281
Ming-Shian Tsai , Hui-Ming Lee , Shih-Che Huang , Cheuk-Kwan Sun , Ting-Chia Chiu , Po-Han Chen , Yu-Chun Lin , Tzu-Min Hung , Po-Huang Lee , Ying-Hsien Kao

Upregulation of nerve growth factor (NGF) in parenchymal hepatocytes has been shown to exert hepatoprotective function during cholestatic liver injury. However, the modulatory role of NGF in regulation of liver autophagy remains unclear. This study aimed to scrutinize the regulatory role of NGF in hepatic expression of farnesoid X receptor (FXR), a bile acid (BA)-activated nuclear receptor, and to determine its cytoprotective effect on BA-induced autophagy and cytotoxicity. Livers of human hepatolithiasis and bile duct ligation (BDL)-induced mouse cholestasis were used for histopathological and molecular detection. The regulatory roles of NGF in autophagy flux and FXR expression, as well as its hepatoprotection against BA cytotoxicity were examined in cultured hepatocytes. FXR downregulation in human hepatolithiasis livers showed positive correlation with hepatic NGF levels. NGF administration upregulated hepatic FXR levels, while neutralization of NGF decreased FXR expression in BDL-induced cholestatic mouse livers. In vitro studies demonstrated that NGF upregulated FXR expression, increased cellular LC3 levels, and exerted hepatoprotective effect in cultured primary rat hepatocytes. Conversely, autophagy inhibition abrogated NGF-driven cytoprotection under BA exposure, suggesting involvement of NGF-modulated auophagy flux. Although FXR agonistic GW4064 stimulation did not affect auophagic LC3 levels, FXR activity inhibition significantly potentiated BA-induced cytotoxicity and increased cellular p62/SQSTM1 and Rab7 protein in SK-Hep1 hepatocytes. Moreover, FXR gene silencing abolished the protective effect of NGF under BA exposure. These findings support that NGF modulates autophagy flux via FXR upregulation and protects hepatocytes against BA-induced cytotoxicity. NGF/FXR axis is a novel therapeutic target for treatment of cholestatic liver diseases.



中文翻译:

神经生长因子诱导的法呢类X受体上调调节自噬通量并保护胆汁淤积性肝中的肝细胞。

研究表明,在胆汁淤积性肝损伤中,实质肝细胞中神经生长因子(NGF)的上调具有肝保护功能。但是,NGF在调节肝脏自噬中的调节作用尚不清楚。这项研究旨在详细研究NGF在法尼醇X​​受体(FXR),胆汁酸(BA)激活的核受体的肝表达中的调节作用,并确定其对BA诱导的自噬和细胞毒性的细胞保护作用。人类肝结石和胆管结扎(BDL)诱导的小鼠胆汁淤积的肝脏用于组织病理学和分子检测。在培养的肝细胞中检查了NGF在自噬通量和FXR表达中的调节作用,以及它对BA细胞毒性的肝保护作用。人肝结石病肝脏中的FXR下调与肝脏NGF水平呈正相关。NGF的施用上调了肝FXR的水平,而NGF的中和降低了BDL诱导的胆汁淤积小鼠肝脏中FXR的表达。体外研究表明,NGF在培养的原代大鼠肝细胞中上调FXR表达,增加细胞LC3水平并发挥保肝作用。相反,在BA暴露下自噬抑制作用取消了NGF驱动的细胞保护作用,提示NGF调节的自噬通量参与其中。尽管FXR激动剂GW4064刺激不影响自噬LC3水平,但FXR活性抑制显着增强了BA诱导的细胞毒性,并增加了SK-Hep1肝细胞中的细胞p62 / SQSTM1和Rab7蛋白。此外,FXR基因沉默消除了在BA暴露下NGF的保护作用。这些发现支持NGF通过FXR上调来调节自噬通量,并保护肝细胞免受BA诱导的细胞毒性作用。NGF / FXR轴是用于治疗胆汁淤积性肝病的新型治疗靶标。

更新日期:2020-01-27
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