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“The only thing necessary for these diseases to the triumph is for good people and governments to do nothing.”



Retinoids Exacerbate Rat Liver Fibrosis by Inducing the Activation of Latent TGF-<Picture: beta> in Liver Stellate Cells

http://www.geocities.com/HotSprings/5670/germander

MASATAKA OKUNO,1 HISATAKA MORIWAKI,1 SHOKO IMAI,1 YASUTOSHI MUTO,1 NORIFUMI KAWADA,2 YASUHIRO SUZUKI,3 AND SOICHI KOJIMA3

SEE EDITORIAL ON PAGE 1072

Liver stellate cells (SCs) play central roles in both the storage of retinol and the development of liver fibrosis. The present study is aimed to understand the mechanism by which retinoic acid (RA, an active metabolite of retinol) enhances hepatic fibrosis in rats. We tested the effect of 9-cis-RA on several aspects in vitro rat SC cultures, including the activity of cellular plasminogen activator (PA), messenger RNA (mRNA), and protein levels of transforming growth factor-<Picture: beta> (TGF-<Picture: beta>) mRNA level of type-I procollagen, and the activity of type-I collagenase. Employing the rat liver fibrosis model produced by porcine serum, 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-<Picture: beta> contents. In vitro SC cultures, 9-cis-RA enhanced cellular PA and plasmin levels thereby induced plasmin-mediated activation of latent TGF-<Picture: beta>. Active TGF-<Picture: beta> generated self-stimulated its synthesis as well as that of collagen and suppressed the production of collagenase in an autocrine manner. In in vivo rat models, an RA analog accelerated the porcine serum-induced fibrosis by enhancing TGF-<Picture: beta> contents and, thus, collagen levels in the liver, although the RA analog alone was not fibrogenic. These results suggest that RA exacerbated liver fibrosis, at least in part, by inducing the activation and production of latent TGF-<Picture: beta> in liver SCs.

    

Address reprint requests to: Soichi Kojima, Ph.D., Laboratory of Gene Technology and Safety, Tsukuba Life Science Center, The Institute of Physical and Chemical Research (RIKEN), Koyadai, Tsukuba, Ibaraki 305, Japan. Fax: 81-298-36-9050.

Copyright © 1997 by the American Association for the Study of Liver Diseases.