Formononetin ameliorates cholestasis by regulating hepatic SIRT1 and PPAR alpha

文献类型： 外文期刊

第一作者： Yang, Shu

作者： Yang, Shu;Qu, Jingtian;Xu, Shixin;Mao, Jingyuan;Fan, Guanwei;Ma, Chuanrui;Yang, Shu;Liu, Lipei;Li, Qi;Feng, Ke;Zhang, Wei;Fan, Guanwei;Ma, Chuanrui;Chen, Yuanli;Wei, Lingling;Fan, Guanwei;Xia, Ronglin;Yu, Miao;Zhang, Wenwen

作者机构：

关键词： Formononetin; SIRT1; PPAR alpha; Hepatic cholestasis

期刊名称：BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS （ 影响因子：3.575； 五年影响因子：3.381 ）

ISSN： 0006-291X

年卷期： 2019 年 512 卷 4 期

页码：

收录情况： SCI

摘要： 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 PPAR alpha 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 PPAR alpha dependent manner. Taken together, our study demonstrates that formononetin ameliorates hepatic cholestasis by upregulating expression of SIRT1 and activating PPAR alpha, which is an important anti-cholestatic mechanism of formononetin. (C) 2019 Elsevier Inc. All rights reserved.

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