アディポサイトカイン分泌異常に基づくＮＡＳＨ病態解析からの新規糖鎖マーカーの開発

2014 Fiscal Year Annual Research Report

• Project/Area Number: 24590972
• Research Institution: Osaka University
• Principal Investigator: 鎌田 佳宏 大阪大学, 医学(系)研究科(研究院), 准教授 (30622609)
• Co-Investigator(Kenkyū-buntansha): 三善 英知 大阪大学, 医学(系)研究科(研究院), 教授 (20322183)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: 肝臓病学 / 糖鎖 / バイオマーカー

Outline of Annual Research Achievements

我々は糖鎖とアディポサイトカインに着目してNASHの病態解析および新規バイオマーカー開発を行った。本研究でアディポサイトカインsecreted frizzled related protein 5 （Sfrp5）欠損が肝臓線維化を進展させることを明らかとし、またフコシル化ハプトグロビン、Mac-2 binding protein（Mac2bp）、フェチュインAが新規NASHバイオマーカーとなることを見いだした。
四塩化炭素誘発肝線維化モデルを用いた検討ではSfrp5 KOマウスでWTマウスに比べ肝線維化進展が有意に増悪した。In vitroの検討ではWnt5aにより肝星細胞の遊走・増殖が促進され、Sfrp5はそれらを完全に抑制した。C-jun N terminal kinase (JNK)リン酸化は肝線維化を促進的に作用することが知られている。Wnt5aは肝星細胞のJNKリン酸化を起こすがSfrp5はこれも抑制した。以上の検討により、新規アディポサイトカインSfrp5はWnt5aの作用を阻害することで肝線維化を抑制することが明らかとなった。
糖鎖バイオマーカー開発のためまず肝生検で組織診断のついている127名のNAFLD患者血清を用いて血中Fuc-Hpt、Mac2bpを測定した。これら2つのマーカーはNASH鑑別診断において従来有用性が最も高いとされているcytokeratin 18 fragmentよりも鑑別能が優れていた。一方血中フェチュインA値は代表的肝臓線維化マーカーであるヒアルロン酸値と逆相関し、肝臓線維化進展と逆相関することがすでに知られている血小板数と正の相関を示した。肝生検NAFLD症例では線維化の早期の段階で血中フェチュインA値が低下することがわかった。

Research Products

• [Journal Article] Serum Mac-2 binding protein levels as a novel diagnostic biomarker for prediction of disease severity and nonalcoholic steatohepatitis. (2015)
  • Author(s): Kamada Y, Fujii H, Fujii H, Sawai Y, Doi Y, Uozumi N, Mizutani K, Akita M, Sato M, Kida S, Kinoshita N, Matuyama N, Yakushijin T, Miyazaki M, Ezaki H, Hiramatsu N, Yoshida Y, Kiso S, Imai Y, Kawada N, Takehara T, Miyoshi E.
  • Journal Title: Proteomics Clin Appl Volume: in press Pages: -
  • DOI: 10.1002/prca.201200137.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Fetuin-A negatively correlates with liver and vascular fibrosis in nonalcoholic fatty liver disease subjects. (2015)
  • Author(s): Kamada Y*, Sato M* (equally contributed), Takeda Y, Kida S, Ohara Y, Fujii H, Akita M, Mizutani K, Yoshida Y, Yamada M, Hougaku H, Takehara T, Miyoshi E.
  • Journal Title: Liver Int Volume: 35 Pages: 925-35
  • DOI: 10.1111/liv.12478.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Serum fucosylated haptoglobin in chronic liver diseases as a potential biomarker of hepatocellular carcinoma development. (2015)
  • Author(s): Kamada Y*, Asazawa H* (equally contributed), Takeda Y, Takamatsu S, Shinzaki S, Kim Y, Nezu R, Kuzushita N, Mita E, Kat M, Miyoshi E.
  • Journal Title: Clin Chem Lab Med Volume: 53 Pages: 95-102
  • DOI: 10.1515/cclm-2014-0427.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] N-Acetylglucosaminyltransferase V exacerbates concanavalin A-induced mouse hepatitis. (2015)
  • Author(s): Kamada Y, Sato M, Kida S, Akita M, Mizutani K, Fujii H, Sobajima T, Yoshida Y, Shinzaki S, Takamatsu S, Takehara T, Miyoshi E.
  • Journal Title: Mol Med Rep Volume: 11 Pages: 3573-84
  • DOI: doi: 10.3892/mmr.2015.3168.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Secreted frizzled-related protein 5 (Sfrp5) decreases hepatic stellate cell activation and liver fibrosis. (2015)
  • Author(s): Chatani N, Kamada Y, Kizu T, Ogura S, Furuta K, Egawa M, Hamano M, Ezaki H, Kiso S, Shimono A, Ouchi N, Yoshida Y, Takehara T.
  • Journal Title: Liver Int Volume: in press Pages: -
  • DOI: 10.1111/liv.12757.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Fucosylation is common type of glycosylation in pancreatic cancer stem cell-like phenotypes. (2015)
  • Author(s): Terao N, Takamatsu S, Minehira T, Sobajima T, Nakayama K, Kamada Y, Miyoshi E.
  • Journal Title: World J Gastroenterol Volume: 21 Pages: 3876-87
  • DOI: 10.3748/wjg.v21.i13.3876.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Loss of Gab1 adaptor protein in hepatocytes aggravates experimental liver fibrosis in mice. (2015)
  • Author(s): Kizu T, Yoshida Y, Furuta K, Ogura S, Egawa M, Chatani N, Hamano M, Takemura T, Ezaki H, Kamada Y, Nishida K, Nakaoka Y, Kiso S, Takehara T.
  • Journal Title: Am J Physiol Gastrointest Liver Physiol Volume: 308 Pages: G613-24
  • DOI: 10.1152/ajpgi.00289.2014.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Loss of α1,6-fucosyltransferase suppressed liver regeneration: implication of core fucose in the regulation of growth factor receptor-mediated cellular signaling. (2015)
  • Author(s): Wang Y, Fukuda T, Isaji T, Lu J, Gu W, Lee HH, Ohkubo Y, Kamada Y, Taniguchi N, Miyoshi E, Gu J.
  • Journal Title: Sci Rep Volume: in press Pages: -
  • DOI: 10.1038/srep08264.
  • Peer Reviewed / Open Access
• [Journal Article] Value of Fetuin-A as a Predictor of Liver Fibrosis in Patients With Nonalcoholic Fatty Liver Disease. Author's reply. (2015)
  • Author(s): Kamada Y, Miyoshi E.
  • Journal Title: Liver Int Volume: in press Pages: -
  • DOI: 10.1111/liv.12833.
  • Peer Reviewed
• [Journal Article] Establishment of a novel lectin-antibody ELISA system to determine core-fucosylated haptoglobin. (2015)
  • Author(s): Shimomura M, Nakayama K, Azuma K, Terao N, Nishino K, Takamatsu S, Nakano M, Takahashi S, Kobayashi Y, Murata K, Kamada Y, Miyoshi E.
  • Journal Title: Clin Chim Acta Volume: in press Pages: -
  • DOI: 10.1016/j.cca.2015.03.037.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Novel effect of ezetimibe to inhibit the development of non-alcoholic fatty liver disease in Fatty Liver Shionogi mouse. (2014)
  • Author(s): Wang X, Sugimoto K, Fujisawa T, Shindo N, Minato S, Kamada Y, Hamano M, Ohishi M, Ikegami H, Rakugi H
  • Journal Title: Hepatol Res Volume: 44 Pages: 102-13
  • DOI: 10.1111/hepr.12092.
  • Peer Reviewed
• [Journal Article] Lipid overloading during liver regeneration causes delayed hepatocyte DNA replication by increasing ER stress in mice with simple hepatic steatosis. (2014)
  • Author(s): Hamano M, Ezaki H, Kiso S, Furuta K, Egawa M, Kizu T, Chatani N, Kamada Y, Yoshida Y, Takehara T.
  • Journal Title: J Gastroenterol Volume: 49 Pages: 305-16
  • DOI: 10.1007/s00535-013-0780-7.
  • Peer Reviewed / Open Access
• [Journal Article] Conditional loss of heparin-binding EGF-like growth factor results in enhanced liver fibrosis after bile duct ligation in mice. (2014)
  • Author(s): Takemura T, Yoshida Y, Kiso S, Kizu T, Furuta K, Ezaki H, Hamano M, Egawa M, Chatani N, Kamada Y, Imai Y, Higashiyama S, Iwamoto R, Mekada E, Takehara T.
  • Journal Title: Biochem Biophys Res Commun Volume: 437 Pages: 185-91
  • DOI: 10.1016/j.bbrc.2013.05.097.
  • Peer Reviewed
• [Journal Article] Twin studies on the effect of genetic factors on serum agalactosyl immunoglobulin G levels. (2014)
  • Author(s): Azuma K, Shinzaki S, Asazawa H, Kuroki E, Kawamoto S, Kamada Y, Hayakawa K, Miyoshi E.
  • Journal Title: Biomed Rep Volume: 2 Pages: 213-16
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Pancreas Fatty Degeneration and Fibrosis as Predisposing Factors of Pancreatic Ductal Adenocarcinoma Development. (2014)
  • Author(s): Tomita Y, Azuma K, Nonaka Y, Kamada Y, Tomoeda M, Kishida M, Tanemura M, Miyoshi E.
  • Journal Title: Pancreas Volume: 43 Pages: 1032-41
  • DOI: 10.1097/MPA.0000000000000159.
  • Peer Reviewed
• [Journal Article] Identification of sialylated glycoproteins in doxorubicin-treated hepatoma cells with glycoproteomic analyses. (2014)
  • Author(s): Azuma K, Serada S, Takamatsu S, Terao N, Takeishi S, Kamada Y, Naka T, Miyoshi E
  • Journal Title: J Proteome Res Volume: 13 Pages: 4869-77
  • DOI: 10.1021/pr5004399.
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] NAFLD患者の血中フェチュインAは肝臓線維化と動脈硬化の程度に逆相関する (2014)
  • Author(s): 鎌田佳宏、竹原徹郎、三善英知
  • Organizer: 第40回日本肝臓学会東部会
  • Place of Presentation: 京王プラザホテル、東京
  • Year and Date: 2014-11-27
• [Presentation] Fetuin-A negatively correlates with liver and vascular fibrosis in NAFLD subjects (2014)
  • Author(s): Yoshihiro Kamada, Motoya Sato, Yuri Takeda, Sachiho Kida, Yuka Ohara, Hironobu Fujii, Maaya Akita, Kayo Mizutani, Yuichi Yoshida, Makoto Yamada, Hidetaka Hougaku, Tetsuo Takehara, Eiji Miyoshi
  • Organizer: AASLD The Liver Meeting 2014
  • Place of Presentation: Boston, U.S.A.
  • Year and Date: 2014-11-09
• [Presentation] 糖転移酵素N-アセチルグルコサミン転移酵素V（GnT-V）はマウスとヒトのHDL新生を促進する (2014)
  • Author(s): 鎌田佳宏、竹原徹郎、三善英知
  • Organizer: JDDW 2014
  • Place of Presentation: 神戸国際展示場、神戸
  • Year and Date: 2014-10-24
• [Presentation] コア型フコシル化ハプトグロビン測定系の開発と肝疾患への臨床応用 (2014)
  • Author(s): 下村真由香、鎌田佳宏、三善英知
  • Organizer: JDDW 2014
  • Place of Presentation: 神戸国際展示場、神戸
  • Year and Date: 2014-10-23
• [Presentation] アディポサイトカインSecreted frizzled-related prtein5 (Sfrp5) は肝線維化進展を抑制する (2014)
  • Author(s): 鎌田佳宏、茶谷徳啓、古田訓丸、木津 崇、木曽真一、下野明彦、大内乗有、吉田雄一、三善英知、竹原徹郎
  • Organizer: 第1回肝臓と糖尿病・代謝研究会
  • Place of Presentation: 伊藤謝恩ホール、東京
  • Year and Date: 2014-07-04
• [Presentation] 血清糖鎖バイオマーカーを用いた非侵襲的Matteoni分類によるNASH診断法の開発 (2014)
  • Author(s): 鎌田佳宏、竹原徹郎、三善英知
  • Organizer: 第50回日本肝臓学会
  • Place of Presentation: ホテルニューオータニ、東京
  • Year and Date: 2014-05-30
• [Presentation] 血中フコシル化タンパクは肝臓ballooning hepatocyteのバイオマーカーである (2014)
  • Author(s): 鎌田佳宏、竹原徹郎、三善英知
  • Organizer: 第100回日本消化器病学会
  • Place of Presentation: 東京国際フォーラム、東京
  • Year and Date: 2014-04-25
• [Book] Glycobiology: Biology and Medicine (2015)
  • Author(s): Miyoshi E and Kamada Y
  • Total Pages: 1568
  • Publisher: Springer
• [Book] 肝疾患Review 2014-2015 (2014)
  • Author(s): 三善英知、鎌田佳宏
  • Total Pages: 208
  • Publisher: 日本メデイカルセンター
• [Book] HEPATOLOGY PRACTICE Vol.5 肝癌の診療を極める 基本から最前線まで (2014)
  • Author(s): 三善英知、鎌田佳宏
  • Total Pages: 338
  • Publisher: 文光堂
• [Remarks] 大阪大学研究者総覧
  • URL: http://www.dma.jim.osaka-u.ac.jp/view?l=ja&u=1660