Additive inhibitory effect of experimentally induced hepatic cirrhosis by agonists of peroxisome proliferator activator receptor gamma and retinoic acid receptor.
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 PPAR gamma 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, alpha-smooth muscle actin, TGF beta 1, and TNFalpha. In vitro studies showed that PPAR gamma ligand 15-deoxy-Delta 12,14-prostaglandin J(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 RXR alpha in HSC-T6 cells. The combination of PPAR-gamma 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 TGF beta 1 and proinflammatory TNFalpha.
Bruck
Rafael
R
Department of Gastroenterology and Liver Diseases, Tel Aviv Sourasky Medical Center, 6 Weizman, Tel Aviv, Israel. rafib@tasmc.health.gov.il
Weiss
Sigal
S
Aeed
Hussein
H
Pines
Mark
M
Halpern
Zamir
Z
Zvibel
Isabel
I
D000077556:Alitretinoin; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D024042:Collagen Type I / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004357:Drug Synergism; D055166:Hepatic Stellate Cells / Q000187:drug effects*; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000517:prevention & control*; D008297:Male; D047495:PPAR gamma / Q000819:agonists*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D047488:Retinoid X Receptors / Q000819:agonists* / Q000378:metabolism; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use; D013853:Thioacetamide / Q000633:toxicity; D014212:Tretinoin / Q000494:pharmacology* / Q000627:therapeutic use
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D024042:Collagen Type I; D016207:Cytokines; D047495:PPAR gamma; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D047488:Retinoid X Receptors; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D013853:Thioacetamide; D000077556:Alitretinoin; D014212:Tretinoin; D015230:Prostaglandin D2