Cross-talk between farnesoid-X-receptor (FXR)and peroxisome proliferator-activated receptor γ contributes to the antifibrotic activity of FXR ligands in rodent models of liver cirrhosis

The nuclear receptors farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor (PPAR)gamma exert counter-regulatory effects on hepatic stellate cells (HSCs) and protect against liver fibrosis development in rodents. Here, we investigated whether FXR ligands regulate PPAR gamma expression in HSCs and models of liver fibrosis induced in rats by porcine serum and carbon tetrachloride administration and bile duct ligation. Our results demonstrate that HSCs trans-differentiation associated with suppression of PPAR gamma mRNA expression, whereas FXR mRNA was unchanged. Exposure of cells to natural and synthetic ligands of FXR, including 6-ethyl chenodeoxycholic acid (6-ECDCA), a synthetic derivative of chenodeoxycholic acid, reversed this effect and increased PPAR gamma mRNA by approximate to 40-fold. Submaximally effective concentrations of FXR and PPAR gamma ligands were additive in inhibiting alpha 1(I) collagen mRNA accumulation induced by transforming growth factor (TGF)beta(1). Administration of 6-ECDCA in rats rendered cirrhotic by porcine serum and carbon tetrachloride administration or bile duct ligation reverted down-regulation of PPAR gamma mRNA expression in HSCs. Cotreatment with 6-ECDCA potentiates the antifibrotic activity of rosiglitazone, a PPAR gamma ligand, in the porcine serum model as measured by morphometric analysis of liver collagen content, hydroxyproline, and liver expression of alpha 1(I) collagen mRNA, alpha-smooth muscle actin, fibronectin, TGF beta(1), and tissue inhibitor of metalloprotease 1 and 2, whereas it enhanced the expression of PPAR gamma and uncoupling protein 2, a PPAR gamma-regulated gene, by 2-fold. In conclusion, by using an in vitro and in vivo approach, we demonstrated that FXR ligands up-regulate PPAR gamma mRNA in HSCs and in rodent models of liver fibrosis. A FXR-PPAR gamma cascade exerts counter-regulatory effects in HSCs activation.