Kinsenoside Alleviates 17α-Ethinylestradiol-Induced Cholestatic Liver Injury in Rats by Inhibiting Inflammatory Responses and Regulating FXR-Mediated Bile Acid Homeostasis.

Qun Zhou,Yanfang Deng,Jie Yin,Qingyi Tong,Jiaxiong Ming,Yonghui Zhang,Qianqian Xu,Limin Gao

doi:10.3390/ph14050452

Abstract

Cholestasis is an important predisposing factor of liver diseases, such as hepatocyte necrosis, liver fibrosis and primary biliary cirrhosis. In this study, we aimed to investigate the effects of Kinsenoside (KD), a natural active ingredient of Anoectochilus roxburghii, on estrogen-induced cholestatic liver injury in Sprague-Dawley rats and the underlying mechanism. The rats were randomly divided into six groups: control group, model group, low-dose KD group (50 mg/kg body weight, KD-L), medium-dose KD group (100 mg/kg body weight, KD-M), high-dose KD group (200 mg/kg body weight, KD-H) and ursodeoxycholic acid group (40 mg/kg body weight, UDCA). 17α-Ethinylestradiol (EE) was used to establish an experimental animal model of estrogen-induced cholestasis (EIC). The results demonstrated that KD alleviated liver pathologic damage, serum biochemical status and inhibited hepatocellular microstructure disorder and bile duct hyperplasia in EE-induced cholestatic rats. Mechanically, KD alleviated EE-induced cholestatic liver injury by inhibiting inflammatory responses and regulating bile acid homeostasis. Concretely, KD reduced the expression of IL-1β and IL-6 by inhibiting NF-κB p65 to suppress EE-mediated inflammation in rat liver. KD enhanced the expression of FXR and inhibited EE-mediated reduction of FXR in vitro and in vivo. It was the potential mechanism that KD mitigates cholestasis by increasing efflux and inhibiting uptake of bile acids via FXR-mediated induction of bile salt export pump (BSEP) and reduction of Na+-dependent taurocholate cotransport peptide (NTCP) to maintain bile acid homeostasis. Moreover, KD repressed the bile acid synthesis through reducing the expression of synthetic enzyme (CYP7A1), thereby normalizing the expression of metabolic enzyme (SULT2A1) of bile acid. In conclusion, our results revealed that KD may be an effective drug candidate for the treatment of cholestasis.

Highlights

In order to investigate the effect of KD on cholestatic liver injury in vivo, we established an experimental animal model of estrogen-induced cholestasis (Figure 1B)
Our results revealed that KD treatment increased the expression of bile salt export pump (BSEP) and restrained the expression of Na+ -dependent taurocholate cotransport peptide (NTCP) and Cytochrome P450 7A1 (CYP7A1) in a dose-dependent manner compared to the EE group (Figure 6A–E)
Cholestatic liver diseases, including estrogen-induced cholestasis (EIC), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), are syndromes associated with intrahepatic retention and the accumulation of bile acids (BAs) [38]

Summary

Introduction

Cholestasis is a clinically pathological condition characterized by excessive accumulation of toxic bile acids (BAs) in liver due to various causes, including viral hepatitis [1], autoimmune liver disease [2], alcoholic and/or fatty liver disease [3,4], as well as the induction of chemicals, such as estrogen [5,6]. Estrogen-induced cholestasis (EIC) is common in women undergoing oral contraceptives, pregnancy or hormone replacement therapy [7,8,9]. Even in men receiving estrogen therapy for prostate cancer [10]. Cholestasis can induce liver cell necrosis, liver fibrosis, primary biliary cirrhosis (PBC) and even liver. Pharmaceuticals 2021, 14, 452 failure [11,12,13]. There are very few effective drugs and therapies for cholestasis

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