Increased 9,13-di-cis-retinoic acid in rat hepatic fibrosis: Implication for a potential link between retinoid loss and TGF-β mediated fibrogenesis in vivo

Masataka Okuno, Takashi Sato, Takuya Kitamoto, Shoko Imai, Norifumi Kawada, Yasuhiro Suzuki, Hiroyuki Yoshimura, Hisataka Moriwaki, Kaori Onuki, Shoichi Masushige, Yasutoshi Muto, Scott L. Friedman, Shigeaki Kato, Soichi Kojima

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65 Citations (Scopus)

Abstract

Background/Aims: During hepatic fibrosis, hepatic stellate cells (HSCs) transform into myofibroblastic cells and lose their intracellular droplets of retinyl esters, the storage form of vitamin A. Recently, we have demonstrated that 9,13-di-cis-retinoic acid (RA), a geometric isomer identified as a stable and major metabolite of vitamin A in circulation, stimulates the synthesis of plasminogen activator (PA) and induces PA/plasmin-dependent latent transforming growth factor (TGF)-β activation in HSC cultures, probably via induction and activation of RA receptor (RAR) α. The aim of the present study was to address a potential link between the loss of retinyl esters to increased formation of RA(s), which might play a role in facilitating TGF-β-mediated liver fibrogenesis in vivo. Methods: We examined the effect of 9,13-di-cis-RA on transactivating activity of RARα in HeLa cells as well as its effect on PA- and TGF-β-dependent collagen synthesis in rat and human HSC cultures. We measured the changes in 9,13-di-cis-RA levels both during activation of rat HSCs in vitro and during porcine serum-induced rat hepatic fibrosis in vivo and correlated this with RAR α/β, PA, TGF-β and type I procollagen mRNA expression in the fibrotic liver. Results: 9,13- di-cis-RA transactivated RARα, and provoked PA/plasmin and TGF-β-dependent procollagen synthesis in HSCs. 9,13-di-cis-RA levels were increased both in activated HSCs in vitro and in fibrotic liver accompanying the enhanced expression of RAR α/β, PA, TGF-β and procollagen in vivo. Conclusions: These findings suggest a potential link between 9,13-di-cis RA formation and hepatic fibrosis via formation of TGF-β in vivo, and thus provide further insight into the biologic role of retinoids during hepatic fibrogenesis.

Original languageEnglish
Pages (from-to)1073-1080
Number of pages8
JournalJournal of Hepatology
Volume30
Issue number6
DOIs
Publication statusPublished - 1999 Jun

Keywords

  • Activation of latent TGF-β
  • Hepatic stellate cells
  • Plasminogen activator

ASJC Scopus subject areas

  • Hepatology

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    Okuno, M., Sato, T., Kitamoto, T., Imai, S., Kawada, N., Suzuki, Y., Yoshimura, H., Moriwaki, H., Onuki, K., Masushige, S., Muto, Y., Friedman, S. L., Kato, S., & Kojima, S. (1999). Increased 9,13-di-cis-retinoic acid in rat hepatic fibrosis: Implication for a potential link between retinoid loss and TGF-β mediated fibrogenesis in vivo. Journal of Hepatology, 30(6), 1073-1080. https://doi.org/10.1016/S0168-8278(99)80262-1