Formononetin ameliorates cholestasis by regulating hepatic SIRT1 and PPAR alpha
Formononetin ameliorates cholestasis by regulating hepatic SIRT1 and PPAR alpha
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芒柄花素通过调节肝脏 SIRT1 和 PPAR α 改善胆汁淤积
DOI：
10.1016/j.bbrc.2019.03.131
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发表时间：
2019
影响因子：
3.1
通讯作者：
Ma Chuanrui
中科院分区：
文献类型：
--
作者：
Yang Shu;Wei Lingling;Xia Ronglin;Liu Lipei;Chen Yuanli;Zhang Wenwen;Li Qi;Feng Ke;Yu Miao;Zhang Wei;Qu Jingtian;Xu Shixin;Mao Jingyuan;Fan Guanwei;Ma Chuanrui
以肝细胞内胆汁酸（BA）过载为特征的胆汁淤积是肝损伤的主要原因。胆汁酸稳态的失调，如胆汁酸合成过量和分泌缺陷，导致疏水性胆汁酸在细胞内滞留，从而破坏肝细胞的生理功能。胆汁淤积可进一步发展为肝纤维化和肝硬化，并最终危及生命的肝功能衰竭。在肝脏中，BA激活的FXR可以通过负反馈调节降低肝脏BA浓度。临床上，FXR和PPARα分别是奥贝胆酸和非诺贝特治疗原发性胆汁性肝硬化的药理学靶点。芒柄花素是一种天然的黄酮类化合物，具有抗炎、抗肿瘤等多种生物学作用。然而，芒柄花素在胆汁酸代谢中的作用仍不清楚。在此，我们发现芒柄花素改善肝脏/全身胆汁酸代谢，并保护抗ANIT诱导的肝损伤。芒柄花素通过调节SIRT 1-FXR信号通路改善胆汁酸稳态的基因谱。此外，芒柄花素通过抑制JNK炎症通路抑制ANIT诱导的炎症反应。综上所述，我们的研究表明芒柄花素通过上调SIRT 1的表达和激活PPARα来改善肝胆汁淤积，这是芒柄花素抗胆汁淤积的重要机制。
Cholestasis, which is characterized by bile acid (BA) overload within the hepatocytes, is a major contributor to liver injury. The dysregulation of bile acid homeostasis, such as excessive bile acid synthesis and defected secretion, leads to intracellular retention of hydrophobic bile acid which undermines the physiological function of hepatocytes. Cholestasis can further develop into hepatic fibrosis and cirrhosis, and eventually life-threating liver failure. In the liver, BA-activated FXR can reduce hepatic BA concentration by negative feedback regulation. Clinically, FXR and PPARα are the pharmacological targets of obeticholic acid and fenofibrate for the treatment of primary biliary cirrhosis, respectively. Formononetin, a natural isoflavone compound, exerts beneficial effects in various biological processes, such as anti-inflammation, anti-tumor. However, the role of formononetin in bile acid metabolism remains unclear. Herein, we show that formononetin improves hepatic/systemic bile acid metabolism and protects against ANIT-induced liver injury. Mechanistically, formononetin improves the genes profile orchestrating bile acid homeostasis through modulating SIRT1-FXR signaling pathway. Moreover, formononetin attenuated ANIT-induced inflammatory response by inactivating JNK inflammation pathway in PPARα dependent manner. Taken together, our study demonstrates that formononetin ameliorates hepatic cholestasis by upregulating expression of SIRT1 and activating PPARα, which is an important anti-cholestatic mechanism of formononetin.