Development of novel glyco-biomarkers for nonalcoholic steatohepatitis (NASH) based on the adipocytokine dysregulation

• Project/Area Number: 24590972
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Osaka University
• Principal Investigator: KAMADA YOSHIHIRO 大阪大学, 医学(系)研究科(研究院), 准教授 (30622609)
• Co-Investigator(Kenkyū-buntansha): MIYOSHI Eiji 大阪大学, 医学系研究科, 教授 (20322183)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 肝臓病 / 糖鎖 / バイオマーカー / 肝臓病学 / 非アルコール性脂肪性肝炎（NASH） / フコシル化ハプトグロビン / Mac-2 binding protein / アディポサイトカイン / Sfrp5 / (1) 非アルコール性脂肪性肝炎（NASH） / Mac2 binding protein

Outline of Final Research Achievements

Nonalcoholic steatohepatitis (NASH) is a growing medical problem, and can progress to liver cirrhosis and hepatocellular carcinoma. Now, liver biopsy remains the gold standard for the diagnosis and the grading liver disease severity in NASH patients. However, liver biopsy is an invasive test, and repeated liver biopsy for the estimation of NASH progression is hard to perform. Therefore, noninvasive NASH biomarkers are needed. We investigated pathophysiology of NASH focusing on adipocytokine and oligosaccharide. We found that lack of secreted frizzled related protein 5 accelerated the liver fibrosis progression. In addition, we established three glyco-biomarkers for NASH. Serum fucosylated haptoglobin and Mac-2 binding protein levels are useful for the NASH diagnosis, and suitable for the prediction of ballooning hepatocyte presence and liver fibrosis severity, respectively. We also found serum fetuin-A levels were decreased with the liver fibrosis progression of NASH patients.

Research Products

• [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 Issue: 3 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 Issue: 1 Pages: 95-102
  • DOI: 10.1515/cclm-2014-0427
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] N-Acetylglucosaminyltransferase V exacerbates concanavalin A‑induced hepatitis in mice. (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: 5 Issue: 5 Pages: 3573-84
  • DOI: 10.3892/mmr.2015.3168
  • Peer Reviewed / Open Access
• [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 Issue: 8 Pages: 2017-26
  • 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 Issue: 13 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 Issue: 7 Pages: 613-624
  • DOI: 10.1152/ajpgi.00289.2014
  • Peer Reviewed / Open Access / 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 Issue: 1 Pages: 925-35
  • 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 Issue: 8 Pages: 2062-2062
  • 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: 30-6
  • DOI: 10.1016/j.cca.2015.03.037
  • Peer Reviewed / Acknowledgement Compliant
• [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 Issue: 2 Pages: 305-316
  • DOI: 10.1007/s00535-013-0780-7
  • Peer Reviewed / Open Access
• [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] Pancreatic Steatosis and Fibrosis as Predisposing Factors of Cancer 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 Issue: 7 Pages: 1032-1041
  • DOI: 10.1097/mpa.0000000000000159
  • Peer Reviewed / Acknowledgement Compliant
• [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 Issue: 11 Pages: 4869-77
  • DOI: 10.1021/pr5004399
  • NAID: 130007499829
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] NAFLDの診断と検査法のupdate (2014)
  • Author(s): 鎌田佳宏、三善英知、竹原徹郎
  • Journal Title: 日本消化器病学会雑誌 Volume: 111 Pages: 25-34
  • NAID: 130003383340
  • Peer Reviewed
• [Journal Article] Novel effect of ezetimibe to inhibit the development of non-alcoholic fatty liver disease in Fatty Liver Shionogi mouse (2013)
  • Author(s): Wang X
  • Journal Title: Hepatol Res Volume: 印刷中 Issue: 1 Pages: 102-13
  • DOI: 10.1111/hepr.12092
  • 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. (2013)
  • 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 Issue: 2 Pages: 185-191
  • DOI: 10.1016/j.bbrc.2013.05.097
  • Peer Reviewed
• [Journal Article] Serum Mac-2 binding protein levels as a novel diagnostic biomarker for prediction of disease severity and nonalcoholic steatohepatitis. (2013)
  • Author(s): Kamada Y, Fujii H,Miyoshi E,et.al.
  • Journal Title: Proteomics Clin Appl. Volume: 6 Issue: 9-10 Pages: 648-656
  • DOI: 10.1002/prca.201200137
  • Peer Reviewed
• [Journal Article] Adiponectin negatively correlates with alcoholic and non-alcoholic liver dysfunction : Health check-up study of Japanese men (2013)
  • Author(s): Hamano M, Kiso S, Yoshida Y, Watabe K,他19人
  • Journal Title: Hepatol Res Volume: 43(3) Issue: 3 Pages: 238-48
  • DOI: 10.1111/j.1872-034x.2012.01066.x
  • NAID: 10031183465
  • Peer Reviewed
• [Journal Article] Pitavastatin ameliorated the progression of steatohepatitis in ovariectomized mice fed a high fat and high cholesterol diet. (2013)
  • Author(s): Kamada Y, Kiso S, Yoshida Y, Chatani N, Kizu T, Hamano M, Egawa M, Takemura T, Ezaki H, Furuta K, Hayashi N, Takehara T.
  • Journal Title: Hepatol Res. Volume: 43 Issue: 4 Pages: 401-412
  • DOI: 10.1111/j.1872-034x.2012.01082.x
  • NAID: 10031194552
  • Peer Reviewed
• [Journal Article] Lectin-based immunoassay for aberrant IgG glycosylation as the biomarker for Crohn's disease. (2013)
  • Author(s): Shinzaki S, 他13名, Naka T, Plevy S E, Takehara T, Miyoshi E.
  • Journal Title: Inflamm Bowel Dis. Volume: 19（2） Issue: 2 Pages: 321-31
  • DOI: 10.1097/mib.0b013e318280eade
  • Peer Reviewed
• [Journal Article] Reevaluation of a lectin antibody ELISA kit for measuring fucosylated haptoglobin in various conditions. (2013)
  • Author(s): Kamada Y, Kinoshita N, Tsuchiya Y, Kobayashi K, Fujii H, Terao N, Kamihagi K, Koyama N, Yamada S, Daigo Y, Nakamura Y, Taniguchi N, Miyoshi E.
  • Journal Title: Clin Chim Acta Volume: 417 Pages: 48-53
  • DOI: 10.1016/j.cca.2012.12.014
  • Peer Reviewed
• [Journal Article] Serum fucosylated haptoglobin as a novel diagnostic biomarker for predicting hepatocyte ballooning and nonalcoholic steatohepatitis. (2013)
  • Author(s): Kamada Y, Akita M, Takeda Y, Yamada S, Fujii H, Sawai Y, Doi Y, Asazawa H, Nakayama K, Mizutani K, Fujii H, Yakushijin T, Miyazaki M, Ezaki H, Hiramatsu N, Yoshida Y, Kiso S, Imai Y, Kawada N, Takehara T, Miyoshi E.
  • Journal Title: PLoS One Volume: 8
  • Peer Reviewed
• [Journal Article] Mutation of GDP-Mannose-4,6-Dehydratase in Colorectal Cancer Metastasis. (2013)
  • Author(s): Nakayama K, Moriwaki K, Imai T, Shinzaki S, Kamada Y, Murata K, Miyoshi E.
  • Journal Title: PLoS One Volume: 8
  • Peer Reviewed
• [Journal Article] Conditional knockout of heparin-binding epidermal growth factor-like growth factor in the liver accelerates carbon tetrachloride-induced liver injury in mice. (2012)
  • Author(s): Takemura, T., YoshidaY., Kiso, S., Saji, Y., Ezaki, H., Hamano, M., Kizu, T., Egawa, M., Chatani, N., Furuta, K., Kamada, Y., Iwamoto, R., Mekada, E., Higashiyama, S., Hayashi, N. and Takehara, T.
  • Journal Title: Hepatol Res Volume: 43 Issue: 4 Pages: 384-393
  • DOI: 10.1111/j.1872-034x.2012.01074.x
  • NAID: 10031194550
  • Peer Reviewed
• [Journal Article] N-Acetylglucosaminyltransferase V regulates TGF- response in hepatic stellate cells and the progression of steatohepatitis. (2012)
  • Author(s): Kamada Y, Miyoshi E, et al.
  • Journal Title: Glycobiology Volume: 22(6) Issue: 6 Pages: 778-87
  • DOI: 10.1093/glycob/cws012
  • Peer Reviewed
• [Journal Article] Protective role of adiponec t in against ethanol-induced gastric injury in mice. (2012)
  • Author(s): Yamamoto S, ffatabe K, Araki H, et al.
  • Journal Title: Am J Physiol Gastrointest Liver Physiol. Volume: 302(Epub 2012 Feb 9) Issue: 8 Pages: G773-G780
  • DOI: 10.1152/ajpgi.00324.2011
  • Peer Reviewed
• [Journal Article] Analysis of polarized secretion of fucosylated alpha-fetoprotein in HepG2 cells. (2012)
  • Author(s): Nakagawa T, Miyoshi E, et al.
  • Journal Title: J. Proteome Res Volume: 11(5) Issue: 5 Pages: 2798-806
  • DOI: 10.1021/pr201154k
  • Peer Reviewed
• [Journal Article] Physiological roles of N-acetylglucosaminyltransferase V (GnT-V) in mice. (2012)
  • Author(s): Miyoshi E, Terao M, Kamada Y
  • Journal Title: BMB Rep Volume: 45 Pages: 554-9
  • Peer Reviewed
• [Journal Article] エストロゲンのNASH病態進展への関与について (2012)
  • Author(s): 鎌田佳宏
  • Journal Title: 医学と薬学 Volume: 68 Pages: 435-435
  • Peer Reviewed
• [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
• [Presentation] 血中Mac-2 binding protein値は新たなNASH鑑別、病期進展のマーカーである (2013)
  • Author(s): 鎌田佳宏、藤井英樹、澤井良之、土井喜宣、水谷佳代、木下憲明、今井康陽、河田則文、竹原徹郎、三善英知
  • Organizer: 第49回日本肝臓学会総会
  • Place of Presentation: 京王プラザホテル（東京）
• [Presentation] 高コレステロール血症の閉経後女性NASH進展におけるの意義について (2013)
  • Author(s): 鎌田佳宏、吉田雄一、三善英知、竹原徹郎
  • Organizer: 第9回消化器病における性差医学・医療研究会
  • Place of Presentation: 大阪大学中之島センター（大阪）
• [Presentation] N-Acetylglucosaminyltransferase V (GnT-V) prevents mice steatohepatitis progression through modulation of lymphocytes and hepatic stellate cells function. (2013)
  • Author(s): Yoshihiro Kamada, Kanako Mori, Hitoshi Matsumoto, Yuichi Yoshida, Shinichi Kiso, Shinichiro Shinzaki, Naoki Hiramatsu, Mayuko Ishii, Kenta Moriwaki, Norifumi Kawada, Tetsuo Takehara and Eiji Miyoshi
  • Organizer: 国際類洞壁細胞研究会（ISCHS 2013）
  • Place of Presentation: 大阪国際会議場（大阪）
• [Presentation] Serum Mac-2 binding protein levels as a novel diagnostic biomarker for prediction of disease severity and nonalcoholic steatohepatitis. (2013)
  • Author(s): Yoshihiro Kamada, Hideki Fujii, Hironobu Fujii, Yoshinori Doi, Kayo Mizutani, Maaya Akita, Motoya Sato, Sachiho Kida, Noriaki Kinoshita, Nobuhiro Maruyama, Takayuki Yakushijin, Masanori Miyazaki, Hisao Ezaki, Naoki Hiramatsu, Yuichi Yoshida, Shinichi Kiso, Norifumi Kawada, Tetsuo Takehara and Eiji Miyoshi
  • Organizer: The 64th Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: Washington, USA
• [Presentation] 閉経女性NASH患者治療における高コレステロール血症の意義:マウスモデル、健診データでの検討 (2013)
  • Author(s): 鎌田佳宏、木曽真一、竹原徹郎
  • Organizer: 第99回日本消化器病学会総会
  • Place of Presentation: 鹿児島城山観光ホテル
• [Presentation] 肝臓癌におけるフコシル化ハプトグロビンのバイオマーカーとしての有用性に関する検討 (2012)
  • Author(s): 鎌田佳宏、浅澤 瞳、佐々木夢香、三田英治3、加藤道夫、金 鏞国、根津理一郎、竹原徹郎、三善英知
  • Organizer: 第48回日本肝臓学会総会
  • Place of Presentation: ホテル日航金沢
• [Presentation] エストロゲンのNASH病態進展への関与について (2012)
  • Author(s): 鎌田佳宏、木曽真一、吉田雄一、三善英知、竹原徹郎
  • Organizer: 第8回消化器病における性差医学・医療研究会
  • Place of Presentation: 京都大学医学部芝蘭会館
• [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
• [Book] Hepatology Practiceシリーズ第2巻 NASH・アルコール性肝障害の診療を極める (2013)
  • Author(s): 鎌田佳宏
  • Total Pages: 416
  • Publisher: 文光堂
• [Book] 肝炎診療マニュアル (2013)
  • Author(s): 鎌田佳宏
  • Total Pages: 398
  • Publisher: 中外医学社
• [Book] 消化器疾患治療マニュアル (2013)
  • Author(s): 吉田雄一、鎌田佳宏
  • Total Pages: 466
  • Publisher: 金芳堂
• [Book] 消化器疾患治療マニュアル (2013)
  • Author(s): 鎌田佳宏、吉田雄一
  • Total Pages: 466
  • Publisher: 金芳堂
• [Remarks] 大阪大学研究者総覧
  • URL: http://www.dma.jim.osaka-u.ac.jp/view?l=ja&u=1660