RETINOIDS EXACERBATE RAT-LIVER FIBROSIS BY INDUCING THE ACTIVATION OFLATENT TGF-BETA IN LIVER STELLATE CELLS

Liver stellate cells (SCs) play central roles in both the storage of r etinol and the development of liver fibrosis. The present study is aim ed to understand the mechanism by which retinoic acid (RA, an active m etabolite of retinol) enhances hepatic fibrosis in rats. We tested the effect of 9-cis-RA on several aspects in vitvo rat SC cultures, inclu ding the activity of cellular plasminogen activator (PA), messenger RN A (mRNA), and protein levels of transforming growth factor-beta (TGF-b eta) mRNA level of type-I procollagen, and the activity of type-I coll agenase Employing the rat liver fibrosis model produced by porcine ser um, we also estimated the effect of oral administration of a stable RA analog on the progression of the fibrosis, as well as on hepatic TGF- beta contents. In vitro SC cultures, 9-cis-RA enhanced cellular PA and plasmin levels thereby induced plasmin-mediated activation of latent TGF-beta. Active TGF-beta generated self-stimulated its synthesis as w ell as that of collagen and suppressed the production of collagenase i n an autocrine manner. In in vivo rat models, an RA analog accelerated the porcine serum-induced fibrosis by enhancing TGF-beta contents and , thus, collagen levels in the Liver, although the RA analog alone was not fibrogenic. These results suggest that RA exacerbated liver fibro sis, at least in part, by inducing the activation and production of la tent TGF-beta in liver SCs.