Search and validation of diagnostic marker for nonalcoholic steatohepatitis using proteomics.

• Project/Area Number: 20590786
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Kagoshima University
• Principal Investigator: UTO Hirofumi Kagoshima University, 医歯学総合研究科, 講師 (20347058)
• Co-Investigator(Kenkyū-buntansha): MORIUCHI Akihiro 鹿児島大学, 医学部・歯学部附属病院, 助教 (40359823)
• Research Collaborator: SATO Yuko 宮崎県産業支援財団, 研究員 ; TANOUE Shiro 鹿児島大学, 医歯学総合研究科, 大学院生 ; KUMAMTO Ryo 鹿児島大学, 医歯学総合研究科, 大学院生 ; ARIMA Shiho 鹿児島大学, 医歯学総合研究科, 大学院生 ; HAMABE Ayaka 鹿児島大学, 医歯学総合研究科, 大学院生 ; IBUSUKI Rie 鹿児島大学, 医歯学総合研究科, 大学院生
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2010: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2009: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2008: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: NASH / NAFLD / 酸化ストレス / MnSOD / フルクトース / 肝再生 / 肝発癌 / SNAFLD / 高血圧 / 脂質代謝異常 / 糖代謝異常 / kininogen / NBS標識法

Research Abstract

First of all, we explored the oxidative stress marker (s) using proteomics and identified that MnSOD may be a useful serum biomarker for distinguishing between simple steatotis (SS) and nonalcoholic steatohepatitis (NASH) in patients with nonalcoholic fatty liver disease (NAFLD). Second, in a rat experimental model, hepatic steatosis (HS) developed in the high fructose diet (H-fruc) group, but was less severe compared to the high fat diet (H-fat) group. In contrast, liver regeneration after 70% partial hepatectomy (PHx) was impaired in the H-fruc group compared to the H-fat and control groups. In addition, the H-fruc group developed a significantly higher incidence of GST-P-positive precancerous lesions compared to the H-fat group. These results indicate that impairment of liver regeneration after PHx and the incidence of precancerous lesions in HS are related to the cause, rather than the degree, of steatosis. Thus, our study demonstrates that serum MnSOD is potential novel marker for NAFLD, and that the pathophysiological condition and progression of NAFLD are potentially affected by different diets.

Research Products

• [Journal Article] Impact of cigarette smoking on onset of nonalcoholic fatty liver disease over a 10-year period. (2011)
  • Author(s): Hamabe A, Uto H, Imamura Y, Kusano K, Mawatari S, Kumagai K, Kure T, Tamai T, Moriuchi A, Sakiyama T, Oketani M, Ido A, Tsubouchi H.
  • Journal Title: J Gastroenterol in press
  • NAID: 10029029629
  • Peer Reviewed
• [Journal Article] Alcohol drinking patterns and the risk of fatty liver in Japanese men. (2011)
  • Author(s): Hiramine Y, Imamura Y, Uto H, Koriyama C, Horiuchi M, Oketani M, Hosoyamada K, Kusano K, Ido A, Tsubouchi H.
  • Journal Title: J Gastroenterol in press
  • NAID: 10029028704
  • Peer Reviewed
• [Journal Article] Liver regeneration after partial hepatectomy in rat is more impaired in a steatotic liver induced by dietary fructose compared to dietary fat. (2011)
  • Author(s): Tanoue S, Uto H, Kumamoto R, Arima S, Hashimoto S, Nasu Y, Takami Y, Moriuchi A, Sakiyama T, Oketani M, Ido A, Tsubouchi H.
  • Journal Title: Biochem Biophys Res Commun 407 Pages: 163-168
  • Peer Reviewed
• [Journal Article] Liver regeneration after partial hepatectomy in rat is more impaired in asteatotic liver induced by dietary fructose compared to dietary fat. (2011)
  • Author(s): Tanoue S, Uto H, Kumamoto, et al.
  • Journal Title: Biochem Biophys Res Commun Volume: 407 Pages: 163-168
  • Peer Reviewed
• [Journal Article] Impact of cigarette smoking on onset of nonalcoholic fatty liver disease over a 10-year period. (2011)
  • Author(s): Hamabe A, Uto H, Imamura Y, et al.
  • Journal Title: J Gastroenterol Volume: (In press)
  • NAID: 10029029629
  • Peer Reviewed
• [Journal Article] Alcohol drinking patterns and the risk of fatty liver in Japanese men. (2011)
  • Author(s): Hiramine Y, Imamura Y, Uto H, et al.
  • Journal Title: J Gastroenterol. Volume: (In press)
  • NAID: 10029028704
  • Peer Reviewed
• [Journal Article] Clinical proteomics for liver disease : a promising approach for discovery of novel biomarkers. (2010)
  • Author(s): Uto H, Kanmura S, Takami Y, Tsubouchi H.
  • Journal Title: Proteome Sci 8 Pages: 70-70
  • Peer Reviewed
• [Journal Article] Identification of a novel biomarker for oxidative stress induced by hydrogen peroxide in primary human hepatocytes using the 2-nitrobenzenesulfenyl chloride isotope labeling method. (2010)
  • Author(s): Takami Y, Uto H, Tamai T, Sato Y, Ishida Y, Morinaga H, Sakakibara Y, Moriuchi A, Oketani M, Ido A, Nakajima T, Okanoue T, Tsubouchi H.
  • Journal Title: Hepatol Res 40 Pages: 438-445
  • NAID: 10027291800
  • Peer Reviewed
• [Journal Article] The complement component C3a fragment is a potential biomarker for hepatitis C virus-related hepatocellular carcinoma. (2010)
  • Author(s): Kanmura S, Uto H, Sato Y, Kumagai K, Sasaki F, Moriuchi A, Oketani M, Ido A, Nagata K, Hayashi K, Stuver SO, Tsubouchi H.
  • Journal Title: J Gastroenterol 45 Pages: 459-467
  • NAID: 10027215830
  • Peer Reviewed
• [Journal Article] Proanthocyanidin derived from the leaves of Vaccinium virgatum suppresses platelet-derived growth factor-induced proliferation of the human hepatic stellate cell line LI90. (2010)
  • Author(s): Takami Y, Uto H, Takeshita M, Akamatsu E, Moriuchi A, Hasegawa S, Oketani M, Ido A, Kataoka H, Tsubouchi H.
  • Journal Title: Hepatol Res 40 Pages: 337-345
  • NAID: 10027407999
  • Peer Reviewed
• [Journal Article] Clinical proteomics for liver disease : a promising approach for discovery of novel biomarkers. (2010)
  • Author(s): Uto H, Kanmura S, Takami Y, Tsubouchi H.
  • Journal Title: Proteome Sci. Volume: 31 Pages: 70-70
  • Peer Reviewed
• [Journal Article] Proanthocyanidin from blueberry leaves suppresses expression of subgenomic hepatitis C virus RNA. (2009)
  • Author(s): Takeshita M, Ishida Y, Akamatsu E, Ohmori Y, Sudoh M, Uto H, Tsubouchi H, Kataoka H.
  • Journal Title: J Biol Chem 284 Pages: 21165-21176
  • Peer Reviewed
• [Journal Article] Increased rate of death related to presence of viremia among hepatitis C virus antibody-positive subjects in a community-based cohort study. (2009)
  • Author(s): Uto H, Stuver SO, Hayashi K, Kumagai K, Sasaki F, Kanmura S, Numata M, Moriuchi A, Hasegawa S, Oketani M, Ido A, Kusumoto K, Hasuike S, Nagata K, Kohara M, Tsubouchi H.
  • Journal Title: Hepatology 50 Pages: 393-399
  • Peer Reviewed
• [Journal Article] Human neutrophil peptides 1-3 are useful biomarkers in patients with active ulcerative colitis (2009)
  • Author(s): Kanmura S, Uto H, et al.
  • Journal Title: Inflamm Bowel Dis. 15 Pages: 909-917
  • Peer Reviewed
• [Journal Article] Human neutrophil peptides 1-3 are useful biomarkers in patients with active ulcerative colitis (2009)
  • Author(s): Kanmura S, Uto H, Numata M, et al
  • Journal Title: Inflamm Bowel Dis (印刷中)
  • Peer Reviewed
• [Journal Article] Association between changes in body composition and the increasing prevalence of fatty liver in Japanese men. (2008)
  • Author(s): Imamura Y, Uto H, Oketani M, Hiramine Y, Hosoyamada K, Sho Y, Hiwaki T, Baba Y, Tahara K, Kubozono O, Kusano K, Tsubouchi H.
  • Journal Title: Hepatol Res 38 Pages: 1083-1086
  • NAID: 10024305060
  • Peer Reviewed
• [Journal Article] Association of a genetic polymorphism in ectonucleotide pyrophosphatase/phosphodiesterase 1 with hepatitis C virus infection and hepatitis C virus core antigen levels in subjects in a hyperendemic area of Japan. (2008)
  • Author(s): Takahama Y, Uto H, Kanmura S, Oketani M, Ido A, Kusumoto K, Hasuike S, Nagata N, Hayashi K, Stuver S, Okayama A, Tsubouchi H
  • Journal Title: J Gastroenterol 43 Pages: 942-950
  • NAID: 10023973646
  • Peer Reviewed
• [Journal Article] Association between changes in body composition and the increasing prevalence of fatty liver in Japanese men (2008)
  • Author(s): Imamura Y, Uto H, Oketani M, et al.
  • Journal Title: Hepatol Res 38 Pages: 1083-1086
  • NAID: 10024305060
  • Peer Reviewed
• [Journal Article] Association of a genetic polymorphism in ectonucleotide pyrophosphatase/phosphodiesterase 1 with hepatitis C virus infection..... (2008)
  • Author(s): Takahama Y, Uto H Kanmura S, et al.
  • Journal Title: J Gastroenterol 43 Pages: 942-950
  • Peer Reviewed
• [Presentation] Liver regeneration after partial hepatectomy was more impaired in liver steatosis induced by dietary fructose than by Dietary fat. (2010)
  • Author(s): Tanoue S, Uto H, Kumamoto R, Arima S, Tamai T, Moriuchi A, Sakiyama T, Oketani M, Ido A, Tsubouchi H.
  • Organizer: The 9th JSH Single Topic Conference "NASH 2010".
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 2010-11-18
• [Presentation] Alchol drinking patterns and risk of fatty liver in Japanese men. (2010)
  • Author(s): Hiramine Y, Imamura Y, Uto H, Koriyama C, Horiuchi M, Oketani M, Hosoyamada K, Kusano K, Ido A, Tsubouchi H.
  • Organizer: 61^<th> annual meeting of the American Association for the Study of Liver Diseases (AASLD).
  • Place of Presentation: Boston, USA
  • Year and Date: 2010-11-02
• [Presentation] Alchol drinking patterns and risk of fatty liver in Japanese men. (2010)
  • Author(s): Hiramine Y, Imamura Y, Uto H, et al.
  • Organizer: 61^<th> annual meeting of the American Association for the Study of Liver Diseases (AASLD)
  • Place of Presentation: Boston, USA
  • Year and Date: 2010-11-02
• [Presentation] Dietary fructose rather than dietary fataffects liver tumor incidence by diethylnitrosamina administration in rats. (2010)
  • Author(s): Kumamoto R, Uto H, Tanoue S, et al.
  • Organizer: 61^<th> annual meeting of the American Association for the Study of Liver Diseases (AASLD)
  • Place of Presentation: Boston, USA
  • Year and Date: 2010-11-02
• [Presentation] Inpact of cigarette smoking on the onset of nonalcoholic fatty liver disease : A 10-year longitudinal study. (2010)
  • Author(s): Hamabe A, Uto H, Imamura Y
  • Organizer: 61^<th> annual meeting of the American Association the Study of Liver Diseases (AASLD)
  • Place of Presentation: Boston, USA
  • Year and Date: 2010-11-02
• [Presentation] Dietary fructose rather than dietary fataffects liver tumor incidence by diethylnitrosamina administration in rats. (2010)
  • Author(s): Kumamoto R, Uto H, Tanoue S, Arima S, Kure T, Kumagai K, Tamai T, Moriuchi A, Sakiyama T, Oketani M, Ido A, Tsubouchi H.
  • Organizer: 61^<th> annual meeting of the American Association for the Study of Liver Diseases (AASLD).
  • Place of Presentation: Boston, USA
  • Year and Date: 2010-11-01
• [Presentation] Inpact of cigarette smoking on the onset of nonalcoholic fatty liver disease : A 10-year longitudinal study. (2010)
  • Author(s): Hamabe A, Uto H, Imamura Y, Mawatari S, Oda K, Saisyoji A, Hashiguchi M, Kure T, Kumagai K, Tamai T, Moriuchi A, Oketani M, Ido A, Tsubouchi H.
  • Organizer: 61^<th> annual meeting of the American Association for the Study of Liver Diseases (AASLD).
  • Place of Presentation: Boston, USA
  • Year and Date: 2010-10-30
• [Presentation] A high-fructose diet impairs liver regeneration more than ahigh-fat diet after partial hepatectomy in a rat fatty liver model. (2009)
  • Author(s): Tanoue S, Uto H, Kumamoto R, Hashimoto S, Nasu Y, Sasaki H, Hunakawa K, Moriuchi A, Sakiyama T, Oketani M, Ido A, Tsubouchi H.
  • Organizer: 60^<th> annual meeting of the American Association for the Study of Liver Diseases (AASLD).
  • Place of Presentation: Boston, USA
  • Year and Date: 2009-11-01
• [Presentation] The serum levels of manganese superpxide dismutase (MnSOD) are elevated in patient with non-alcoholic steathohepatitis (NASH). (2009)
  • Author(s): Takami Y, Uto H, Tamai T, Sato Y, Moriuchi A, Funakawa K, Sakiyama T, Oketani M, Ido A, Nakajima T, Okanoue t, Tsubouchi H.
  • Organizer: 60^<th> Annual Meeting of the American Association for the Study of Liver Diseases (AASLD).
  • Place of Presentation: Boston, USA
  • Year and Date: 2009-11-01
• [Presentation] The serum levels of manganese superpxide dismutase(MNSOD)are elevated in patient with non-alcoholic steathohepatitis(NASH) (2009)
  • Author(s): Takami Y, Uto H, et al.
  • Organizer: The 60th Annual Meeting of the American Association for the Study of the Live Disease(AASLD)
  • Place of Presentation: ボストン(米国)
• [Presentation] A fragment of high molecular weight kininogen is upregulated in patients with non-alcoholic fatty liver diserse. (2008)
  • Author(s): Uto H, Sato Y, Tanoue S, Ishida Y, Tamai T, Hasegawa S, Oketani M, Ido A, Nakajima T, Okanoue T, Tsubouchi H.
  • Organizer: The 58th Annual Meeting of the American Association for the Study of the Live Disease(AASLD).
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2008-11-02
• [Presentation] Identification of a nover biomarker for oxidative stress induced by hydrogen peroxide in prymary human hepatocytes using the 〔13C〕-2-nitrobenzenesulfenyl stable isotope labeling method. (2008)
  • Author(s): Takami Y, Uto H, Takahama Y, Ishida Y, Morinaga H, Sakakibara Y, Moriuchi A, Oketani M, Ido A, Tsubouchi H.
  • Organizer: The 58th Annual Meeting of the American Association for the Study of the Live Disease(AASLD).
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2008-11-02
• [Presentation] A fragment of high molecular weight kininogen is upregulated in patients with non-alcoholic fatty liver diserses. (2008)
  • Author(s): Uto H, et al.
  • Organizer: 59th Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: 米国サンフランシスコ
  • Year and Date: 2008-11-02
• [Book] 肝臓フォーラム'08 記録集(消化器疾患におけるプロテオーム解析)(戸田剛太郎,沖田極(編)) (2009)
  • Author(s): 宇都浩文、上村修司、坪内博仁
  • Publisher: 医事出版社
• [Book] 消化器病学の進歩-原点から未来への情報発信-(脂肪肝は内臓脂肪の指標になりえるか)(飯田三雄(編)) (2009)
  • Author(s): 今村也寸志、桶谷真、宇都浩文、坪内博仁
  • Publisher: 日本消化器病学会
• [Book] Annual Review 消化器2009(肝疾患の血清プロテオミクスを用いた診断)(林紀夫、日比紀文、上西紀夫、下瀬川徹(編)) (2009)
  • Author(s): 宇都浩文、上村修二、坪内博仁
  • Publisher: 中外医学社
• [Book] 【NASH/NAFLDの臨床および研究の進歩】NASH/NAFLDとメタボリツクシンドローム (2008)
  • Author(s): 宇都浩文, 他
  • Total Pages: 28
  • Publisher: メディカル・サイエンス・ダイジェスト
• [Patent(Industrial Property Rights)] 非アルコール性脂肪性肝炎を推定するための検出方法. (2008)
  • Inventor(s): 宇都浩文, 他
  • Industrial Property Rights Holder: 鹿児島大学, 他
  • Industrial Property Number: 2008-323982
  • Filing Date: 2008-12-19