Modulation by amino acids of the expression of factors produced by hepatic stellate cells : its implication in injured liver

• Project/Area Number: 18590719
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: The University of Tokyo
• Principal Investigator: TOMIYA Tomoaki The University of Tokyo, Faculty of Medicine, Assistant (90227637)
• Co-Investigator(Kenkyū-buntansha): IKEDA Hitoshi The University of Tokyo, Faculty of Medicme, Associate Professor (80202422) ; TEJIMA Kazuaki The University of Tokyo, Faculty of Medicine, Clinical Fellow (30396733) ; 柳瀬 幹雄 東京大学, 医学部附属病院, 助手 (50334397)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥3,810,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥210,000); Fiscal Year 2007: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2006: ¥2,900,000 (Direct Cost: ¥2,900,000)
• Keywords: Regenerative medicine / Nutrition / Translational research / Bioactivity / トランスレイショナルリサー

Research Abstract

The mechanisms involved in the specific benefits of protein-or amino acid-enriched diet in patients with liver cirrhosis remain to be elucidated. The ideal formula of amino acids in patients with liver injury is still uncertain. In addition to providing substrates for protein synthesis, amino acids are known to influence the regulation of cellular functions in a variety of cell types. Hepatic stellate cells produce a variety of factors associated with cell growth, protein production, lipid and glucose metabolism and so on such as hepatocyte growth factor (HGF) and insulin-like growth factor 1 (IGF-1). The aim of this study is to investigate the contribution of amino acids on the factors produced by hepatic stellate cells. Among 20 amino acids evaluated, treatment with glutamine and proline, in addition to leucine, significantly increased HGF levels in the culture medium of a rat hepatic stellate cell clone. The HGF levels were increased in a dose-dependent manner by the addition of up to 100 mM and 1 mM of glutamine and proline, respectively. While phosphorylation of p70 S6 kinase and 4E-binding protein 1 was rapidly up-regulated after leucine treatment in hepatic stellate cell done, treatment of glutamine or proline induced minor or undetectable phosphorylation of p70 S6 kinase and 4E binding protein 1, suggesting that the stimulatory effect of these amino acids on HGF production seems not to be dependent on mTOR signaling pathway. When rats received an intraperitoneal injection of glutamine or proline, hepatic and circulating HGF levels at 12 hours after treatment were significantly higher than in control rats. Furthermore, leucine treatment stimulated IGF-1 production by hepatic stellate cell clone. Glutamine and proline, in addition to leucine, stimulate HGF production by hepatic stellate cells. The mechanism underlying the stimulation of HGF production may vary depending on the amino acids. In addition, amino acids can induce IGF-1 production by hepatic stellate cells.

Research Products

• [Journal Article] Leucine stimulates HGF production by hepatic stellate cells through mTOR pathway. (2007)
  • Author(s): Tomiya T, Nishikawa T, Inoue Y, Ohtomo N, Ikeda H, Tejima K, Watanabe N, Tanoue Y, Omata M, Fujiwara K.
  • Journal Title: Biochem Biophys Res Commun 358 Pages: 176-180
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Effect of rapamycin on hepatocyte function and proliferation induced by growth factors (2007)
  • Author(s): Tomiya T, Yamaoka M, Inoue Y, Nishikawa T, Yanase M, Ikeda H, Tejima K, Nagashima K, Watanabe N, Omata M, Fujiwara K.
  • Journal Title: Chemotherapy 53 Pages: 59-69
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Stimulation by glutamine and proline of HGF production in hepatic stellate cells. (2007)
  • Author(s): Nishikawa T, Tomiya T, Ohtomo N, Inoue Y, Ikeda H, Tejima K, Watanabe N, Tanoue Y, Omata M, Fujiwara K.
  • Journal Title: Biochem Biophys Res Commun 363 Pages: 978-982
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Expression of transforming growth factor-alpha and -beta in hepatic lobes after hemihepatic portal vein embolization. (2007)
  • Author(s): Kusaka K, Imamura H, Tomiya T, Takayama T, Makuuchi M.
  • Journal Title: Dig Dis Sci 51 Pages: 1404-1412
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Hepatic stellate cell damage may lead to decreased plasma ADAMTS13 activity in rats (2007)
  • Author(s): Kume Y, Ikeda H, Inoue M, Tejima K, Tomiya T, Nishikawa T, Watanabe N, Ichikawa T, Kaneko M, Okubo S, Yokota H, Omata M, Fujiwara K, Yatomi Y
  • Journal Title: FEBS Lett 581 Pages: 1631-1634
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Rho-kinase inhibitor prevents hepatocyte damage in acute liver injury induced by carbon tetrachloride in rats. (2007)
  • Author(s): Ikeda H, Kume Y, Tejima K, Tomiya T, Nishikawa T, Watanabe N, Ohtomo N, Arai M, Arai C, Omata M, Fujiwara K, Yatomi Y.
  • Journal Title: Am J Physiol Gastrointest Liver Physiol 293 Pages: 911-917
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Induction of ischemic tolerance in rat liver via reduced nicotinamide adenine dinucleotide phosphate oxidase in Kupffer cells. (2007)
  • Author(s): Tejima K, Arai M, Ikeda H, Tomiya T, Yanase M, moue Y, Nishikawa T, Watanabe N, Ohtomo N, Omata M, fujiwara K.
  • Journal Title: World J Gastroenterol 13 Pages: 5071-5078
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Plasma 1ysophosphatidic acid level and serum autotaxin activity are increased in in liver injury in rats in relation to its severity (2007)
  • Author(s): Watanabe N, Ikeda H, Nakamura K, Ohkawa R, Kume Y, Tomiya T, Tejima K, Nishikawa T, Arai M, Yanase M, Aoki J, Arai H, Omata M Fujiwara K, Yatomi Y.
  • Journal Title: Life Sci 81 Pages: 1009-1015
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Expression of transforming growth factor-alpha and-beta in hepatic lobes after hemihepatic portal vein embolization (2007)
  • Author(s): Kusaka K, Imamura H, Tomiya T, Takayama T, Makuuchi M.
  • Journal Title: Dig Dis Sci 51 Pages: 1404-1412
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Hepatic stellate cell damage may lead to decreased plasma ADAMTS13 activity in rats (2007)
  • Author(s): Kume Y, Ikeda H, Inoue M, Tejima K, Tomiya T, Nishikawa T, Watanabe N, Ichikawa T, Kaneko M, Okubo S, Yokota H, Omata M, Fujiwara K, Yatomi Y.
  • Journal Title: FEBS Lett 581 Pages: 1631-1634
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Leucine stimulates HGF production by hepatic stellate cells through mTOR pathway (2007)
  • Author(s): Tomiya T, Nishikawa T, Inoue Y, Ohtomo N, Ikeda H, Tejima K, Watanabe N, Tanoue Y, Omate, M, Fujiwara K.
  • Journal Title: Biochem Biophys Res Common 358 Pages: 176-180
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Both plasma lysophosphatidic acid and serum autotaxin levels are increased in chronic hepatitis C. (2007)
  • Author(s): Watanabe N, Ikeda H, Nakamura K, Obkawa R, Kume Y, Aoki J, Hama K, Okudaira S, Tanaka M, Tonriya T, Yanase M, Tejima K, Nishikawa T, Arai M, Arai H, Omata M, Fujiwara K, Yatomi Y.
  • Journal Title: J Clin Gastroenterol 41 Pages: 616-623
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Rho-kinase inhibitor prevents hepatocyte damage in acute liver injury induced by carbon tetrachloride in rats (2007)
  • Author(s): Ikeda H, Kume Y, Tejima K, Tomiya T, Nishikawa T, Watanabe N, Ohtomo N, Arai M, Arai C, Omata M, Fujiwara K, Yatomi Y.
  • Journal Title: Am J Physiol Gastrointest Liver Physiol 293
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Plasma lysophosphatidic acid level and serum autotaxin activity are increased in liver injury in rats in relation to its severity (2007)
  • Author(s): Watanabe N, Ikeda H, Nakamura K, Ohkawa R, Kume Y, Tomiya T, Tejima K, Nishikawa T, Arai M, Yanase M, Aoki J, Arai H, Omata M, Fujiwara K, Yatomi Y.
  • Journal Title: Life Sci 81 Pages: 1009-1015
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Induction of ischemic tolerance in rat liver via reduced nicotinamide adenine dinucleotide phosphate oxidase in Kupffer cells (2007)
  • Author(s): Tejima K, Arai M, Ikeda H, Tomiya T, Yanase M, Inoue Y, Nishikawa T, Watanabe N, Ohtomo N, Omata M, Fujiwara K.
  • Journal Title: World J Gastroenterol 13 Pages: 5071-5078
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Stimulation by glutamine and proline of HGF production in hepatic stellate cells (2007)
  • Author(s): Nishikawa T, Tomiya T, Ohtomo N, Inoue Y, Ikeda H, Tejima K, Watanabe N, Tanoue Y, Omata M, Fujiwara K.
  • Journal Title: Biochem Biophys Res Commun 363 Pages: 978-982
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Ischemic preconditioning in liver pathophysiology (2007)
  • Author(s): Arai M, Tejima K, Ikeda H, Tomiya T, Yanase M, Inoue Y, Nagashima K, Nishikawa T, Watanabe N, Omata M, Fujiwara K.
  • Journal Title: J Gastroenterol Hepatol 22 : S1
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Leucine stimulates HGF production by hepatic stellate cells through mTOR pathway. (2007)
  • Author(s): Tomiya T, Nishikawa T, Inoue Y, Ohtomo N, Ikeda H, Tejima K, Watanabe N, Tanoue Y, Omata M. Fujiwara K
  • Journal Title: Biochem Biophys Res Commun 358 Pages: 176-180
  • Peer Reviewed
• [Journal Article] Effect of rapamycin on hepatocyte function and proliferation induced by growth factors. (2007)
  • Author(s): Tomiya T, Yamaoka M, Inoue Y, Nishikawa T, Yanase M, Ikeda H, Tejima K, Nagashima K, Watanabe N, Omata M, Fujiwara K.
  • Journal Title: Chemotherapy 53 Pages: 59-69
  • Peer Reviewed
• [Journal Article] Effect of rapamycin on hepatocyte function and proliferation induced by growth factors. (2007)
  • Author(s): Tomiya T, Yamaoka M, Inoue Y, Nishikawa T, Yanase M, Ikeda H, Tejima K, et al.
  • Journal Title: Chemotherapy 53・1 Pages: 59-69
• [Journal Article] Hepatic stellate cell damage may lead to decreased plasma ADAMTS13 activity in rats. (2007)
  • Author(s): Kume Y, Ikeda H, Inoue M, Tejima K, Tomiya T, Nishikawa T, Watanabe N, et al.
  • Journal Title: FEBS Letters 58・18 Pages: 1631-1634
• [Journal Article] Leucine stimulates HGF production by hepatic stellate cells through mTOR pathway (2007)
  • Author(s): Tomiya T, Nishikawa T, Inoue Y, Ohtomo N, Ikeda H, Tejima K, et al.
  • Journal Title: Biochemical And Biophysical Research Communications (印刷中)
• [Journal Article] Expression of trnsforming growth factor-alpha and -beta in hepatic lobes after hemihepatic portal vein embolization. (2006)
  • Author(s): Kusaka K, H, Tomiya, T, Takayama, T, Makuuchi M
  • Journal Title: Digestive Diseases and Sciences 51・8 Pages: 1404-1412
• [Journal Article] The herbal medicine inchin-ko-to (TJ-135) induces apoptosis in cultured rat hepatic stellate cells. (2006)
  • Author(s): Ikeda H, Nagashima K, Yanase M, Tomiya T, Arai M, Inoue Y, Tejima K, et al.
  • Journal Title: Life Sciences 78・19 Pages: 2226-2233
• [Journal Article] Impaired liver regeneration in acute liver failure: the significance of cross-comm unication of growth associated factors in liver regeneration
  • Author(s): Tomiya T, Omata M, Imamura H, Fujiwara K.
  • Journal Title: Hepatol Res
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Impaired liver regeneration in acute liver failure : the significance of cross-communication of growth associated actors in liver regeneration
  • Author(s): Tomiya T, Omata M, Imamura H, Fujiwara K.
  • Journal Title: Hepatol Res (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Impaired Liver regeneration in acute liver failure (2007)
  • Author(s): Tomiya T, Omata M, Imamura H, Fujiwara K.
  • Organizer: Sixth JSH Single Topic Conference
  • Place of Presentation: Iwate, Japan
  • Year and Date: 2007-09-28
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Pharmacological action of BCAAs on the liver: Possible contribution of BCAAs to the function of hepatic stellate cells. (2007)
  • Author(s): Tomiya T, Nishikawa T, Ohtomo N, moue Y, Tejima K, Ikeda H, Watanabe N, Tanoue Y, Omata M, fujiwara K.
  • Organizer: Sixth JSH Single Topic Conference
  • Place of Presentation: Iwate, Japan
  • Year and Date: 2007-09-28
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Impaired liver regeneration in acute liver failure. (2007)
  • Author(s): Tomiya T, Omata M, Imamura H, Fujiwara K.
  • Organizer: Sixth JSH Single Topic Conference
  • Place of Presentation: Iwate, Japan
  • Year and Date: 2007-09-28
• [Presentation] The relationship between serum follistatin levels and liver regeneration in hepatectomized patients (2007)
  • Author(s): Tomiya T, Takabe K, Inoue Y, Tejima K, Ikeda H, Nishikawa T, Watanabe N, Ohtomo N, Omata M, Vale W, Fujiwara K.
  • Organizer: The Asian Pacific Association for the Study of Liver Diseases
  • Place of Presentation: Kyoto, Japan
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Inhibition of Rho-kinase leads to hepatocyte protection in vitro and in vivo (2007)
  • Author(s): Ikeda H, Tomiya T, Tejima K, Nishikawa T, Watanabe N, Ohtomo N, Yatomi Y, Fujiwara K, Omata M.
  • Organizer: The Asian Pacific Association for the Study of Liver Diseases
  • Place of Presentation: Kyoto, Japan
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Chemotherapy-induced HB V reactivation in an HBV carrier showing negative for HBs Ag and HBs Ab (2007)
  • Author(s): Ohtomo N, Tomiya T, Sakamoto K, Yoshida H, Kato N, Tejima K, Nishikawa T, Watanabe N, Ikeda H, Omata M.
  • Organizer: The Asian Pacific Association for the Study of Liver Diseases
  • Place of Presentation: Kyoto, Japan
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Oxygen radical production by NADPH oxidase in Kupffer cells promotes ischemic tolerance (2007)
  • Author(s): Tejima K, Arai M, Ikeda H, Tomiya T, Nishikawa T, Watanabe N, Ohtomo N, Yatomi Y, Omata M, Fujiwara K.
  • Organizer: The Asian Pacific Association for the Study of Liver Diseases
  • Place of Presentation: Kyoto, Japan
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Impaired liver regeneration in acute liver failure (2007)
  • Author(s): Tomiya T, Omata M, Imamma H, Fujiwara K.
  • Organizer: Sixth JSH Single Topic Conference
  • Place of Presentation: Iwate, Japan
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Pharmacological action of BCAAs on the liver : Possible contribution of BCAAs to the function of hepatic stellate cells (2007)
  • Author(s): Tomiya T, Nishikawa T, Ohtomo N, Inoue Y, Tejima K, Ikeda H, Watanabe N, Tanoue Y, Omate. M, Fujiwara K.
  • Organizer: Sixth JSH Single Topic Conference
  • Place of Presentation: Iwate, Japan
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Serum follistatin levels as a marker of hepato-gastrointestinal carcinomas (2007)
  • Author(s): Tomiya T, Takabe K, Inoue Y, Tejima K, Ikeda H, Nishikawa T, Watanabe N, Ohtomo N, Omata M, Vale W, Fujiwara K.
  • Organizer: Asian Pacific Digestive Week 2007
  • Place of Presentation: Kobe, Japan
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Induction of p53-related effector genes may regulate hepatocyte proliferation stimulated by hepatocyte growth factor (2007)
  • Author(s): Inoue Y, Tomiya T, Nishikawa T, Ohtomo N, Tanoue Y, Tejima K, Ikeda H, Watanabe N, Omata M, Fujiwara K.
  • Organizer: Asian Pacific Digestive Week 2007
  • Place of Presentation: Kobe, Japan
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Stimulatory effect of amino acids on HGF production in hepatic stellate cells (2007)
  • Author(s): Nishikawa T, Tomiya T, Ohtomo N, Inoue Y, Tanoue Y, Tejima K, Ikeda H, Watanabe N, Omata M, Fujiwara K.
  • Organizer: Asian Pacific Digestive Week 2007
  • Place of Presentation: Kobe, Japan
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Plasma lysophosphatidic acid level and serum autotaxin activity are increased in liver injury in rats in relation to its severity (2007)
  • Author(s): Watanabe N, Ikeda H, Tomiya T, Tejima K, Nishikawa T, Ohtomo N, Yatomi Y, Omta M, Fuiwara K.
  • Organizer: Asian Pacific Digestive Week 2007
  • Place of Presentation: Kobe, Japan
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Sublethal oxidative stress induces hepatic ischemic tolerance via NADPH oxidase in Kupffer cells (2007)
  • Author(s): Tejima K, Arai M, Ikeda H, Tomiya T, Nishikawa T, Watanabe N, Ohtomo N, Yatomi Y, Omata M, Fujiwara K.
  • Organizer: Asian Pacific Digestive Week 2007
  • Place of Presentation: Kobe, Japan
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Induction of P53-related effector genes may regulate hepatocyte proliferation stimulated by hepatocyte growth factor (2006)
  • Author(s): Tomiya T, Inoue Y, Nishikawa T, Ohtomo N, Yanase M, Ikeda H, Tejima K, Omata M, Fujiwara K.
  • Organizer: FASEB Summer Research Conference
  • Place of Presentation: Colorado, USA
  • Year and Date: 2006-07-24
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Induction of P53-related effector genes may regulate hepatocyte proliferation stimulated by hepatocyte growth factor (2006)
  • Author(s): Tomiya T, Inoue Y, Nishikawa T, Ohtomo N, Yanase M, Ikeda H, Tejima K, Omata M, Fujiwara K.
  • Organizer: FASEB Summer Research Conference
  • Place of Presentation: Snowmass, Colorado, USA
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Expression of growth associated factors in regenerative and non-regenerative regions of the liver in patients with fulminant hepatic failure (2006)
  • Author(s): Soeda J, Imamura ra H, Tomiya T, Hashikura Y, Kawasaki S, Fujiwara K, Miyagawa S.
  • Organizer: FASEB Summer Research Conference
  • Place of Presentation: Snowmess, Colorado, USA
  • Description: 「研究成果報告書概要(欧文)」より