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

Abstract

The nuclear receptors farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor (PPAR)␥ exert counterregulatory effects on hepatic stellate cells (HSCs) and protect against liver fibrosis development in rodents. Here, we investigated whether FXR ligands regulate PPAR␥ 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␥ 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␥ mRNA by Ϸ40-fold. Submaximally effective concentrations of FXR and PPAR␥ ligands were additive in inhibiting ␣1(I) collagen mRNA accumulation induced by transforming growth factor (TGF)␤ 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␥ mRNA expression in HSCs. Cotreatment with 6-ECDCA potentiates the antifibrotic activity of rosiglitazone, a PPAR␥ ligand, in the porcine serum model as measured by morphometric analysis of liver collagen content, hydroxyproline, and liver expression of ␣1(I) collagen mRNA, ␣-smooth muscle actin, fibronectin, TGF␤ 1 , and tissue inhibitor of metalloprotease 1 and 2, whereas it enhanced the expression of PPAR␥ and uncoupling protein 2, a PPAR␥-regulated gene, by 2-fold. In conclusion, by using an in vitro and in vivo approach, we demonstrated that FXR ligands up-regulate PPAR␥ mRNA in HSCs and in rodent models of liver fibrosis. A FXR-PPAR␥ cascade exerts counterregulatory effects in HSCs activation.Hepatic fibrosis is a scarring process of the liver that includes both increased and altered deposition of extracellular matrix components (Friedman, 2003). In chronic liver disease, hepatic stellate cells (HSCs) undergo a process of trans-differentiation (Friedman, 2003) from a resting, fatstoring, phenotype toward a myofibroblast-like phenotype characterized by expression of fibroblastic cell markers such as ␣1(I) collagen and ␣-smooth muscle actin (␣-SMA). Although the mediators involved in this process are not completely understood, a growing body of evidence suggests that members of the nuclear receptor (NR) superfamily (Fiorucci et al., 2004b) exert counter-regulatory effects acting as braking signals to prevent HSCs trans-differentiation.The farnesoid X receptor (FXR) is a ligand-activated transcription factor that regulates cholesterol and fatty acid metabolism and functions as an endogenous sensor for bile acids (Forman et al., 1995;Makishima et al., 1999;Parks et al., This study was partially supported by a research grant from Intercept Pharmaceuticals (New York, NY).Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.doi:10.1124/jpet.105.085597. AB...

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