Formononetin ameliorates cholestasis by regulating hepatic SIRT1 and PPARα.

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.

• Publication year

  2019

• Venue

  Biochemical and Biophysical Research Communications - BBRC

• Publication date

  2019-05-14

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1016/j.bbrc.2019.03.131PMID 30928103
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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