Role of "metabolic" tissue remodeling in the pathophysiology of obesity-induced chronic inflammation

• Project/Area Number: 16H05171
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Nagoya University
• Principal Investigator: Suganami Takayoshi 名古屋大学, 環境医学研究所, 教授 (50343752)
• Research Collaborator: Itoh Michiko
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000); Fiscal Year 2018: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2017: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000)
• Keywords: 慢性炎症 / 肥満 / 非アルコール性脂肪肝炎 / マクロファージ / 細胞死 / メタボリックシンドローム / 組織リモデリング / 線維化

Outline of Final Research Achievements

In this study, to understand the molecular mechanism underlying NASH, we employed genetically obese melanocortin-4 receptor-deficient mice, which sequentially developed simple steatosis, NASH, and hepatocellular carcinoma (HCC) when they were fed a Western diet. We also develop novel accelerated animal models which exhibited NASH and HCC in the short-term. Using these animal models, we identified a unique histological structure termed “crown-like structure”, in which macrophages aggregated around dead hepatocytes, thereby accelerating tissue remodeling during the disease progression from simple steatosis to NASH. Our data suggest that CLS is useful to examine the molecular mechanisms how certain drugs ameliorated NASH.

Academic Significance and Societal Importance of the Research Achievements

近年、数多くの抗糖尿病薬が上市され、糖尿病治療は、単に血糖値を低下させるのみならず、合併症を予防することに重点が置かれるようになってきた。即ち、脂肪肝やNASHに対する抗糖尿病薬の効果が注目されている。そこで本研究では、種々の薬剤のNASHに対する薬効評価を実施した。CLSに着目することにより、治療効果の定量的評価が可能となり、作用機序の一端も明らかになるなど、今後の治療法の開発に資すると考えられた。

Research Products

• [Int'l Joint Research] University of Texas(米国)
• [Int'l Joint Research] University of Texas(United States of America)
• [Int'l Joint Research] テキサス大学(米国)
• [Journal Article] Evaluation of hepatic function using dynamic contrast-enhanced magnetic resonance imaging in melanocortin 4 receptor-deficient mice as a model of nonalcoholic steatohepatitis. (2019)
  • Author(s): T. Yamada, Y. Kashiwagi, T. Rokugawa, H. Kato, H. Konishi, T. Hamada, R. Nagai, Y. Masago, M. Itoh, T. Suganami, Y. Ogawa, H. Watabe, K. Abe.
  • Journal Title: Magn Reson Imaging Volume: 57 Pages: 210-217
  • DOI: 10.1016/j.mri.2018.11.013
  • Peer Reviewed / Open Access
• [Journal Article] Obeticholic acid protects against hepatocyte death and liver fibrosis in a murine model of nonalcoholic steatohepatitis. (2018)
  • Author(s): T. Goto, M. Itoh, T. Suganami, S. Kanai, I. Shirakawa, T. Sakai, M. Asakawa,T. Yoneyama, T. Kai, Y. Ogawa.
  • Journal Title: Sci Rep. Volume: 8 Pages: 8157-8157
  • DOI: 10.1038/s41598-018-26383-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Canagliflozin, an SGLT2 inhibitor, attenuates the development of hepatocellular carcinoma in a mouse model of human NASH (2018)
  • Author(s): Shiba K、Tsuchiya K、Komiya C、Miyachi Y、Mori K、Shimazu N、Yamaguchi S、Ogasawara N、Katoh M、Itoh M、Suganami T、Ogawa Y
  • Journal Title: Sci. Rep. Volume: 8 Pages: 2362-2362
  • DOI: 10.1038/s41598-018-19658-7
  • Peer Reviewed / Open Access
• [Journal Article] Fatty Acid Binding Protein 4 (FABP4) Overexpression in Intratumoral Hepatic Stellate Cells within Hepatocellular Carcinoma with Metabolic Risk Factors (2018)
  • Author(s): Chiyonobu N、Shimada S、Akiyama Y、Mogushi K、Itoh M、Akahoshi K、Matsumura S、Ogawa K、Ono H、Mitsunori Y、Ban D、Kudo A、Arii S、Suganami T、Yamaoka S、Ogawa Y、Tanabe M、Tanaka S
  • Journal Title: Am. J. Pathol. Volume: 188 Pages: 1213-1224
  • DOI: 10.1016/j.ajpath.2018.01.012
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Molecular mechanism of obesity-induced ‘metabolic’ tissue remodeling (2017)
  • Author(s): Tanaka Miyako、Itoh Michiko、Ogawa Yoshihiro、Suganami Takayoshi
  • Journal Title: Journal of Diabetes Investigation Volume: 9 Pages: 256-261
  • DOI: 10.1111/jdi.12769
  • Peer Reviewed / Open Access
• [Journal Article] CD11c+ resident macrophages drive hepatocyte death-triggered liver fibrosis in a murine model of nonalcoholic steatohepatitis (2017)
  • Author(s): Itoh Michiko、Suganami Takayoshi、Kato Hideaki、Kanai Sayaka、Shirakawa Ibuki、Sakai Takeru、Goto Toshihiro、Asakawa Masahiro、Hidaka Isao、Sakugawa Hiroshi、Ohnishi Koji、Komohara Yoshihiro、Asano Kenichi、Sakaida Isao、Tanaka Masato、Ogawa Yoshihiro
  • Journal Title: JCI insight Volume: 2 Pages: 1-16
  • DOI: 10.1172/jci.insight.92902
  • Peer Reviewed / Open Access
• [Journal Article] Synthetic “smart gel” provides glucose-responsive insulin delivery in diabetic mice (2017)
  • Author(s): Matsumoto Akira、Tanaka Miyako、Matsumoto Hiroko、Ochi Kozue、Moro-oka Yuki、Kuwata Hirohito、Yamada Hironori、Shirakawa Ibuki、Miyazawa Taiki、Ishii Hitoshi、Kataoka Kazunori、Ogawa Yoshihiro、Miyahara Yuji、Suganami Takayoshi
  • Journal Title: Science Advances Volume: 3 Pages: 0723-0723
  • DOI: 10.1126/sciadv.aaq0723
  • Peer Reviewed / Open Access
• [Journal Article] Antifibrotic effect of pirfenidone in a mouse model of human nonalcoholic steatohepatitis. (2017)
  • Author(s): C. Komiya, M. Tanaka, K. Tsuchiya, N. Shimazu, K. Mori, S. Furuke, Y. Miyachi, K. Shiba, S. Yamaguchi, K. Ikeda, K. Ochi, K. Nakabayashi, K. Hata, M. Itoh, T. Suganami, Y. Ogawa.
  • Journal Title: Sci Rep Volume: 7 Pages: 44754-44754
  • DOI: 10.1038/srep44754
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The H3K9 methyltransferase Setdb1 regulates TLR4-mediated inflammatory responses in macrophages. (2016)
  • Author(s): R. Hachiya, T. Shiihashi, I. Shirakawa, Y. Iwasaki, Y. Matsumura, Y. Oishi, Y. Nakayama, Y. Miyamoto, I. Manabe, K. Ochi, M. Tanaka, N. Goda, J. Sakai, T. Suganami, Y. Ogawa.
  • Journal Title: Scientific Reports Volume: 6 Pages: 28845-28845
  • DOI: 10.1038/srep28845
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Inflammatory responses increase secretion of MD-1 protein. (2016)
  • Author(s): RT. Jennings, E. Odkhuu, A. Nakashima, N. Morita, T. Kobayashi, I. Yamai, M. Tanaka, T. Suganami, S. Haga, M. Ozaki, Y. Watanabe, Y. Nagai, K. Takatsu, T. Kikuchi-Ueda, I. Ichimonji, Y. Ogawa, H. Takagi, T. Yamazaki, K. Miyake, S. Akashi-Takamura.
  • Journal Title: Int. Immunol. Volume: 28 Pages: 503-512
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 過栄養により誘導される慢性炎症の分子機構 (2018)
  • Author(s): 菅波孝祥、田中 都、伊藤美智子、小川佳宏
  • Organizer: 第55回日本臨床分子医学会
  • Invited
• [Presentation] 脂肪組織の炎症と脂肪毒性 (2018)
  • Author(s): 菅波孝祥、田中 都、伊藤美智子、小川佳宏
  • Organizer: 第40回日本臨床栄養学会総会・第39回日本臨床栄養協会総会 第16回大連合大会
  • Invited
• [Presentation] Emerging concept of immunometabolism response and cellular metabolism (2018)
  • Author(s): Takayoshi Suganami
  • Organizer: 第47回日本免疫学会学術集会
  • Invited
• [Presentation] CD11c+ resident macrophages drive hepatocyte death-triggered liver fibrosis in nonalcoholic steatohepatitis (2018)
  • Author(s): Takayoshi Suganami, Michiko Itoh, Yoshihiro Ogawa
  • Organizer: 2018 Keystone Symposia
  • Int'l Joint Research / Invited
• [Presentation] Obesity-induced “metabolic” tissue remodeling in adipose tissue and liver (2017)
  • Author(s): Takayoshi Suganami, Miyako Tanaka, Michiko Itoh, Yoshihiro Ogawa
  • Organizer: 16th Surugadai International Symposium
  • Int'l Joint Research / Invited
• [Presentation] 脂肪組織-肝臓連関の破綻と非アルコール性脂肪肝炎の新たな病態メカニズム (2017)
  • Author(s): 菅波孝祥、田中 都、伊藤美智子、小川佳宏
  • Organizer: 第38回日本肥満学会
  • Invited
• [Presentation] 脂肪組織-肝臓連関の破綻による異所性脂肪蓄積の新たな分子機構 (2016)
  • Author(s): 菅波孝祥、田中 都、伊藤美智子、小川佳宏
  • Organizer: 第20回日本心血管内分泌学会学術総会
  • Place of Presentation: 東京
  • Year and Date: 2016-12-16
  • Invited
• [Presentation] Obesity-induced adipose tissue inflammation and ectopic lipid accumulation (2016)
  • Author(s): Takayoshi Suganami, Miyako Tanaka, Michiko Itoh, Yoshihiro Ogawa
  • Organizer: The 10th Congress of the Asian-Pacific Society of Atherosclerosis and Vascular Diseases
  • Place of Presentation: 東京
  • Year and Date: 2016-07-14
  • Int'l Joint Research / Invited
• [Presentation] Role of obesity-induced tissue remodeling in the metabolic syndrome (2016)
  • Author(s): Takayoshi Suganami, Miyako Tanaka, Michiko Itoh, Yoshihiro Ogawa
  • Organizer: 第38回日本血栓止血学会学術集会
  • Place of Presentation: 奈良
  • Year and Date: 2016-06-16
  • Invited
• [Presentation] 脂肪組織の慢性炎症 (2016)
  • Author(s): 菅波孝祥、田中 都、伊藤美智子、小川佳宏
  • Organizer: 第59回日本糖尿病学会年次学術集会
  • Place of Presentation: 京都
  • Year and Date: 2016-05-19
  • Invited
• [Book] Chronic Inflammation: Mechanisms and Regulation. (2016)
  • Author(s): T. Suganami, M. Tanaka, Y. Ogawa.
  • Total Pages: 702
  • Publisher: Springer Japan
• [Remarks] 名古屋大学環境医学研究所分子代謝医学分野
  • URL: http://www.riem.nagoya-u.ac.jp/4/mmm/index.html
• [Remarks] 名古屋大学環境医学研究所 分子代謝医学分野
  • URL: http://www.riem.nagoya-u.ac.jp/4/mmm/index.html
• [Patent(Industrial Property Rights)] 非アルコール性脂肪肝炎及び/又は肝臓がんのモデル動物の製造方法 (2018)
  • Inventor(s): 菅波孝祥、田中 都、越智 梢
  • Industrial Property Rights Holder: 名古屋大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2018-198437
  • Filing Date: 2018