Unraveling the role of Angptl2 in the pathogenesis of steatohepatitis and liver cancer

• Project/Area Number: 23591001
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: National Defense Medical College
• Principal Investigator: TOMITA Kengo 防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究, 病院, 講師 (50317129)
• Co-Investigator(Kenkyū-buntansha): SEKI Shuji 防衛医科大学校, 医学教育部医学科専門課程, 教授 (80531392)
• Co-Investigator(Renkei-kenkyūsha): OIKE Yuichi 熊本大学, 大学院, 教授 (90312321)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2012: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2011: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: 非アルコール性脂肪肝炎 / 肝臓線維化 / 肝臓癌 / Angptl2

Research Abstract

Angiopoietin-like protein 2 (Angptl2) is an adipocytokine, which induces chemotaxis of macrophages to adipose tissue, exaggerates adipose tissue inflammation, and aggravates insulin resistance and obesity. Nonalcoholic steatohepatitis (NASH) is thought to be a hepatic manifestation of metabolic syndrome. Therefore, Angptl2 may play an important role in the pathogenesis of NASH and NASH-related liver cancer. In the present study, we tried to unravel the role of Angptl2 in the progression of NASH and NASH-related liver cancer, using Angptl2-deficient mice and human liver samples in patients with NASH or liver cancer. We intend to promote necessary study and research for clinical application.

Research Products

• [Journal Article] Acyl-CoA : cholesterol acyltransferase 1 mediates liver fibrosis by regulating free cholesterol accumulation in hepatic stellate cells (2014)
  • Author(s): Tomita K, et al.
  • Journal Title: J Hepatol Volume: (in press)
  • Peer Reviewed
• [Journal Article] A pregnant woman with noncomatose autoimmune acute liver failure in the second trimester rescued using medical therapy : A case report (2014)
  • Author(s): Tomita K, et al.
  • Journal Title: Hepatol Res. Volume: (in press)
  • Peer Reviewed
• [Journal Article] Free cholesterol accumulation in hepatic stellate cells : mechanism of liver fibrosis aggravation in nonalcoholic steatohepatitis in mice (2014)
  • Author(s): Tomita K, et al.
  • Journal Title: Hepatology Volume: 59(1) Pages: 154-69
  • Peer Reviewed
• [Journal Article] Fibroblast growth factor-5 participates in the progression of hepatic fibrosis (2014)
  • Author(s): Tomita K, et al.
  • Journal Title: Exp Anim Volume: 63(1) Pages: 85-92
  • NAID: 130003391608
  • Peer Reviewed
• [Journal Article] Prevalence of serum celliac antibody in patients with IBD in Japan (2014)
  • Author(s): Tomita K, et al.
  • Journal Title: J Gastroenterol Volume: 49(5) Pages: 825-834
  • Peer Reviewed
• [Journal Article] Free cholesterol accumulation in hepatic stellate cells: Mechanism of liver fibrosis aggravation in nonalcoholic steatohepatitis in mice (2014)
  • Author(s): Tomita, K. Teratani, T. Suzuki, T. Shimizu, M. Sato, H. Narimatsu, K. Okada, Y. Kurihara, C. Irie, R. Yokoyama, H. Shimamura, K. Usui, S. Ebinuma, H. Saito, H. Watanabe, C. Komoto, S. Kawaguchi, A. Nagao, S. Sugiyama, K. Hokari, R. Kanai, T. Miura, S. Hibi, T.
  • Journal Title: Hepatology Volume: 59 Issue: 1 Pages: 154-169
  • DOI: 10.1002/hep.26604
  • Peer Reviewed
• [Journal Article] Acyl-CoA:cholesterol acyltransferase 1 mediates liver fibrosis by regulating free cholesterol accumulation in hepatic stellate cells. (2014)
  • Author(s): Tomita K, Teratani T, Suzuki T, Shimizu M, Sato H, Narimatsu K, Usui S, Furuhashi H, Kimura A, Nishiyama K, Maejima T, Okada Y, Kurihara C, Shimamura K, Ebinuma H, Saito H, Yokoyama H, Watanabe C, Komoto S, Nagao S, Sugiyama K, Aosasa S, Hatsuse K, Yamamoto J, Hibi T, Miura S, Hokari R, Kanai T.
  • Journal Title: Journal of Hepatology Volume: 印刷中 Issue: 1 Pages: 98-106
  • DOI: 10.1016/j.jhep.2014.03.018
  • Peer Reviewed
• [Journal Article] Effect of Telmisartan or Losartan for Treatment of Nonalcoholic Fatty Liver Disease : Fatty Liver Protection Trial by Telmisartan or Losartan Study (FANTASY) (2013)
  • Author(s): Tomita K, et al.
  • Journal Title: Int J Endocrinol Volume: 2013 Pages: 587140-587140
  • DOI: 10.1155/2013/587140
  • Peer Reviewed
• [Journal Article] C-C motif chemokine receptor 9 positive macrophages activate hepatic stellate cells and promote liver fibrosis in mice (2013)
  • Author(s): Tomita K, et al.
  • Journal Title: Hepatology Volume: 58 Pages: 337-350
  • Peer Reviewed
• [Journal Article] Trans fatty acids in diets act as a precipitating factor for gut inflammation? (2013)
  • Author(s): Tomita K, et al.
  • Journal Title: J Gastroenterol Hepatol Volume: 4 Pages: 29-32
  • Peer Reviewed
• [Journal Article] Trans fatty acids exacerbate dextran sodium sulphate-induced colitis by promoting the upregulation of macrophage-derived proinflammatory cytokines involved in T helper 17 cell polarization (2013)
  • Author(s): Tomita K, et al.
  • Journal Title: Clin Exp Immunol Volume: 174(3) Pages: 459-471
  • Peer Reviewed
• [Journal Article] Phlebosclerotic colitis that was difficult to distinguish from collagenous colitis (2013)
  • Author(s): Tomita K, et al.
  • Journal Title: Dig Endosc Volume: 26 Issue: 4 Pages: 594-598
  • DOI: 10.1111/den.12151
  • Peer Reviewed
• [Journal Article] 1,4-Dihydroxy-2-naphthoic acid from Propionibacterium freudenreichii reduces inflammation in interleukin-10-deficient mice with colitis by suppressing macrophage-derived proinflammatory cytokines (2013)
  • Author(s): Tomita K, et al.
  • Journal Title: J Leukoc Biol Volume: 94 Pages: 473-480
  • Peer Reviewed
• [Journal Article] Involvement of autotaxin/lysophospholipase D expression in intestinal vessels in aggravation of intestinal damage through lymphocyte migration (2013)
  • Author(s): Tomita K, et al.
  • Journal Title: Lab Invest Volume: 93 Pages: 508-519
  • Peer Reviewed
• [Journal Article] Endoscopic finding of spontaneous hemorrhage correlates with tumor necrosis factor alpha expression in colonic mucosa of patients with ulcerative colitis (2013)
  • Author(s): Tomita K, et al.
  • Journal Title: Dis Int J Colorectal Volume: 28 Pages: 1049-1055
  • Peer Reviewed
• [Journal Article] Dietary lipids and sweeteners regulate glucagon-like peptide-2 secretion (2013)
  • Author(s): Tomita K, et al.
  • Journal Title: Am J Physiol Gastrointest Liver Physiol Volume: 304
  • Peer Reviewed
• [Journal Article] C-C motif chemokine receptor 9 positive macrophages activate hepatic stellate cells and promote liver fibrosis in mice. (2013)
  • Author(s): Chu PS, Nakamoto N, Ebinuma H, Usui S, Saeki K, Matsumoto A, Mikami Y, Sugiyama K, Tomita K, Kanai T, Saito H, Hibi T.
  • Journal Title: Hepatology Volume: 58 Issue: 1 Pages: 337-350
  • DOI: 10.1002/hep.26351
  • Peer Reviewed
• [Journal Article] A high-cholesterol diet exacerbates liver fibrosis in mice via accumulation of free cholesterol in hepatic stellate cells (2012)
  • Author(s): Tomita K, et al.
  • Journal Title: Gastroenterology Volume: 142 Pages: 152-164
  • Peer Reviewed
• [Journal Article] p53/p66Shc-mediated signaling contributes to the progression of non-alcoholic steatohepatitis in humans and mice (2012)
  • Author(s): Tomita K, et al.
  • Journal Title: J Hepatol Volume: 57 Pages: 837-843
  • Peer Reviewed
• [Journal Article] Indomethacin-induced small intestinal injury is ameliorated by cilostazol, a specific PDE-3 inhibitor (2012)
  • Author(s): Tomita K, et al.
  • Journal Title: Scand J Gastroenterol Volume: 47 Pages: 993-1002
  • Peer Reviewed
• [Journal Article] HIF-1 in T cells ameliorated dextran sodium sulfate-induced murine colitis (2012)
  • Author(s): Tomita K, et al.
  • Journal Title: J Leukoc Biol Volume: 91 Pages: 901-909
  • Peer Reviewed
• [Journal Article] p53/p66Shc-mediated signaling contributes to the progression of non-alcoholic steatohepatitis in humans and mice. (2012)
  • Author(s): Tomita K, Teratani T, Shimamura K, Nishiyama N, Mataki R, Irie T, Minamino Y, Okada C, Kurihara H, Sugiyama K, et al
  • Journal Title: J Hepatol Volume: 57 Issue: 4 Pages: 837-843
  • DOI: 10.1016/j.jhep.2012.05.013
  • Peer Reviewed
• [Journal Article] A high-cholesterol diet exacerbates liver fibrosis in mice via accumulation of free cholesterol in hepatic stellate cells (2012)
  • Author(s): Teratani T, Tomita K, Suzuki T, Oshikawa T, Yokoyama H, Shimamura K, Tominaga S, Hiroi S, Irie R, Okada Y, Kurihara C, Ebinuma H, Saito H, Hokari R, Sugiyama K, Kanai T, Miura S, Hibi T
  • Journal Title: Gastroenterology Volume: 142 Issue: 1 Pages: 152-164
  • DOI: 10.1053/j.gastro.2011.09.049
  • Peer Reviewed
• [Journal Article] Serum immunoglobulin A concentration is an independent predictor of liver fibrosis in nonalcoholic steatohepatitis before the cirrhotic stage (2011)
  • Author(s): Tomita K, et al.
  • Journal Title: Dig Dis Sci. Volume: 56 Pages: 3648-3654
  • Peer Reviewed
• [Journal Article] Plasma free myristic acid proportion is a predictor of nonalcoholic steatohepatitis (2011)
  • Author(s): Tomita K, et al.
  • Journal Title: Dig Dis Sci. Volume: 56 Pages: 3648-3654
  • Peer Reviewed
• [Journal Article] Fbxw7 regulates lipid metabolism and cell fate decisions in the mouse liver (2011)
  • Author(s): Tomita K, et al.
  • Journal Title: J Clin Invest Volume: 121 Pages: 342-354
  • Peer Reviewed
• [Presentation] The characteristic Mechanisms of Free Cholesterol Accumulation in Hepatic Stellate Cells Aggravate liver fibrosis in Nonalcoholic Steatohepatitis in Mice (2013)
  • Author(s): Tomita K
  • Organizer: The 48th Annual Meeting of the European Association for the Study of Liver Diseases
  • Place of Presentation: Amsterdam, The Netherlands
• [Presentation] The characteristic Mechanisms of Free Cholesterol Accumulation in Hepatic Stellate Cells Aggravate liver fibrosis in Nonalcoholic Steatohepatitis in Mice (2013)
  • Author(s): Tomita K, Teratani T, Suzuki T, Yokoyama H, Shimamura K, Nishiyama K, Okada Y, Kurihara C, Ebinuma H, Saito H, Hokari R, Sugiyama K, Hatsuse K, Yamamoto J, Kanai T, Hibi T, Miura S.
  • Organizer: The 48th Annual Meeting of the European Associatiion for the Study of Liver Diseases
  • Place of Presentation: オランダ アムステルダム
• [Presentation] p53/p66Shc signaling pathway plays a role in nonalcoholic steatohepatitis progression in human and mice (2012)
  • Author(s): Tomita K
  • Organizer: The 47th Annual Meeting of the European Association for the Study of Liver Diseases
  • Place of Presentation: Barcelona, Spain
• [Presentation] 肝星細胞の遊離コレステロール蓄積を介した、肝臓線維化進展機序の解析 (2012)
  • Author(s): 冨田謙吾、寺谷俊昭、日比紀文
  • Organizer: 第39回日本肝臓学会東部会
  • Place of Presentation: 東京
• [Presentation] 肝臓P53/p66Shcシグナル増強は、ヒトNASH病態を進展させる増悪因子である (2012)
  • Author(s): 冨田謙吾、日比紀文、三浦総一郎
  • Organizer: 第39回日本肝臓学会東部会
  • Place of Presentation: 東京
• [Presentation] コレステロール多量摂取は、肝星細胞の遊離コレステロール蓄積を介して、肝臓線維化進展を引き起こす (2012)
  • Author(s): 冨田謙吾、寺谷俊昭、鈴木貴博、横山裕一、 岡田義清、栗原千枝、海老沼浩利、齋藤英胤、渡辺知佳子、高本俊介、穂苅量太、川口淳、永尾重昭、杉山和夫、金井隆典、日比紀文、三浦総一郎
  • Organizer: 第48回日本肝臓学会総会
  • Place of Presentation: 金沢
• [Presentation] p53/p66Shc signaling pathway plays a role in nonalcoholic steatohepatitis progression in human and mice. (2012)
  • Author(s): Tomita K, Teratani T, Suzuki T, Yokoyama H, Shimamura K, Nishiyama K, Okada Y, Kurihara C, Ebinuma H, Saito H, Hokari R, Sugiyama K, Hatsuse K, Yamamoto J, Kanai T, Hibi T, Miura S
  • Organizer: The 47th Annual Meeting of the European Associatiion for the Study of Liver Diseases
  • Place of Presentation: スペイン バルセロナ