Crosstalk between iron metabolic disorder and lipid metabolic disorder in hepatocarcinogenesis

• Project/Area Number: 20590782
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Kawasaki Medical School
• Principal Investigator: HINO Keisuke Kawasaki Medical School, 医学部, 教授 (80228741)
• Co-Investigator(Kenkyū-buntansha): KORENAGA Masaaki 川崎医科大学, 医学部, 准教授 (70420536)
• Co-Investigator(Renkei-kenkyūsha): GONDO Toshikazu 山口大学, 医学部附属病院, 准教授 (30221253)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2010: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2009: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2008: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: C型肝炎ウイルス / 肝発癌 / 鉄代謝 / 肝脂肪化 / ミトコンドリア / 小胞体ストレス / C型肝炎 / 鉄 / 活性酸素 / グリチルリチン / トランスジェニックマウス / 鉄過剰 / SREBP1

Research Abstract

Metabolic disorders such as iron overload and/or fatty deposition in the liver are one of the well-known pathophysiological features in hepatitis C virus (HCV)-associated hepatocarcinogenesis. Using male transgenic mice expressing the HCV polyprotein which develop hepatic steatosis followed by hepatocellular carcinoma in the presence of hepatic iron overload, we investigated the mechanisms by which hepatic iron overload contributed to the development of hepatic steatosis. Hepatic iron levels were positively correlated with triglyceride concentrations in the liver. Iron-related oxidative stress aggravated mitochondrial injury leading to reduced expression of carnitine palmitoyl transferase I, and induced unfolded protein response which in turn increased the expression of sterol-regulatory element binding protein I, a transcription factor involved in lipid synthesis.

Research Products

• [Journal Article] Type I interferon receptor in peripheral blood mononuclear cells may predict response to intraarterial 5-fluorouracil/interferon combination therapy for advanced hepatocellular carcinoma-a pilot study- (2011)
  • Author(s): Tomiyama Y, Yoshioka N, Yanai Y, Kawase T, Nishina S, Hara Y, Yoshida K, Korenaga K, Korenaga M, Hino K
  • Journal Title: Hepat Med 3 Pages: 45-52
  • Peer Reviewed
• [Journal Article] Focal nodular hyperplasia-like nodule with reduced expression of organic anion transporter 1B3 in alcoholic liver cirrhosis. (2011)
  • Author(s): Doi N, Tomiyama Y, Kawase T, Nishina S, Yoshioka N, Hara Y, Yoshida K, Korenaga K, Korenaga M, Moriya T, Urakami A, Nakashima O, Kojiro M, Hino K
  • Journal Title: Intern Med 50 Pages: 1193-9
  • NAID: 130000770471
  • Peer Reviewed
• [Journal Article] The rs80999 polymorphism, determined by a suitable genotyping method, is a better predictor for response to pegylated interferon-α/ribavirin therapy in Japanese patients than other SNPs associated with IL28B. (2011)
  • Author(s): Ito K, Higami K, Masaki N, Sugiyama M, Mukaide M, Saito H, Aoki Y, sato Y, Imamura M, Murata K, Nomura H, Hige S, Adachi H, Hino K, Yatsuhashi H, Orito E, Kani S, Tanaka Y, Mizokami M
  • Journal Title: J Clin Microbiol 49 Pages: 1853-60
  • Peer Reviewed
• [Journal Article] Recommendation of lamivudine-to-entecavir switching treatment in chronic hepatitis B responders : Randomized controlled study. (2011)
  • Author(s): Matsuura K, Tanaka Y, Kusakabe A, Hige S, Inoue J, Komatsu M, Kuramitsu T, Hirano K, Ohno T, Hasegawa I, Kobashi H, Hino K, Hiasa Y, Nomura H, Sugauchi F, Nojiri S, Joh T, Mizokami M
  • Journal Title: Hepatol Res 41 Pages: 505-11
  • Peer Reviewed
• [Journal Article] A glycyrrhizin-containing preparation reduces hepatic steatosis induced by hepatitis C virus protein and iron in mice. (2011)
  • Author(s): Korenaga M, Hidaka I, Nishina S, Sakai A, Shinozaki A, Gondo T, Furutani T, Kawano H, Sakaida I, Hino K
  • Journal Title: Liver Int 31 Pages: 552-60
  • Peer Reviewed
• [Journal Article] A glycyrrhtzin-containing prepazation reduces hepatic steatosis induced by hepatitis C virus protein and iron in mice (2011)
  • Author(s): Korenaga M
  • Journal Title: Liver Int Volume: 31 Pages: 552-60
  • Peer Reviewed
• [Journal Article] The rs80999 polymorphism, determined by a suitable genotyping method, is a better predictor for response to pegylated interferon-α/ribavirin therapy in Japanese patients than other SNPs associated with IL28B (2011)
  • Author(s): Ito K
  • Journal Title: J Clin Microbiol Volume: 49 Pages: 1853-60
  • Peer Reviewed
• [Journal Article] Type I interferon receptor in peripheral blood mononuclear cems may predict response to intraarterial 5-fluorouracil/interferon combination therapy for advanced hepatocellular carcinoma-a pilot study- (2011)
  • Author(s): Tomiyama Y
  • Journal Title: Hepat Med Volume: 3 Pages: 45-52
  • Peer Reviewed
• [Journal Article] Recommendation of Lamivudine-to-Entecavir switching treatment in chronic hepatitis B responders : Randomized controlled trial (2011)
  • Author(s): Tanaka Y
  • Journal Title: Hepatol Res Volume: (In press)
  • Peer Reviewed
• [Journal Article] Molecular typing of Bartonella henselae DNA extracted from human clinical specimens and cat isolates in Japan. (2010)
  • Author(s): Yanagihara M, Tsuneoka H, Hoshide S, Ishido E, Umeda A, Tsukahara M, Nojima J, Ichihara K, Hino K, Hirai I, Yamamoto Y
  • Journal Title: FEMS Immunol Med Microbiol 60 Pages: 44-8
  • Peer Reviewed
• [Journal Article] Hepatitis C virus protein and iron overload induce hepatic steatosis through the unfolded protein response in mice. (2010)
  • Author(s): Nishina S, Korenaga M, Hidaka I, Shinozaki A, Sakai A, Gondo T, Tabuchi M, Kishi F, Hino K
  • Journal Title: Liver Int 30 Pages: 683-92
  • Peer Reviewed
• [Journal Article] Management of hepatitis C ; Report of the Consensus Meeting at the 45th Annual Meeting of the Japan Society of Hepatology (2009). (2010)
  • Author(s): Namiki I, Nishiguchi S, Hino K, Suzuki F, Kumada H, Itoh Y, Asahina Y, Tamori A, Hiramatsu N, Hayashi N, Kudo M
  • Journal Title: Hepatol Res 40 Pages: 347-68
  • NAID: 10027291334
  • Peer Reviewed
• [Journal Article] Molecular typing of Bartonella henselae DNA extracted from human clinical specimens and cat isolates in Japan (2010)
  • Author(s): Yanagihara M
  • Journal Title: FEMS Immunol Med Microbiol Volume: 60 Pages: 44-48
  • Peer Reviewed
• [Journal Article] Hepatitis C virus protein and iron overload induce hepatic steatosis through the unfolded protein response in mice (2010)
  • Author(s): Nishina S
  • Journal Title: Liver Int Volume: 30 Pages: 683-92
  • Peer Reviewed
• [Journal Article] Management of hepatitis C ; Report of the Consensus Meeting at the 45th Annual Meeting of the Japan Society of Hepatology (2009) (2010)
  • Author(s): Namiki I
  • Journal Title: Hepatol Res Volume: 40 Pages: 347-68
  • Peer Reviewed
• [Journal Article] Hepatitis C virus protein and iron overload induce hepatic steatosis through the unfolded protein response in mice (2010)
  • Author(s): Nishina S, Korenaga M, Hino K, et al.
  • Journal Title: Liver Int 30 Pages: 683-692
  • Peer Reviewed
• [Journal Article] Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. (2009)
  • Author(s): Tanaka Y, Nsihsida N, Sugiyama M, Kurosaki M, Matsuura K, Sakamoto N, Nakagawa M, Korenaga M, Hino K, Hige S, Ito Y, Mita Y, Tanaka E, Mochida S, Murawaki Y, Honda M, Sakai A, Hiasa Y, Nishiguchi S, Koike A, Sakaida I, Imamura M, Ito K, Yano K, Masaki N, Sugauchi F, Izumi N, Tokunaga K, Mizokami M
  • Journal Title: Nat Genet 41 Pages: 1105-9
  • Peer Reviewed
• [Journal Article] Direct cytopathic effects of particular hepatitis B virus genotypes in severe Control combined immunodeficiency transgenic with urokinase-type plasminogen activator mouse with human hepatocytes. (2009)
  • Author(s): Sugiyama M, Tanaka Y, Kurbanov F, Maruyama I, Shimada T, Takahashi S, Shirai T, Hino K, Sakaida I, Mizokami M
  • Journal Title: Gastroenterology 136 Pages: 652-62
  • Peer Reviewed
• [Journal Article] Distribution of hepatitis B virus genotypes among patients with chronic infection in Japan shifting toward an increase of genotype A. (2009)
  • Author(s): Matsuura K, Tanaka Y, Hige S, Yamada G, Murawaki Y, Komatsu M, Kuramitsu T, Kawata S, Tanak E, Izumi N, Okuse C, Kakumu S, Okanoue T, Hino K, Hiasa Y, Sata M, Maeshiro T, Sugauchi F, Nojiri S, Joh T, Miyakawa Y, Mizokami M
  • Journal Title: J Clin Microbiol 47 Pages: 1476-83
  • Peer Reviewed
• [Journal Article] Usefulness of Sonazoid contrast-enhanced ultrasonography for hepatocellular carcinoma : comparison with pathological diagnosis and superparamagnetic iron oxide magnetic resonance images. (2009)
  • Author(s): Korenaga K, Korenaga M, Furukawa M,Yamasaki T, Sakaida I
  • Journal Title: J Gastroenterol 44 Pages: 733-41
  • NAID: 10025176213
  • Peer Reviewed
• [Journal Article] Direct cytopathic effects of particular hepatitis B virus genotypes in severe combined immunodeficiency transgenic with urokinase- type plasminogen activator mouse with human hepatocytes (2009)
  • Author(s): Sugiyama M, Tanaka Y, Hino K, et al.
  • Journal Title: Gastroenterology 136 Pages: 652-62
  • Peer Reviewed
• [Journal Article] Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C (2009)
  • Author(s): Tanaka Y, Nishida N, Hino K, et al.
  • Journal Title: Nat Genet 41 Pages: 1105-9
  • Peer Reviewed
• [Journal Article] Distribution of hepatitis B virus genotypes among patients with chronic infection in Japan shifting toward an increase genotype A. (2009)
  • Author(s): Matsuura K, Tanaka Y, Hino K, et al.
  • Journal Title: J Clin Microbial 47 Pages: 1476-1483
  • Peer Reviewed
• [Journal Article] Hepatitis C virus-induced reactive oxygen species raise hepatic iron level in mice by reducing hepcidin transcription. (2008)
  • Author(s): Nishina S, Hino K, Korenaga M, Vecchi C, Pietrangelo A, Mizukami Y, Furutani T, Sakai A, Okuda M, Hidak I, Okita K, Sakaida I
  • Journal Title: Gastroenterology 134 Pages: 226-38
  • Peer Reviewed
• [Journal Article] Validating a Markov model of treatment for hepatitis C virus-related hepatocellular carcinoma. (2008)
  • Author(s): Ishida H, Wong JB, Hino K, Kurikawa F, Nishina S, Sakaida I, Okita K, Tamesa T, Oka M, Torimura T, Sata M, Takahashi S, Chayama K, Inoue Y
  • Journal Title: Methods Inf Med 47 Pages: 529-40
  • Peer Reviewed
• [Journal Article] Mitochondrial electron transport inhibition in full genomic hepatitis C virus replicon cells is restored by reducing viral replication. (2008)
  • Author(s): Ando M, Korenaga M, Hino K, Ikeda M, Kato N, Nishina S, Hidaka I, Sakaida I
  • Journal Title: Liver Int 28 Pages: 1158-66
  • Peer Reviewed
• [Journal Article] Effects of a late evening snack combined with alpha-glucosidase inhibitor on liver cirrhosis. (2008)
  • Author(s): Korenaga K, Korenaga M, Uchida K, Yamasaki T, Sakaida I
  • Journal Title: Hepatol Res 38 Pages: 1087-97
  • Peer Reviewed
• [Journal Article] Validating a Markov model of treatment for hepatitis C virus-related hepatocellular carcinoma. (2008)
  • Author(s): Ishida H, Wong BJ, Hino K, et al.
  • Journal Title: Methods Inf Med 47 Pages: 529-540
  • Peer Reviewed
• [Journal Article] Mitochondrial electron transport inhibition in full genomic hepatitis C virus replicon cells is restored by reducing viral replication. (2008)
  • Author(s): Ando M, Korenaga M, Hino K, et al
  • Journal Title: Liver Int 28 Pages: 1158-1166
  • Peer Reviewed
• [Presentation] Iron induced oxidative stress inhibits viral replication in full genomic hepatitis C virus replicon cells. (2010)
  • Author(s): Korenaga M, Hino K, et al
  • Organizer: The 61^<th> Annual Meeting of the American Association for the Study of Liver Disease
  • Place of Presentation: Boston, USA
  • Year and Date: 2010-11-04
• [Presentation] Glycyrrhizin reduces hepatic steatosis induced b6y hepatitis C virus protein and iron overload in mice. (2010)
  • Author(s): Korenaga M, Hino K, et al
  • Organizer: The 61^<th> Annual Meeting of the American Association for the Study of Liver Disease
  • Place of Presentation: Boston, USA
  • Year and Date: 2010-11-04
• [Presentation] Iron induced oxidative stress inhibits viral replication in full genomic hepatitis C virus replicon cells (2010)
  • Author(s): Korenaga M
  • Organizer: The 61^<th> Annual Meeting of the American Association for the Study of Liver Disease
  • Place of Presentation: Boston, USA
  • Year and Date: 2010-11-04
• [Presentation] Glycyrrhizin reduces hepatic steatosis induced by hepatitis C virus protein and iron overload in mice (2010)
  • Author(s): Korenaga M
  • Organizer: The 61^<th> Annual Meeting of the American Association for the Study of Liver Disease
  • Place of Presentation: Boston, USA
  • Year and Date: 2010-11-04
• [Presentation] Inhibition of the oxidative stress reduces hepatic iron overload through the upregulation of hepcidin level in transgenic mice expressing the hepatitis C virus polyprotein. (2009)
  • Author(s): Korenaga M, Nishina S, Hino K, et al
  • Organizer: The 60^<th> Annual Meeting of the American Association for the Study of Liver Disease
  • Place of Presentation: Boston, USA
  • Year and Date: 2009-11-03
• [Presentation] Inhibition of the oxidative stress reduces hepatic iron overload through the upregulation of hepcidin level in transgenic mice expressing the hepatitis Cvirus polyprotein (2009)
  • Author(s): Korenaga M, Nishina S, Hino K, et al.
  • Organizer: The 60^<th> Annual Meeting of the American Association for the Study of Liver Disease
  • Place of Presentation: Boston, USA
  • Year and Date: 2009-11-03
• [Presentation] Iron overload causes hepatic steatosis through the endopasmic reticulum stress in transgenic mice expressing the hepatitis C virus polyprotein. (2008)
  • Author(s): Nishina S, Hino K, Korenaga M, et al
  • Organizer: The 59^<th> Annual Meeting of the American Association for the Study of Liver Disease
  • Place of Presentation: Boston, USA
  • Year and Date: 2008-11-02