肝発癌における鉄代謝異常と脂質代謝異常のクロストーク

• 研究課題/領域番号: 20590782
• 研究種目: 基盤研究(C)
• 配分区分: 補助金
• 応募区分: 一般
• 研究分野: 消化器内科学
• 研究機関: 川崎医科大学
• 研究代表者: 日野 啓輔 川崎医科大学, 医学部, 教授 (80228741)
• 研究分担者: 是永 匡紹 川崎医科大学, 医学部, 准教授 (70420536)
• 連携研究者: 権藤 俊一 山口大学, 医学部附属病院, 准教授 (30221253)
• 研究期間 (年度): 2008 – 2010
• 研究課題ステータス: 完了 (2010年度)
• 配分額: 4,680千円 (直接経費: 3,600千円、間接経費: 1,080千円); 2010年度: 780千円 (直接経費: 600千円、間接経費: 180千円); 2009年度: 1,430千円 (直接経費: 1,100千円、間接経費: 330千円); 2008年度: 2,470千円 (直接経費: 1,900千円、間接経費: 570千円)
• キーワード: 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

研究概要

C型肝炎ウイルス(HCV)全遺伝子を発現するトランスジェニックマウス(HCV TgM)に鉄を負荷して肝発癌を引き起こすモデルを用いて、肝発癌過程における鉄代謝異常が脂質代謝異常を引き起こす機序を明らかにした。すなわち鉄代謝異常による肝内鉄蓄積が酸化ストレスを増強してミトコンドリア障害ならびに小胞体ストレスを惹起し、β酸化障害や脂質関連転写因子であるSREBP1を活性化して肝内脂肪蓄積を引き起こすことを明らかにした。

研究成果

• [雑誌論文] 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)
  • 著者名/発表者名: Tomiyama Y, Yoshioka N, Yanai Y, Kawase T, Nishina S, Hara Y, Yoshida K, Korenaga K, Korenaga M, Hino K
  • 雑誌名: Hepat Med 3 ページ: 45-52
  • 査読あり
• [雑誌論文] Focal nodular hyperplasia-like nodule with reduced expression of organic anion transporter 1B3 in alcoholic liver cirrhosis. (2011)
  • 著者名/発表者名: 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
  • 雑誌名: Intern Med 50 ページ: 1193-9
  • NAID: 130000770471
  • 査読あり
• [雑誌論文] 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)
  • 著者名/発表者名: 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
  • 雑誌名: J Clin Microbiol 49 ページ: 1853-60
  • 査読あり
• [雑誌論文] Recommendation of lamivudine-to-entecavir switching treatment in chronic hepatitis B responders : Randomized controlled study. (2011)
  • 著者名/発表者名: 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
  • 雑誌名: Hepatol Res 41 ページ: 505-11
  • 査読あり
• [雑誌論文] A glycyrrhizin-containing preparation reduces hepatic steatosis induced by hepatitis C virus protein and iron in mice. (2011)
  • 著者名/発表者名: Korenaga M, Hidaka I, Nishina S, Sakai A, Shinozaki A, Gondo T, Furutani T, Kawano H, Sakaida I, Hino K
  • 雑誌名: Liver Int 31 ページ: 552-60
  • 査読あり
• [雑誌論文] A glycyrrhtzin-containing prepazation reduces hepatic steatosis induced by hepatitis C virus protein and iron in mice (2011)
  • 著者名/発表者名: Korenaga M
  • 雑誌名: Liver Int 巻: 31 ページ: 552-60
  • 査読あり
• [雑誌論文] 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)
  • 著者名/発表者名: Ito K
  • 雑誌名: J Clin Microbiol 巻: 49 ページ: 1853-60
  • 査読あり
• [雑誌論文] 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)
  • 著者名/発表者名: Tomiyama Y
  • 雑誌名: Hepat Med 巻: 3 ページ: 45-52
  • 査読あり
• [雑誌論文] Recommendation of Lamivudine-to-Entecavir switching treatment in chronic hepatitis B responders : Randomized controlled trial (2011)
  • 著者名/発表者名: Tanaka Y
  • 雑誌名: Hepatol Res 巻: (In press)
  • 査読あり
• [雑誌論文] Molecular typing of Bartonella henselae DNA extracted from human clinical specimens and cat isolates in Japan. (2010)
  • 著者名/発表者名: Yanagihara M, Tsuneoka H, Hoshide S, Ishido E, Umeda A, Tsukahara M, Nojima J, Ichihara K, Hino K, Hirai I, Yamamoto Y
  • 雑誌名: FEMS Immunol Med Microbiol 60 ページ: 44-8
  • 査読あり
• [雑誌論文] Hepatitis C virus protein and iron overload induce hepatic steatosis through the unfolded protein response in mice. (2010)
  • 著者名/発表者名: Nishina S, Korenaga M, Hidaka I, Shinozaki A, Sakai A, Gondo T, Tabuchi M, Kishi F, Hino K
  • 雑誌名: Liver Int 30 ページ: 683-92
  • 査読あり
• [雑誌論文] Management of hepatitis C ; Report of the Consensus Meeting at the 45th Annual Meeting of the Japan Society of Hepatology (2009). (2010)
  • 著者名/発表者名: Namiki I, Nishiguchi S, Hino K, Suzuki F, Kumada H, Itoh Y, Asahina Y, Tamori A, Hiramatsu N, Hayashi N, Kudo M
  • 雑誌名: Hepatol Res 40 ページ: 347-68
  • NAID: 10027291334
  • 査読あり
• [雑誌論文] Molecular typing of Bartonella henselae DNA extracted from human clinical specimens and cat isolates in Japan (2010)
  • 著者名/発表者名: Yanagihara M
  • 雑誌名: FEMS Immunol Med Microbiol 巻: 60 ページ: 44-48
  • 査読あり
• [雑誌論文] Hepatitis C virus protein and iron overload induce hepatic steatosis through the unfolded protein response in mice (2010)
  • 著者名/発表者名: Nishina S
  • 雑誌名: Liver Int 巻: 30 ページ: 683-92
  • 査読あり
• [雑誌論文] Management of hepatitis C ; Report of the Consensus Meeting at the 45th Annual Meeting of the Japan Society of Hepatology (2009) (2010)
  • 著者名/発表者名: Namiki I
  • 雑誌名: Hepatol Res 巻: 40 ページ: 347-68
  • 査読あり
• [雑誌論文] Hepatitis C virus protein and iron overload induce hepatic steatosis through the unfolded protein response in mice (2010)
  • 著者名/発表者名: Nishina S, Korenaga M, Hino K, et al.
  • 雑誌名: Liver Int 30 ページ: 683-692
  • 査読あり
• [雑誌論文] Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. (2009)
  • 著者名/発表者名: 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
  • 雑誌名: Nat Genet 41 ページ: 1105-9
  • 査読あり
• [雑誌論文] 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)
  • 著者名/発表者名: Sugiyama M, Tanaka Y, Kurbanov F, Maruyama I, Shimada T, Takahashi S, Shirai T, Hino K, Sakaida I, Mizokami M
  • 雑誌名: Gastroenterology 136 ページ: 652-62
  • 査読あり
• [雑誌論文] Distribution of hepatitis B virus genotypes among patients with chronic infection in Japan shifting toward an increase of genotype A. (2009)
  • 著者名/発表者名: 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
  • 雑誌名: J Clin Microbiol 47 ページ: 1476-83
  • 査読あり
• [雑誌論文] Usefulness of Sonazoid contrast-enhanced ultrasonography for hepatocellular carcinoma : comparison with pathological diagnosis and superparamagnetic iron oxide magnetic resonance images. (2009)
  • 著者名/発表者名: Korenaga K, Korenaga M, Furukawa M,Yamasaki T, Sakaida I
  • 雑誌名: J Gastroenterol 44 ページ: 733-41
  • NAID: 10025176213
  • 査読あり
• [雑誌論文] Direct cytopathic effects of particular hepatitis B virus genotypes in severe combined immunodeficiency transgenic with urokinase- type plasminogen activator mouse with human hepatocytes (2009)
  • 著者名/発表者名: Sugiyama M, Tanaka Y, Hino K, et al.
  • 雑誌名: Gastroenterology 136 ページ: 652-62
  • 査読あり
• [雑誌論文] Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C (2009)
  • 著者名/発表者名: Tanaka Y, Nishida N, Hino K, et al.
  • 雑誌名: Nat Genet 41 ページ: 1105-9
  • 査読あり
• [雑誌論文] Distribution of hepatitis B virus genotypes among patients with chronic infection in Japan shifting toward an increase genotype A. (2009)
  • 著者名/発表者名: Matsuura K, Tanaka Y, Hino K, et al.
  • 雑誌名: J Clin Microbial 47 ページ: 1476-1483
  • 査読あり
• [雑誌論文] Hepatitis C virus-induced reactive oxygen species raise hepatic iron level in mice by reducing hepcidin transcription. (2008)
  • 著者名/発表者名: Nishina S, Hino K, Korenaga M, Vecchi C, Pietrangelo A, Mizukami Y, Furutani T, Sakai A, Okuda M, Hidak I, Okita K, Sakaida I
  • 雑誌名: Gastroenterology 134 ページ: 226-38
  • 査読あり
• [雑誌論文] Validating a Markov model of treatment for hepatitis C virus-related hepatocellular carcinoma. (2008)
  • 著者名/発表者名: 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
  • 雑誌名: Methods Inf Med 47 ページ: 529-40
  • 査読あり
• [雑誌論文] Mitochondrial electron transport inhibition in full genomic hepatitis C virus replicon cells is restored by reducing viral replication. (2008)
  • 著者名/発表者名: Ando M, Korenaga M, Hino K, Ikeda M, Kato N, Nishina S, Hidaka I, Sakaida I
  • 雑誌名: Liver Int 28 ページ: 1158-66
  • 査読あり
• [雑誌論文] Effects of a late evening snack combined with alpha-glucosidase inhibitor on liver cirrhosis. (2008)
  • 著者名/発表者名: Korenaga K, Korenaga M, Uchida K, Yamasaki T, Sakaida I
  • 雑誌名: Hepatol Res 38 ページ: 1087-97
  • 査読あり
• [雑誌論文] Validating a Markov model of treatment for hepatitis C virus-related hepatocellular carcinoma. (2008)
  • 著者名/発表者名: Ishida H, Wong BJ, Hino K, et al.
  • 雑誌名: Methods Inf Med 47 ページ: 529-540
  • 査読あり
• [雑誌論文] Mitochondrial electron transport inhibition in full genomic hepatitis C virus replicon cells is restored by reducing viral replication. (2008)
  • 著者名/発表者名: Ando M, Korenaga M, Hino K, et al
  • 雑誌名: Liver Int 28 ページ: 1158-1166
  • 査読あり
• [学会発表] Iron induced oxidative stress inhibits viral replication in full genomic hepatitis C virus replicon cells. (2010)
  • 著者名/発表者名: Korenaga M, Hino K, et al
  • 学会等名: The 61^<th> Annual Meeting of the American Association for the Study of Liver Disease
  • 発表場所: Boston, USA
  • 年月日: 2010-11-04
• [学会発表] Glycyrrhizin reduces hepatic steatosis induced b6y hepatitis C virus protein and iron overload in mice. (2010)
  • 著者名/発表者名: Korenaga M, Hino K, et al
  • 学会等名: The 61^<th> Annual Meeting of the American Association for the Study of Liver Disease
  • 発表場所: Boston, USA
  • 年月日: 2010-11-04
• [学会発表] Iron induced oxidative stress inhibits viral replication in full genomic hepatitis C virus replicon cells (2010)
  • 著者名/発表者名: Korenaga M
  • 学会等名: The 61^<th> Annual Meeting of the American Association for the Study of Liver Disease
  • 発表場所: Boston, USA
  • 年月日: 2010-11-04
• [学会発表] Glycyrrhizin reduces hepatic steatosis induced by hepatitis C virus protein and iron overload in mice (2010)
  • 著者名/発表者名: Korenaga M
  • 学会等名: The 61^<th> Annual Meeting of the American Association for the Study of Liver Disease
  • 発表場所: Boston, USA
  • 年月日: 2010-11-04
• [学会発表] 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)
  • 著者名/発表者名: Korenaga M, Nishina S, Hino K, et al
  • 学会等名: The 60^<th> Annual Meeting of the American Association for the Study of Liver Disease
  • 発表場所: Boston, USA
  • 年月日: 2009-11-03
• [学会発表] Inhibition of the oxidative stress reduces hepatic iron overload through the upregulation of hepcidin level in transgenic mice expressing the hepatitis Cvirus polyprotein (2009)
  • 著者名/発表者名: Korenaga M, Nishina S, Hino K, et al.
  • 学会等名: The 60^<th> Annual Meeting of the American Association for the Study of Liver Disease
  • 発表場所: Boston, USA
  • 年月日: 2009-11-03
• [学会発表] Iron overload causes hepatic steatosis through the endopasmic reticulum stress in transgenic mice expressing the hepatitis C virus polyprotein. (2008)
  • 著者名/発表者名: Nishina S, Hino K, Korenaga M, et al
  • 学会等名: The 59^<th> Annual Meeting of the American Association for the Study of Liver Disease
  • 発表場所: Boston, USA
  • 年月日: 2008-11-02