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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Cross-Talk between Farnesoid-X-Receptor (FXR) and Peroxisome Proliferator-Activated Receptor Contributes to the Antifibrotic Activity of FXR Ligands in Rodent Models of Liver Cirrhosis

Dipartimento di Medicina Clinica e Sperimentale, Università degli Studi di Perugia, Perugia, Italy (S.F., G.R., E.A., B.R., A.Me., L.R., A.Mo.); Intercept Pharmaceuticals, New York, New York (M.P.); and Dipartimento di Chimica e Tecnologia del Farmaco, Università di Perugia, Perugia, Italy (R.P.)

The nuclear receptors farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor (PPAR) 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 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 40-fold. Submaximally effective concentrations of FXR and PPAR ligands were additive in inhibiting 1(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 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, TGFβ₁, 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 counter-regulatory effects in HSCs activation.

Address correspondence to: Dr. Stefano Fiorucci, Gastroenterologia ed Epatologia, Policlinico Monteluce, Via E dal Pozzo, 06111 Perugia, Italy. E-mail: fiorucci{at}unipg.it

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