| Research Abstract |
We investigated the mechanism by which retinoic acid (RA,active metabolite of vitamin A) activates transforming growth factor-beta (TGF-beta) in liver stellate cells (SCs). In vitro SC cultures, RA induced plasminogen activator and activated cell surface plasmin, resulting in the activation of latent TGF-beta. Active TGF-beta generaed, then, stimulated the synthesis of itself as well as collagen, and suppressed the production of collagenase in an autocrine manner. In vivo rat models, RA accelerated the fibrosis by enhancing TGF-beta contents and, thus, collagen levels in the liver. These results suggest that RA exacerbated liver fibrosis, at least in part by inducing the activation and production of latent TGF-beta in liver SCs.
We also developed retinoid antagonists which specifically block the binding of RA to nuclear RA receptors. Retinoid antagonists inhibit the production of plasminnogen activator and suppressed the activation of latent TGF-beta, suggesting a possibility of a future use of retinoid antagonist for the therapy of liver fibrosis.
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