Protective effect of dehydroandrographolide on obstructive cholestasis in bile duct-ligated mice.

Zhiyong Weng,Chenjuan Yao,Jingzhou Mu,Lihua Li,Jiehua Hu,Jing Xie,Xuefeng Liu

doi:10.18632/oncotarget.21233

Abstract

BackgroundDehydroandrographolide (DA) is the main contributor to the therapeutic properties of the medicinal plant Andrographis paniculata (AP). However, it is unknown whether DA has a hepatoprotective effect on obstructive cholestasis in mice and humans.MethodsWe administered DA to mice for 5 days prior to bile duct ligation (BDL) and for the 7 days. Liver function markers, liver histology and necrosis, compensatory responses of hepatocytes, liver fibrosis and the expression of hepatic fibrogenesis markers were evaluated in BDL mice and/or human LX-2 cells.ResultsMice treated with DA demonstrated lower levels of serum alanine transarninase (ALT), milder liver damage, liver necrosis and fibrosis formation than in vehicle control with carboxymethylcellulose (CMC) mice after BDL. DA treatment also enhanced the Mrp3 expression of hepatocytes but not Mrp4 following BDL. Further, DA treatment in BDL mice significantly reduced liver mRNA and/or protein expression of Tgf-β, Col1a1, α-Sma and Mmp2. This result was also supported by hydroxyproline analysis. The molecular mechanisms of DA treatment were also assessed in human hepatic stellate cell line (LX-2 cell). DA treatment significantly inhibited Tgf-β-induced Col1a1, Mmp2 and α-Sma expression in human LX-2 cells. These data suggested that DA treatment reduced liver damage through development of a hepatic adaptive response and inhibition of the activation of HSCs, which led to a reduction in liver fibrosis formation in BDL mice.ConclusionsDA treatment protected against liver damage and fibrosis following BDL and might be an effective therapy for extrahepatic cholestasis due to bile duct obstruction.

Highlights

Obstructive cholestasis is caused by occlusion of the common bile duct or its tributaries and is associated with reduced bile flow, hepatic accumulation of bile acids, progressive liver injury and development of fibrosis
DA treatment significantly inhibited Tgf-β-induced Col1a1, Mmp2 and α-Sma expression in human LX-2 cells. These data suggested that DA treatment reduced liver damage through development of a hepatic adaptive response and inhibition of the activation of hepatic stellate cells (HSCs), which led to a reduction in liver fibrosis formation in bile duct ligation (BDL) mice
DA treatment protected against liver damage and fibrosis following BDL and might be an effective therapy for extrahepatic cholestasis due to bile duct obstruction

Summary

Introduction

Obstructive cholestasis is caused by occlusion of the common bile duct or its tributaries and is associated with reduced bile flow, hepatic accumulation of bile acids, progressive liver injury and development of fibrosis. Production and accumulation of extracellular matrix (ECM) constituents is the primary cause of liver fibrosis [1]. Effective inhibition of HSC activation is a promising therapeutic target to protect the liver against fibrosis in cholestatic liver diseases. Dehydroandrographolide (DA) is the main contributor to the therapeutic properties of the medicinal plant Andrographis paniculata (AP). It is unknown whether DA has a hepatoprotective effect on obstructive cholestasis in mice and humans

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Conclusion