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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.
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