Premium
Retinoids exacerbate rat liver fibrosis by inducing the activation of latent TGF‐β in liver stellate cells
Author(s) -
Okuno M,
Moriwaki H,
Imai S,
Muto Y,
Kawada N,
Suzuki Y,
Kojima S
Publication year - 1997
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.510260417
Subject(s) - hepatic stellate cell , retinoic acid , plasmin , endocrinology , collagenase , fibrosis , transforming growth factor , medicine , hepatic fibrosis , procollagen peptidase , plasminogen activator , chemistry , autocrine signalling , biology , biochemistry , receptor , enzyme , gene
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‐β (TGF‐β) 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‐β contents. In vitro SC cultures, 9‐ cis ‐RA enhanced cellular PA and plasmin levels thereby induced plasmin‐mediated activation of latent TGF‐β. Active TGF‐β 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‐β 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‐β in liver SCs.