A Farnesoid X Receptor-Small Heterodimer Partner Regulatory Cascade Modulates Tissue Metalloproteinase lnhibitor-1 and Matrix Metalloprotease Expression in Hepatic Stellate Cells and Promotes Resolution of Liver Fibrosis

摘要

The farnesoid X receptor (FXR) is expressed by and regulates hepatic stellate cells (HSCs).In the present study,we investigated whether 6-ethyl chenodeoxycholic acid (6-ECDCA or INT-747),a semisynthetic derivative of chenodeoxycholic acid (CDCA),modulates tissue metalloproteinase inhibitor (TIMP)-1 and matrix metalloprotease (MMP)-2 expression/activity in HSCs and in the liver of rats rendered cirrhotic by 4-week administration of CCI_4.Exposure of HSCs to FXR ligands increases small heterodimer partner (SHP) mRNA by 3-fold and reduces basal and thrombin-stimulated expression of alpha1(l)col-lagen,alpha-smooth muscle actin (alpha-SMA),TIMP-1,and TIMP-2 by approx =60 to 70%,whereas it increased matrix metal loprotease (MMP)-2 activity by 2-fold.In coimmunoprecipitation,electro-mobility shift,and transactivation experiments,FXR activation/ overexpression caused a SHP-dependent inhibition of JunD binding to its consensus element in the TIMP-1 promoter.Inhibition of TIMP-1 expression by SHP overexpression enhanced the sensitivity of HSCs to proapoptogenic stimuli.Administration of 3 mg/kg 6-ECDCA,but not 15 mg/kg ursode-oxycholic acid,resulted in early (3-5-day) induction of SHP and prevention of early up-regulation of TIMP-1 mRNA induced by CCI_4.In the prevention protocol,4-week administration of 6-ECDCA reduced alpha1(l)collagen,alpha-SMA,and TIMP-1 mRNA by 60 to 80%,whereas it increased MMP-2 activity by 5-fold.In the resolution protocol,administration of 3 mg/kg 6-ECDCA promoted liver fibrosis resolution and increased the apoptosis of nonparenchyma liver cells.By demonstrating that a FXR-SHP regulatory cascade promotes the development of a quiescent phenotype and increases apoptosis of HSCs,this study establishes that FXR ligands may be beneficial in treatment of liver fibrosis.