Molecular mechanism of tissue fibrosis and develpment of revolutionary anti-fibrotic therapy

2013 Fiscal Year Final Research Report

• Project/Area Number: 25670439
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Endocrinology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: OGAWA Yoshihiro 東京医科歯科大学, 医歯(薬)学総合研究科, 教授 (70291424)
• Co-Investigator(Kenkyū-buntansha): YAMASAKI Sho 九州大学, 生体防御医学研究所, 教授 (40312946)
• Co-Investigator(Renkei-kenkyūsha): TANAKA Miyako 東京医科歯科大学, 大学院医歯(薬)学総合研究科, メディカルフェロー (60622793)
• Project Period (FY): 2013-04-01 – 2014-03-31
• Keywords: 線維化 / マクロファージ / Mincle / 脂肪組織 / 線維芽細胞

Research Abstract

Fibrosis is a final, common pathological outcome of a variety of chronic inflammatory diseases. In this study, we focused on Macrophage-inducible C-type lectin (Mincle), a pathogen sensor that recognizes Mycobacterium tuberculosis and is induced in obese adipose tissue and investigated the role of Mincle in the regulation of adipose tissue fibrosis. In the obese adipose tissue, Mincle was expressed mainly in proinflammatory M1 macrophages. Mincle stimulation caused the upregulation of genes related to fibrogenesis in peritoneal macrophages. Furthermore, Mincle stimulation by trehalose 6,6'-dimycolate, an exogenous ligand for Mincle, in adipose tissue resulted in adipose tissue fibrosis. These observations suggest that Mincle activation in obese adipose tissue leads to the progression of adipose tissue fibrosis, thereby suggesting that Mincle antagonism offers an novel anti-fibrotic therapy for chronic fibrotic diseases.

Research Products

• [Journal Article] PGC-1α-mediated branched-chain amino acid metabolism in the skeletal muscle (2014)
  • Author(s): Hatazawa Y, Tadaishi M, Nagaike Y, Morita A, Ogawa Y, Ezaki O, Takai-Igarashi T, Kitaura Y, Shimomura Y, Kamei Y, Miura S.
  • Journal Title: PLoS ONE Volume: 9(3) Pages: e91006
  • DOI: 10.1371/journal.pone.0091006.
• [Journal Article] (2014)
  • Author(s): Inoue K, Maeda N, Mori T, Sekimoto R, Tsushima Y, Matsuda K, Yamaoka M, Suganami T, Nishizawa H, Ogawa Y, Funahashi T, Shimomura I.
  • Journal Title: PLoS ONE Volume: 9(2) Pages: e87661
  • DOI: 10.1371/journal.pone.0087661
• [Journal Article] Endothelial PGC-1α mediates vascular dysfunction in diabetes. (2014)
  • Author(s): Sawada N, Jiang A, Takizawa F, Safdar A, Manika A, Tesmenitsky Y, Kang KT, Bischoff J, Kalwa H, Sartoretto JL, Kamei Y, Benjamin LE, Watada H, Ogawa Y, Higashikuni Y, Kessinger CW, Jaffer FA, Michel T, Sata M, Croce K, Tanaka R, Arany Z.
  • Journal Title: Cell Metab Volume: 19(2) Pages: 246-58
  • DOI: 10.1016/j.cmet.2013.12.014.
• [Journal Article] Paternal allele influences high fat diet-induced obesity (2014)
  • Author(s): Morita S, Horii T, Kimura M, Arai Y, Kamei Y, Ogawa Y, Hatada I.
  • Journal Title: PLoS ONE Volume: 9(1) Pages: e85477
  • DOI: 10.1371/journal.pone.0085477.
• [Journal Article] Vascular complications and coagulation-related changes in the perioperative period in Japanese patients undergoing non-cardiac surgery (2014)
  • Author(s): Aoyama-Mani C, Kawachi S, Ogawa Y, Kato N.
  • Journal Title: J. Atheroscler. Thromb. Volume: 21(5) Pages: 414-34
• [Journal Article] An increase in the EPA/AA ratio is associated with improved arterial stiffness in obese patients with Dyslipidemia (2014)
  • Author(s): Ito R, Satoh-Asahara N, Yamakage H, Sasaki Y, Odori S, Kono S, Wada H, Suganami T, Ogawa Y, Hasegawa K, Shimatsu A.
  • Journal Title: J. Atheroscler. Thromb. Volume: 21(3) Pages: 248-60
• [Journal Article] Activating transcription factor 4 links metabolic stress to interleukin-6 expression in macrophages (2014)
  • Author(s): Iwasaki Y, Suganami T, Hachiya R, Shirakawa I, Kim-Saijo M, Tanaka M, Hamaguchi M, Takai-Igarashi T, Nakai M, Miyamoto Y, Ogawa Y.
  • Journal Title: Diabetes Volume: 63(1) Pages: 152-61
  • DOI: 10.2337/db13-0757.
• [Journal Article] Hepatic crown-like structure : a unique histological feature in non-alcoholic steatohepatitis in mice and humans (2013)
  • Author(s): Itoh M, Kato H, Suganami T, Konuma K, Marumoto Y, Terai S, Sakugawa H, Kanai S, Hamaguchi M, Fukaishi T, Aoe S, Akiyoshi K, Komohara Y, Takeya M, Sakaida I, Ogawa Y.
  • Journal Title: PLoS ONE Volume: 8(12) Pages: e82163
  • DOI: 10.1371/journal.pone.0082163.
• [Journal Article] A novel role for adipose ephrin-B1 in inflammatory response. (2013)
  • Author(s): Mori T, Maeda N, Inoue K, Sekimoto R, Tsushima Y, Matsuda K, Yamaoka M, Suganami T, Nishizawa H, Ogawa Y, Funahashi T, Shimomura I.
  • Journal Title: PLoS ONE Volume: 8(10) Pages: e76199
  • DOI: 10.1371/journal.pone.0076199.
• [Journal Article] Role of chronic inflammation in adipose tissue in the pathophysiology of obesity. (2013)
  • Author(s): Suganami T, Ogawa Y.
  • Journal Title: Nihon Rinsho Volume: 71(2) Pages: 225-30
• [Journal Article] Analysis of DNA methylation change induced by Dnmt3b in mouse hepatocytes (2013)
  • Author(s): Takahashi M, Kamei Y, Ehara T, Yuan X, Suganami T, Takai-Igarashi T, Hatada I, Ogawa Y.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 434(4) Pages: 873-8
  • DOI: 10.1016/j.bbrc.2013.04.041.
• [Journal Article] Association between body weight at weaning and remodeling in the subcutaneous adipose tissue of obese adult mice with undernourishment in utero (2013)
  • Author(s): Kohmura YK, Kanayama N, Muramatsu K, Tamura N, Yaguchi C, Uchida T, Suzuki K, Sugihara K, Aoe S, Sasaki T, Suganami T, Ogawa Y, Itoh H.
  • Journal Title: Reprod. Sci. Volume: 20(7) Pages: 813-27
  • DOI: 10.1177/1933719112466300.
• [Presentation] Role of parenchymal-stromal cell interaction in metabolic diseases. (2014)
  • Author(s): Ogawa Y.
  • Organizer: 2014 Keystone Symposia on Molecular and Cellular Biology:
  • Place of Presentation: Innate Immunity, Metabolism and Vascular Injury Whistler, Canada
  • Year and Date: 20140323-28
• [Presentation] Regulation of metabolic genes by DNA methylation. 8th World Congress on Developmental Origins of Health and Disease. (2013)
  • Author(s): Ogawa Y.
  • Organizer: SUTEC
  • Place of Presentation: Singapore
  • Year and Date: 20131117-20
• [Presentation] Chronic inflammation and ectopic fat accumulation in the metabolic syndrome. (2013)
  • Author(s): Ogawa Y.
  • Organizer: 2013 International Conference on Diabetes and Metabolism (ICDM2013) & 5th Scientific Meeting of the Asian Association for the Study of Diabetes (5th AASD Scientific Meeting)
  • Place of Presentation: Seoul, Korea
  • Year and Date: 20131106-09
• [Remarks]
  • URL: http://www.tmd.ac.jp/grad/cme/index.html