Increased 9,13-di-cis-retinoic acid in rat hepatic fibrosis: implication for a potential link between retinoid loss and TGF-beta mediated fibrogenesis in vivo

Background/Aims: During hepatic fibrosis:, hepatic stellate cells (HSCs) tr ansform into myofibroblastic cells and lose their intracellular droplets of retinyl esters, the storage form of vitamin A. Recently, we have demonstra ted that 9,13-di-cis-retinoic;acid (RA), a geometric isomer identified as. a stable and major metabolite of vitamin A in circulation, stimulates the s ynthesis of plasminogen activator (PA) and induces PA/plasmin-dependent lat ent transforming growth factor (TGF)-beta activation in HSC cultures, proba bly via induction and activation of RA receptor (RAR) a, The aim of the pre sent study was to address a potential link between the loss of retinyl este rs to increased formation of RA(s), which might play a role in facilitating TGF-beta-mediated liver fibrogenesis in vivo, Methods: We examined the effect of 9,13-di-cis-RA on transactivating activi ty of RARa in HeLa cells as well as its effect on PA- and TGF-beta-dependen t collagen synthesis in rat and human HSC cultures, We measured the changes in 9,13-di-cis-RA levels both during activation of rat HSCs in vitro and d uring porcine serum-induced rat hepatic fibrosis in vivo and correlated thi s with RAR alpha/beta, PA, TGF-beta and type I procollagen mRNA expression in the fibrotic liver. Results: B,13-di-cis-RA transactivated RARa, and provoked PA/plasmin and TG F-beta-dependent procollagen synthesis in HSCs. 9,13-di-cis-RA levels were increased both in activated HSCs in vitro and in fibrotic liver accompanyin g the enhanced expression of RAR alpha/beta, PA, TGF-beta and procollagen i n vivo. Conclusions: These findings suggest a potential link between 9,13-di-cis RA formation and hepatic fibrosis via formation of TGF-beta in vivo and thus provide further insight into the biologic role of retinoids during hepatic fibrogenesis.