Ursolic acid alleviates cholestasis by regulating Nrf2- UGT2B7/BSEP/MRP2 pathway in vivo and in vitro

Abstract Human hepatoblastoma cell line HepG2 has been widely used in the study of liver and liver cancer. α-naphthyl-isothiocyanate (ANIT) is a poison widely used in rodents to simulate human intrahepatic cholestasis. Ursolic acid (UA), a pentacyclic triterpenoid, exhibits various pharmacological actions. However, the role of nuclear factor E2 related factor 2 (Nrf2)-uridine diphosphate glucuronosyltransferase (UGT2B7)/bile salt output pump (BSEP)/multidrug resistance-associated protein 2 (MRP2) pathway in UA against cholestatic liver injury has not been cleared. The purpose of this study is to explore the effect of UA on cholestatic liver injury and its potential mechanism. Compared with the control group, UA could increase the expression of Nrf2, UGT2B7, BSEP, and MRP2 in HepG2 cells by Rt-qPCR and Western Blot. This up-regulation was inhibited after silencing Nrf2. The results of pathological sections and biochemical indexes showed that UA could alleviate cholestatic liver injury induced by ANIT and significantly activate the mRNA and protein of UGT2B7, BSEP, and MRP2 in liver tissue. However, this activation was inhibited in rats silenced with Nrf2. We confirmed that UA can reduce cholestasis. And it's related to Nrf2-UGT2B7/BSEP/MRP2. Therefore, this study expands the understanding of the anti-cholestatic effect of UA and provides a new therapeutic target for cholestasis.