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1996 Fiscal Year Final Research Report Summary

Inhibition of Liver Fibrosis by Retinoid Antagonist

Research Project

Project/Area Number 06670534
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Gastroenterology
Research InstitutionGifu University

Principal Investigator

OKUNO Masataka  First Department of Internal Medicine Gifu University School of Medicine Assistant Professor, 医学部・附属病院, 助手 (10204140)

Co-Investigator(Kenkyū-buntansha) MORIWAKI Hisataka  First Department of Internal Medicine Gifu University School of Medicine Associa, 医学部, 助教授 (50174470)
Project Period (FY) 1994 – 1996
KeywordsLiver Fibrosis / Retinoid / TGF-beta / Stellate Cell / Collagen
Research Abstract

We investigated the mechanism by which retinoic acid (RA,active metabolite of vitamin A) activates transforming growth factor-beta (TGF-beta) in liver stellate cells (SCs). In vitro SC cultures, RA induced plasminogen activator and activated cell surface plasmin, resulting in the activation of latent TGF-beta. Active TGF-beta generaed, then, stimulated the synthesis of itself as well as collagen, and suppressed the production of collagenase in an autocrine manner. In vivo rat models, RA accelerated the fibrosis by enhancing TGF-beta contents and, thus, collagen levels in the liver. These results suggest that RA exacerbated liver fibrosis, at least in part by inducing the activation and production of latent TGF-beta in liver SCs.
We also developed retinoid antagonists which specifically block the binding of RA to nuclear RA receptors. Retinoid antagonists inhibit the production of plasminnogen activator and suppressed the activation of latent TGF-beta, suggesting a possibility of a future use of retinoid antagonist for the therapy of liver fibrosis.

  • Research Products

    (24 results)

All Other

All Publications (24 results)

  • [Publications] Numaguchi S, Okuno M et al.: "Modulation of collagen synthesis and degradation by retinoids and cytokines in 3T3L1 preadiptcytes" Int Med. 33. 309-316 (1994)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Okuno M, Moriwaki H, et al.: "Changes in the ratio of branched-chain to aromatic amino acids affect the secretion of albumin in cultured rat hepatocytes" Biochem Biophys Res Commun. 214. 1045-1050 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Okuno M, Caraueo VE, et al.: "Regulation of gene expression by retinoic acid and hormones : effects on the gene encoding cellular retinol-binding protein" J Lipid Res. 36. 137-147 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Miwa Y, Okuno M, et al.: "Effects of branched-chain amino acid infusion on protein metabolism in rats with acute hepatic failure" Hepatology. 22. 291-296 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Iwamine T, Okuno M, et al.: "Impaired synthesis of retinol-binding protein and trans thyretin in rat liver with obstractive jaundice" Dig Dis Sci. 41. 1038-1042 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Usui T, Okuno M, et al.: "Oral supplementation with branched-chain amino acids improves trans thyretin turnover in rats with CCl_4-induced liver cirrhosis" J Nutr. 126. 1412-1420 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Muto Y, Okuno M, et al.: "Prevention of second primary tumor by a retinoid, polyprenoic acid, in patients with hepato cellular carcinoma" N Engl J Med. 334. 1561-1567 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Katsumura N, Okuno M, et al.: "Suppression of mouse skin papilloma by canthaxanthin and β-carotene in vivo" Nutr Cancer. 26. 203-206 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Onogi N, Okuno M, et al.: "Suppressing effect of perilla oil on azoxymethane-induced foci of colonic aberrant crypts in rats." Carcinogenesis. 17. 1291-1296 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Koda H, Okuno M, et al.: "Retinoic acid-stimulated liver stellate cells suppress the production of albumin from parenchymal cells via TGF-β." Biochem Biophys Res Commun. 221. 565-569 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Komaki C, Okuno M, et al.: "Synergistic suppression of azoxymethane-induced foci of aberrant crypts by the combmation of β-carotene and perilla oil in rats" Carcinogenesis. 17. 1897-1901 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Moriwaki H, Okuno M, et al.: "Deletion of serum lectin-reactive α-fetoprotein by acyctic retinoid : a potent biomarker in the chemoprevention of second hepatoma" Clin Cancer Res. (in press).

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Numaguchi S,Okuno M,Moriwaki H,Muto Y.: "Modulation of collagen synthesis and degradation by retinoids and cytokines in 3T3L1 preadipocytes." Int Med. 33. 309-316 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Okuno M,Moriwaki H,Kato M,Muto Y,Kojima S.: "Changes in the ratio of branched-chain to aromatic amino acids affect the secretion of albumin in cultured rat hepatocytes." Biochem Biophys Res Commun. 214. 1045-1050 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Okuno M,Caraveo VE,Goodman DS,Blaner WS.: "Regulation of adipocyte gene expression by retinoic acid and hormones : effects on the gene encoding cellular retinol-binding protein." J Lipid Res. 36. 137-147 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Miwa Y,Kato M,Moriwaki H,Okuno, M,Sugihara J,Ohnishi H,Yoshida T,Muto Y,Nakayama M,Morioka Y,Asagi K.: "Effects of branched-chain amino acid infusion on protein metabolism in rats with acute hepatic failure." Hepatology. 22. 291-296 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Imamine T,Okuno M,Moriwaki H,Shidoji Y,Muto Y,Seishima M,Noma A,Kojima S.: "Impaired synthesis of retinol-binding protein and transthyretin in rat liver with obstructive jaundice." Dig Dis Sci. 41. 1038-1042 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Usui T,Moriwaki H,Hatakeyama H,Kanai T,Kato M,Okuno M,Ohnishi H,Yoshida T, Muto Y.: "Oral supplementation with branched-chain amino acids improves transthyretin turnover in rats with carbon tetrachloride-induced liver cirrhosis." J Nutr. 126. 1412-1420 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Muto Y,Moriwaki H,Ninomiya M,Adachi S,Saito A,Takasaki KT,Tanaka T,Tsurumi K,Okuno M,Uematsu T,Tomita E,Nakamura T,Kojima T.: "Prevention of secondary primary tumors by a retinoid, polyprenoic acid, in patients with hepatocellular carcnoma." N Eng J Med. 334. 1561-1567 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Katsumura N,Okuno M,Onogi N,Moriwaki H,Muto Y,Kojima S.: "Suppresion of mouse skin papilloma by canthaxanthin and beta-carotene in vivo : possibility of the regulation of tumorigenesis by carotenoids without being converted to retinoic acid." Nutr Cancer. 26. 203-206 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Onogi N,Okuno M,Komaki C,Moriwaki H,Kawamori T,Tanaka T,Mori H,Muto Y.: "Suppressing effect of perilla oil on azoxymethane-induced foci of colonic aberrant crypts in rats." Carcinogenesis. 17. 1291-1296 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Koda H,Okuno M,Imai S,Moriwaki H,Muto Y,Kawada N,Kojima S.: "Retinoic acid-stimulated liver stellate cells suppress the production of albumin from parenchymal cells via TGF-beta." Biochem Biophys Res Commun. 221. 565-569 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Komaki C,Okuno M,Onogi N,Moriwaki H,Kawamori T,Tanaka T,Mori H,Muto Y.: "Synergistic suppression of azoxymethane-induced foci of abberant crypts by the combination ofbeta-carotene and perilla oil in rats." Carcinigenesis. 17. 1897-1901 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Moriwaki H,Yasuda I,Shiratori Y,Uematsu T,Okuno M,Muto Y.: "Deletion of serum lectin-reactive alpha-fetoprotein by acyclic retinoid : a potent biomarker in the chemoprevention of second primary hepatoma." Clin Cancer Res. (in press).

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 1999-03-09  

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