C型肝炎における代謝異常:肝疾患進展への関与とその制御

2010 Fiscal Year Annual Research Report

• Project/Area Number: 20390204
• Research Institution: The University of Tokyo
• Principal Investigator: 小池 和彦 東京大学, 医学部附属病院, 教授 (80240703)
• Keywords: C型肝炎 / 脂質代謝異常 / 酸化ストレス / 脂肪酸 / ミトコンドリア

Research Abstract

C型肝炎患者の肝臓に蓄積する脂肪には特徴があり、オレイン酸などの一価不飽和脂肪酸(モノエン酸)が増加している。不飽和脂肪酸の増加をもたらすdesaturase活性はコア蛋白発現HepG2細胞においてδ-9、δ-6、δ-5 desaturaseのいずれもが亢進していた。多価不飽和脂肪酸(PUFA)であるeicosatetraynoic acid (EPA)やarachidonic acid (AA)の投与によって一価不飽和脂肪酸はコア蛋白非特異的に減少したが、活性酸素種(ROS, reactive oxygen species)は減少しなかった。これに対して、ピルビン酸の投与によって解糖系においてNADHを消費させると、中性脂肪、一価不飽和脂肪酸、ROS産生のいずれもがコア蛋白発現細胞で特異的に減少した。コア蛋白発現HepG2細胞において、対照細胞に比して発現の増加していた脂質代謝遺伝子の発現制御に重要な転写因子であるSREBP-1cは、EPAやAAの投与によって低下が認められた。HCVによるミトコンドリア電子伝達系の機能障害が、ROS産生、脂質代謝異常を含むC型肝炎の肝病態において中心的な役割を演じている事が示された。一方、C型肝炎患者にみられる鉄過剰状態を、マウスへの腹腔内鉄投与によりシミュレートしたところ、鉄増加時に誘導される抗酸化系酵素であるヘムオキシゲナーゼ(HO)-1とNADH dehydrogenase, quinone (NQO)-1がHCVコア蛋白存在下では誘導が阻害され、酸化ストレス消去能が低下することが見いだされた。HO-1制御因子として知られている転写因子Nrf2は、この現象に関与していなかった。HCVは酸化ストレス産生を増加させるだけでなく、抗酸化系を阻害し、酸化ストレスをより増悪させることが明らかになった。

Research Products

• [Journal Article] Apoptosis signal-regulating kinase 1 inhibits hepatocarcinogenesis by controlling the tumor-suppressing function of stress-activated MAPK (2011)
  • Author(s): Nakagawa H, Hirata Y, Iakeda K, Hayakawa Y, Sato T, Kinoshita H, Sakamoto K, Nakata W, Hikiba Y, Omata M, Yoshida H, Koike K, Ichijo H, Maeda S.
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• [Journal Article] Direct differentiation of hepatic cells from human induced pluripotent stem cells using a limited number of cytokines (2011)
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• [Journal Article] Hepatocellular carcinoma with extrahepatic metastasis : Clinical features and prognostic factors (2011)
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• [Journal Article] Autotaxin as a novel serum marker of liver fibrosis (2011)
  • Author(s): Nakagawa H, Ikeda H, Nakamura K, Ohkawa R, Masuzaki R, Tateishi R, Yoshida H, Watanabe N, Tejima K, Kume Y, Iwai T, Suzuki A, Tomiya T, Inoue Y, Nishikawa T, Ohtomo N, Tanoue Y, Omata M, Igarashi K, Aoki, J, Koike K, Yatomi Y.
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• [Journal Article] Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma (2011)
  • Author(s): Yasui K, Hashimoto E, Komorizono Y, Koike K, Arii S, Imai Y, Shima T, Kanhara Y, Saihara T, Mori T, Kawata S, Uto H, Takami S, Sumida Y, Takamura T, Kawanaka M, Okanoue T
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• [Journal Article] Effect of treatment with polynsatured fatty acids on HCV-or diet-induced fatty liver (2011)
  • Author(s): Koike K, Miyoshi H, Yotsyanagi H, Moriya K.
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• [Journal Article] Intrahepatic bile duct dilatation after percutaneous radiofrequency ablation for hepatocellular carcinoma : impact on patient's prognosis (2011)
  • Author(s): Kondo Y, Shiina S, Tateishi R, Arano T, Uchino K, Enooku K, Goto E, Nakagawa H, Masuzaki R, Asaoka Y, Fujie H, Goto T, Omata M, Yoshida H, Koike K.
  • Journal Title: Liver Int Volume: 31 Pages: 197-205
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• [Journal Article] Pathogenesis of lipid metabolism disorder in hepatitis C : polyunsaturated fatty acids counteract lipid alterations induced by the core protein. (2011)
  • Author(s): Miyoshi H, Moriya K, Tsutsumi T, Shinzawa S, Fujie H, Shintani Y, Fujinaga H, Goto K, Todoroki T, Suzuki T, Miyamura T, Matsuura Y, Yotsuyanagi H, Koike K.
  • Journal Title: J Hepatol Volume: 54 Pages: 432-438
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• [Journal Article] Serum level of adiponectin and the risk of liver cancer development in chronic hepatitis C patients (2010)
  • Author(s): Arano T, Nakagawa H, Tateishi R, Ikeda H, Uchino K, Enooku K, Goto E, Masuzaki R, Asaoka Y, Kondo Y, Goto T, Shiina S, Omata M, Yoshida H, Koike K.
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• [Journal Article] Utility of contrast enhanced ultrasonography with sonazoid in radiofre quency ablation for hepatocellular carcinoma (2010)
  • Author(s): Masuzaki R, Shiina S, Tateishi R, Yoshida H, Goto E, Sugioka Y, Kondo Y, Goto T, Ikeda H, Omata M, Koike K.
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• [Journal Article] Usefulness of multi-detector helical CT with multiplanar reconstruction for depicting the duodenal varices with multiple collateral shunt vessels (2010)
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• [Journal Article] Impact of changes in obesity parameters on glucose metabolism and insulin resistance over a one-year period. (2010)
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• [Journal Article] Lipid metabolism and pathogenesis of liver disease in hepatitis C viral infection. (2010)
  • Author(s): Koike K, Tsutsumi T, Yotsuyanagi H, Moriya K.
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• [Journal Article] Thrombocytopenia is more severe in advanced chronic hepatitis C than B with the same grade of splenomegaly. (2010)
  • Author(s): Tejima K, Masuzaki R, Ikeda H, Yoshida H, Tateishi R, Sugioka Y, Kume Y, Okano T, Iwai T, Gotoh H, Katoh S, Suzuki S, Yatomi Y, Omata M, Koike K.
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• [Journal Article] Association between gamma-glutamyl transferase levels and insulin resistance according to alcohol consumption and number of cigarettes smoked. (2010)
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• [Journal Article] Expression of alpha-taxilin in hepatocellular carcinoma correlates with growth activity and malignant potential of the tumor. (2010)
  • Author(s): Ohtomo N, Tomiya T, Tanoue Y, Inoue Y, Nishikawa T, Ikeda H, Seyama Y, Kokudo N, Shibahara J, Fukayama M, Koike K, Shirataki H, Fujiwara K.
  • Journal Title: Int J Oncol Volume: 37 Pages: 1417-1423
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• [Journal Article] Plasma sphingosine 1-phosphate level is reduced in patients with chronic liver disease caused by hepatitis C (2010)
  • Author(s): Ikeda H, Ohkawa R, Watanahe N, Nakamura K, Kume Y, Okubo S, Yokota H, Tomiya T, Inoue Y, Nishikawa T, Ohtomo N, Tanoue Y, Koike K, Yatomi Y.
  • Journal Title: Clin Chim Acta Volume: 411 Pages: 765-770
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• [Journal Article] Effect of nucleoside analogue-interferon sequential therapy on patients with acute exacerbation of chronic hepatitis B (2010)
  • Author(s): Okuse C, Yotsuyanagi H, Yamada N, Okamoto M, Ikeda H, Kobayashi M, Fukuda Y, Takahashi H, Nagase Y, Suzuki Y, Malsunaga K, Ishii T, Matsumoto N, Koike K, Suzuki M, Itoh F.
  • Journal Title: Hepatol Res Volume: 40 Pages: 461-469
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• [Journal Article] RNA dependent RNA polymerase of hepatitis C virus binds to its coding region RNA stem-loop structure, 5BSL3.2, and its negative strand (2010)
  • Author(s): Kanamori H, Yuhashi K, Ohnishi S, Koike K, Kodama T.
  • Journal Title: J Gen Virol Volume: 91 Pages: 1207-1212
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• [Journal Article] Hepatitis C virus core protein compromises iron-induced activation of antioxidants in mice and HepG2 cells (2010)
  • Author(s): Moriya K, Miyoshi H, Shinzawa S, Tsutsumi T, Fujie H, Goto K, Shintani Y, Yotsuyanagi H, Koike K.
  • Journal Title: J Med Virol Volume: 82 Pages: 776-792
  • Peer Reviewed
• [Journal Article] Expression of pituitary tumor transforming gene 1 (PTTG1)/securin in hepatitis B virus-associated liver diseases : Evidence for a hepatitis B virus X protein-mediated inhibition of PTTG1 ubiquitination and degradation (2010)
  • Author(s): Molina-Jimenez F, Benedicto I, Murata M, Martin-Vilchez S, Seki T, Pintor-Toro JA, Tortotero M, Moreno-Otero R, Okazaki K, Koike K, Barbero JL, Matsuzaki K, Majano PL, Lopez-Cabrera M
  • Journal Title: Hepatology Volume: 51 Pages: 777-787
  • Peer Reviewed
• [Journal Article] Identification of hepatitis C virus genotype 2a replicon variants with reduced susceptibility to ribavirin. (2010)
  • Author(s): Hmwe SS, Aizakia H, Date T, Murakami K, Ishii K, Miyamura T, Koike K, Wakita T, Suzuki T.
  • Journal Title: Antiviral Res Volume: 85 Pages: 520-524
  • Peer Reviewed
• [Journal Article] Prolonged treatment with PEG-IFN a-2b and ribavirin can improve SVR in chronic hepatitis C genotype 1 patients with late response in a clinical real-life setting in Japan (2010)
  • Author(s): Watanabe S, Enomoto N, Koike K, Izumi N, Takikawa H, Hashimoto E, Moriyasu F, Kumada H, Imawari M, PERFECT STUDY GROUP
  • Journal Title: Hepatol Res Volume: 40 Pages: 135-144
  • Peer Reviewed
• [Journal Article] Animal models for hepatitis C and related liver disease (2010)
  • Author(s): Koike K, Moriya K, Matsuura Y
  • Journal Title: Hepatol Res Volume: 40 Pages: 69-82
  • Peer Reviewed
• [Presentation] Association of the substitution of amino acid 75 in the hepatitis virus core region with IL-8 upregulation and hepatocarcinogenesis (2010)
  • Author(s): Tsutsumi T, Miyoshi H, Goto Koji, Moriya K, Koike K.
  • Organizer: 17th International Meeting on Hepatitis C Virus and Related Viruses
  • Place of Presentation: Yokohama
  • Year and Date: 2010-09-17
• [Book] 肥満と消化器疾患 (2010)
  • Author(s): 小池和彦(共著)
  • Total Pages: 224
  • Publisher: 金原出版
• [Patent(Industrial Property Rights)] 肝細胞癌発生予測因子としての血中ADAMTS13 (2010)
  • Inventor(s): 池田均、矢冨裕、建石良介、小池和彦、小野智子
  • Industrial Property Rights Holder: 東京大学
  • Industrial Property Number: 12B10Y001-1
  • Filing Date: 2010-11-05