RT Journal Article
SR Electronic
T1 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
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 58
OP 68
DO 10.1124/jpet.105.085597
VO 315
IS 1
A1 Stefano Fiorucci
A1 Giovanni Rizzo
A1 Elisabetta Antonelli
A1 Barbara Renga
A1 Andrea Mencarelli
A1 Luisa Riccardi
A1 Antonio Morelli
A1 Mark Pruzanski
A1 Roberto Pellicciari
YR 2005
UL http://jpet.aspetjournals.org/content/315/1/58.abstract
AB The nuclear receptors farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor (PPAR)γ exert counter-regulatory effects on hepatic stellate cells (HSCs) and protect against liver fibrosis development in rodents. Here, we investigated whether FXR ligands regulate PPARγ 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 PPARγ 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 PPARγ mRNA by≈ 40-fold. Submaximally effective concentrations of FXR and PPARγ ligands were additive in inhibiting α1(I) collagen mRNA accumulation induced by transforming growth factor (TGF)β1. Administration of 6-ECDCA in rats rendered cirrhotic by porcine serum and carbon tetrachloride administration or bile duct ligation reverted down-regulation of PPARγ mRNA expression in HSCs. Cotreatment with 6-ECDCA potentiates the antifibrotic activity of rosiglitazone, a PPARγ ligand, in the porcine serum model as measured by morphometric analysis of liver collagen content, hydroxyproline, and liver expression of α1(I) collagen mRNA,α -smooth muscle actin, fibronectin, TGFβ1, and tissue inhibitor of metalloprotease 1 and 2, whereas it enhanced the expression of PPARγ and uncoupling protein 2, a PPARγ-regulated gene, by 2-fold. In conclusion, by using an in vitro and in vivo approach, we demonstrated that FXR ligands up-regulate PPARγ mRNA in HSCs and in rodent models of liver fibrosis. A FXR-PPARγ cascade exerts counter-regulatory effects in HSCs activation. The American Society for Pharmacology and Experimental Therapeutics