Bruck, R., Department of Gastroenterology and Liver Diseases, Tel Aviv Sourasky Medical Center, 6 Weizman, Tel Aviv, Israel, Sackler School of Medicine, Tel-Aviv University, Tel Aviv 64239, Israel
Weiss, S., Department of Gastroenterology and Liver Diseases, Tel Aviv Sourasky Medical Center, 6 Weizman, Tel Aviv, Israel
Aeed, H., Institute of Gastroenterology, E. Wolfson Medical Center, Holon, Israel
Pines, M., Institute of Animal Science, Agriculture Research Organization, Volcani Center, Bet Dagan, Israel
Halpern, Z., Department of Gastroenterology and Liver Diseases, Tel Aviv Sourasky Medical Center, 6 Weizman, Tel Aviv, Israel, Sackler School of Medicine, Tel-Aviv University, Tel Aviv 64239, Israel
Zvibel, I., Department of Gastroenterology and Liver Diseases, Tel Aviv Sourasky Medical Center, 6 Weizman, Tel Aviv, Israel

Peroxisome proliferator activator receptor (PPAR) ligands prevent liver fibrosis, while the role of all-trans retinoic acid (ATRA) and its metabolite 9-cis retinoic acid (9-cis RA) is less clear. We have investigated the ability of the combination of PPARγ ligand rosiglitazone (RSG) and of ATRA to prevent liver fibrosis. In vivo treatment with RSG or ATRA reduced fibrotic nodules, spleen weight, and hydroxyproline levels in rat model of thioacetamide-induced liver fibrosis. The combination of ATRA + RSG caused the strongest inhibition, accompanied by decreased expression of collagen I, α-smooth muscle actin, TGFβ1, and TNFα. In vitro studies showed that PPARγ ligand 15-deoxy-Δ12,14-prostaglandinJ(2)[PJ(2)] and RXR ligand 9-cis RA or PJ(2) and ATRA inhibited proliferation of hepatic stellate cells HSC-T6. 9-cis RA inhibited c-jun levels and also inhibited expression of its receptor RXRα in HSC-T6 cells. The combination of PPAR-γ and RAR agonists demonstrated an additive effect in the inhibition of TAA-induced hepatic fibrosis, due to inhibition of HSC proliferation and reduction of profibrotic TGFβ1 and proinflammatory TNFα. © 2008 Springer Science+Business Media, LLC.