Molecular mechanism of cell death-induced tissue remodeling in metabolic syndrome

• Project/Area Number: 20H03447
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 49010:Pathological biochemistry-related
• Research Institution: Nagoya University
• Principal Investigator: Suganami Takayoshi 名古屋大学, 環境医学研究所, 教授 (50343752)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000); Fiscal Year 2022: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2021: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2020: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000)
• Keywords: 慢性炎症 / メタボリックシンドローム / マクロファージ / 肥満 / NASH / 肝がん / 非アルコール性脂肪肝炎

Outline of Research at the Start

近年、過栄養に伴う代謝ストレスが慢性炎症を誘導し、生活習慣病の病態基盤となることが注目されている。研究代表者は、代謝ストレスによる細胞死が自然免疫応答を惹起して、メタボリックシンドロームにおける慢性炎症をもたらすことを見出した。本研究では、どのような細胞死が、どのようにして疾患・臓器特異的に炎症慢性化をもたらすかを解明し、新たな病態メカニズムの解明を目指す。

Outline of Final Research Achievements

To elucidate the molecular mechanisms of chronic inflammation associated with overnutrition, this study focused on the unique histological feature "crown-like structure (CLS)" observed in obesity and non-alcoholic steatohepatitis (NASH), and investigated the molecular mechanism of CLS formation and its pathophysiological significance. Specifically, we addressed (1) the application of the plant-derived flavonoid taxifolin to the treatment of NASH, (2) the functional significance of iron-rich macrophages in NASH, and (3) the mechanism of hepatic fibrosis induced by altered macrophage cholesterol metabolism.

Academic Significance and Societal Importance of the Research Achievements

現在、NASHの病態メカニズムは未だ不明の点が多く、厚労省に認可されたNASH治療薬も存在しない。本研究では、既に健康食品として世界中で使用されているタキシフォリンが抗メタボリックシンドローム効果に加えて、抗NASH効果も有することを初めて明らかにするとともに、CLSが薬効評価の点で有用であることを示した。また、鉄やコレステロールに着目してNASH病態メカニズムの一端を明らかにし、新たな治療戦略の創出につながると期待できる。

Research Products

• [Int'l Joint Research] University of Texas/Prof. Joel Elmquist(米国)
• [Int'l Joint Research] Univ. of Texas(米国)
• [Int'l Joint Research] Univ. of Texas(米国)
• [Journal Article] Tissue transglutaminase exacerbates renal fibrosis via alternative activation of monocyte-derived macrophages (2023)
  • Author(s): Shinoda Yoshiki、Tatsukawa Hideki、Yonaga Atsushi、Wakita Ryosuke、Takeuchi Taishu、Tsuji Tokuji、Tanaka Miyako、Suganami Takayoshi、Hitomi Kiyotaka
  • Journal Title: Cell Death & Disease Volume: 14 Issue: 2 Pages: 136-136
  • DOI: 10.1038/s41419-023-05622-5
  • Peer Reviewed / Open Access
• [Journal Article] Novel Therapeutic Potentials of Taxifolin for Obesity-Induced Hepatic Steatosis, Fibrogenesis, and Tumorigenesis (2023)
  • Author(s): Inoue Takayuki、Fu Bin、Nishio Miwako、Tanaka Miyako、Kato Hisashi、Tanaka Masashi、Itoh Michiko、Yamakage Hajime、Ochi Kozue、Ito Ayaka、Shiraki Yukihiro、Saito Satoshi、Ihara Masafumi、Nishimura Hideo、Kawamoto Atsuhiko、Inoue Shian、Saeki Kumiko、Enomoto Atsushi、Suganami Takayoshi、Satoh-Asahara Noriko
  • Journal Title: Nutrients Volume: 15 Issue: 2 Pages: 350-350
  • DOI: 10.3390/nu15020350
  • Peer Reviewed / Open Access
• [Journal Article] Medium-chain fatty acids suppress lipotoxicity-induced hepatic fibrosis via the immunomodulating receptor GPR84 (2023)
  • Author(s): Ohue-Kitano Ryuji、Nonaka Hazuki、Nishida Akari、Masujima Yuki、Takahashi Daisuke、Ikeda Takako、Uwamizu Akiharu、Tanaka Miyako、Kohjima Motoyuki、Igarashi Miki、Katoh Hironori、Tanaka Tomohiro、Inoue Asuka、Suganami Takayoshi、Hase Koji、Ogawa Yoshihiro、Aoki Junken、Kimura Ikuo
  • Journal Title: JCI Insight Volume: 8 Issue: 2 Pages: 165469-165469
  • DOI: 10.1172/jci.insight.165469
  • Peer Reviewed / Open Access
• [Journal Article] Molecular mechanism of crosstalk between immune and metabolic systems in metabolic syndrome (2022)
  • Author(s): Hachiya Rumi、Tanaka Miyako、Itoh Michiko、Suganami Takayoshi
  • Journal Title: Inflammation and Regeneration Volume: 42 Issue: 1 Pages: 13-13
  • DOI: 10.1186/s41232-022-00198-7
  • Peer Reviewed / Open Access
• [Journal Article] FOXO1 cooperates with C/EBPδ and ATF4 to regulate skeletal muscle atrophy transcriptional program during fasting (2022)
  • Author(s): Oyabu Mamoru、Takigawa Kaho、Mizutani Sako、Hatazawa Yukino、Fujita Mariko、Ohira Yuto、Sugimoto Takumi、Suzuki Osamu、Tsuchiya Kyoichiro、Suganami Takayoshi、Ogawa Yoshihiro、Ishihara Kengo、Miura Shinji、Kamei Yasutomi
  • Journal Title: The FASEB Journal Volume: 36 Issue: 2
  • DOI: 10.1096/fj.202101385rr
  • Peer Reviewed / Open Access
• [Journal Article] Dietary Supplementation With Eicosapentaenoic Acid Inhibits Plasma Cell Differentiation and Attenuates Lupus Autoimmunity (2021)
  • Author(s): Kobayashi Azusa、Ito Ayaka、Shirakawa Ibuki、Tamura Atsushi、Tomono Susumu、Shindou Hideo、Hedde Per Niklas、Tanaka Miyako、Tsuboi Naotake、Ishimoto Takuji、Akashi-Takamura Sachiko、Maruyama Shoichi、Suganami Takayoshi
  • Journal Title: Frontiers in Immunology Volume: 12 Pages: 650856-650856
  • DOI: 10.3389/fimmu.2021.650856
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Obesity accelerates hair thinning by stem cell-centric converging mechanisms (2021)
  • Author(s): Morinaga H, Mohri Y, Grachtchouk M, Asakawa K, Matsumura H, Oshima M, Takayama N, Kato T, Nishimori Y, Sorimachi Y,?Takubo K, Suganami T, Iwama A, Iwakura Y, Dlugosz AA, Nishimura EK.
  • Journal Title: Nature Volume: 595 Issue: 7866 Pages: 266-271
  • DOI: 10.1038/s41586-021-03624-x
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Macrophages rely on extracellular serine to suppress aberrant cytokine production (2021)
  • Author(s): Kurita Kento、Ohta Hiroya、Shirakawa Ibuki、Tanaka Miyako、Kitaura Yasuyuki、Iwasaki Yorihiro、Matsuzaka Takashi、Shimano Hitoshi、Aoe Seiichiro、Arima Hiroshi、Ogawa Yoshihiro、Ito Ayaka、Suganami Takayoshi
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 11137-11137
  • DOI: 10.1038/s41598-021-90086-w
  • Peer Reviewed / Open Access
• [Journal Article] The sodium-glucose cotransporter-2 inhibitor Tofogliflozin prevents the progression of nonalcoholic steatohepatitis-associated liver tumors in a novel murine model. (2021)
  • Author(s): Yoshioka N, Tanaka M, Ochi K, Watanabe A, Ono K, Sawada M, Ogi T, Itoh M, Ito A, Shiraki Y, Enomoto A, Ishigami M, Fujishiro M, Ogawa Y, Suganami T.
  • Journal Title: Biomed Pharmacother Volume: 140 Pages: 111738-111738
  • DOI: 10.1016/j.biopha.2021.111738
  • Peer Reviewed / Open Access
• [Journal Article] Iron-rich Kupffer cells exhibit phenotypic changes during the development of liver fibrosis in NASH. (2021)
  • Author(s): Kanamori Y, Tanaka M, Itoh M, Ochi K, Ito A, Hidaka I, Sakaida I, Ogawa Y, Suganami T
  • Journal Title: iScience Volume: 24 Issue: 2 Pages: 2102032-2102032
  • DOI: 10.1016/j.isci.2020.102032
  • Peer Reviewed / Open Access
• [Journal Article] Digenic mutations in ALDH2 and ADH5 impair formaldehyde clearance and cause a multisystem disorder, AMeD syndrome (2020)
  • Author(s): Oka Y, Hamada M, Nakazawa Y, ..., Tanaka M, Suganami T, Nakada S, Mitsutake N, Hara Y, Kato K, ..., Kaneko H, Matsumoto N, Matsuda F, Matsuo K, Takahashi Y, Mashimo T, Kojima S, Ogi T
  • Journal Title: Science Advances Volume: 6 Issue: 51 Pages: 7197-7197
  • DOI: 10.1126/sciadv.abd7197
  • Peer Reviewed / Open Access
• [Journal Article] Chronic inflammation as a molecular basis of nonalcoholic steatohepatitis : role of macrophages and fibroblasts in the liver (2020)
  • Author(s): Itoh M, Ogawa Y, Suganami T
  • Journal Title: Nagoya Journal of Medical Science Volume: 82 Issue: 3 Pages: 391-397
  • DOI: 10.18999/nagjms.82.3.391
  • NAID: 120006881540
  • ISSN: 2186-3326
  • URL: https://nagoya.repo.nii.ac.jp/records/30409
  • Peer Reviewed / Open Access
• [Journal Article] C-type lectin Mincle mediates cell death-triggered inflammation in acute kidney injury. (2020)
  • Author(s): Tanaka M, Saka-Tanaka M, Ochi K, Fujieda K, Sugiura Y, Miyamoto T, Kohda H, Ito A, Miyazawa T, Matsumoto A, Aoe S, Miyamoto Y, Tsuboi N, Maruyama S, Suematsu M, Yamasaki S, Ogawa Y, Suganami T.
  • Journal Title: J Exp Med. Volume: 217 Issue: 11
  • DOI: 10.1084/jem.20192230
  • Peer Reviewed / Open Access
• [Journal Article] Blocking sphingosine 1-phosphate receptor 2 accelerates hepatocellular carcinoma progression in a mouse model of NASH (2020)
  • Author(s): Yoshida T, Tsuchiya A, Kumagai M, Takeuchi S, Nojiri S, Watanabe T, Ogawa M, Itoh M, Takamura M, Suganami T, Ogawa Y, Terai S.
  • Journal Title: Biochem Biophys Res Commun Volume: 530 Issue: 4 Pages: 665-672
  • DOI: 10.1016/j.bbrc.2020.07.099
  • Peer Reviewed / Open Access
• [Journal Article] Gut Hormone GIP Induces Inflammation and Insulin Resistance in the Hypothalamus (2020)
  • Author(s): Fu Yukiko、Kaneko Kentaro、Lin Hsiao-Yun、Mo Qianxing、Xu Yong、Suganami Takayoshi、Ravn Peter、Fukuda Makoto
  • Journal Title: Endocrinology Volume: 161 Issue: 9
  • DOI: 10.1210/endocr/bqaa102
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Hollow fiber-combined glucose-responsive gel technology as an in vivo electronics-free insulin delivery system. (2020)
  • Author(s): Matsumoto A, Kuwata H, Kimura S, Matsumoto H, Ochi K, Moro-oka Y, Watanabe A, Yamada H, Ishii H, Miyazawa T, Chen S, Baba T, Yoshida H, Nakamura T, Inoue H, Ogawa Y, Tanaka M, Miyahara Y, Suganami T.
  • Journal Title: Commun. Biol. Volume: 3 Issue: 1 Pages: 313-313
  • DOI: 10.1038/s42003-020-1026-x
  • Peer Reviewed / Open Access
• [Journal Article] Development of a non-alcoholic steatohepatitis model with rapid accumulation of fibrosis, and its treatment using mesenchymal stem cells and their small extracellular vesicles (2020)
  • Author(s): Watanabe Takayuki、Tsuchiya Atsunori、Takeuchi Suguru、Nojiri Shunsuke、Yoshida Tomoaki、Ogawa Masahiro、Itoh Michiko、Takamura Masaaki、Suganami Takayoshi、Ogawa Yoshihiro、Terai Shuji
  • Journal Title: Regenerative Therapy Volume: 14 Pages: 252-261
  • DOI: 10.1016/j.reth.2020.03.012
  • Peer Reviewed / Open Access
• [Presentation] 脂肪肝・NASHの分子病態 (2023)
  • Author(s): 菅波孝祥
  • Organizer: 第57回日本糖尿病学会・糖尿病学の進歩・臨床医が知っておくべき糖尿病の基礎
  • Invited
• [Presentation] Dysregulation of cholesterol metabolism in macrophages promotes liver fibrosis in nonalcoholic steatohepatitis (2022)
  • Author(s): 菅波孝祥
  • Organizer: 第65回日本糖尿病学会年次学術集会・シンポジウム：代謝制御の中心としての肝臓
  • Invited
• [Presentation] 死細胞を取り巻くニッシェ特異的なマクロファージリプログラミング (2022)
  • Author(s): 菅波孝祥
  • Organizer: 第22回日本抗加齢医学会総会・シンポジウム：ニッシェ特異的なリプログラミング
  • Invited
• [Presentation] スマートインスリンデバイスの研究開発；「貼るだけで血糖コントロール」の実現を目指して (2022)
  • Author(s): 菅波孝祥, 松元 亮
  • Organizer: 第60回日本糖尿病学会九州地方会・ランチョンセミナー
  • Invited
• [Presentation] 細胞死が駆動する代謝変容による炎症慢性化機構 (2022)
  • Author(s): 菅波孝祥
  • Organizer: 第95回日本生化学会大会・シンポジウム：代謝で免疫を制御する；疾患をコントロールする免疫-代謝ネットワークの新知見
  • Invited
• [Presentation] 非アルコール性脂肪性肝疾患と肥満症 (2022)
  • Author(s): 菅波孝祥
  • Organizer: 第43回日本肥満学会・教育講演
  • Invited
• [Presentation] マクロファージの鉄代謝変容による肝線維化機構 (2021)
  • Author(s): 菅波孝祥
  • Organizer: 第94回日本生化学会大会
  • Invited
• [Presentation] 死細胞センサーMincleと急性腎障害 (2021)
  • Author(s): 菅波孝祥
  • Organizer: 第51回日本腎臓学会西部学術大会
  • Invited
• [Presentation] Molecular mechanism underlying cell death-triggered chronic inflammation in the metabolic syndrome (2021)
  • Author(s): Takayoshi Suganami
  • Organizer: 日本分子生物学会年会
  • Invited
• [Presentation] Obesity-induced “metabolic” tissue remodeling in adipose tissue and liver (2021)
  • Author(s): Takayoshi Suganami
  • Organizer: The 14th Asia Pacific Federation of Pharmacologists
  • Int'l Joint Research / Invited
• [Presentation] C-type lectin Mincle mediates cell death-triggered inflammation in acute kidney injury (2021)
  • Author(s): Takayoshi Suganami
  • Organizer: ASN Kidney Week 2021
  • Int'l Joint Research / Invited
• [Presentation] 代謝ストレス応答による臓器線維症の病態メカニズム (2021)
  • Author(s): 菅波孝祥
  • Organizer: 第20回分子予防環境医学研究会 メインシンポジウム：環境ストレス応答としての臓器線維症の病態と予防治療戦略
  • Invited
• [Presentation] 糖尿病と脂肪肝の最前線 (2021)
  • Author(s): 菅波孝祥
  • Organizer: 第55回日本糖尿病学会・糖尿病学の進歩
  • Invited
• [Presentation] 脂肪肝・NASHの新たな病態メカニズム (2021)
  • Author(s): 菅波孝祥
  • Organizer: 第41回日本肥満学会・第38回日本肥満症治療学会学術集会 JASSOシンポジウム２：内臓脂肪蓄積と異所性脂肪/臓器連関Up to Date
  • Invited
• [Presentation] 栄養がもたらす慢性炎症とメタボリックシンドローム (2020)
  • Author(s): 菅波孝祥
  • Organizer: 第74回日本栄養・食糧学会大会 教育講演5「過栄養がもたらす慢性炎症とメタボリックシンドローム」
  • Invited
• [Presentation] 脂肪肝と炎症 (2020)
  • Author(s): 菅波孝祥
  • Organizer: 第63回日本糖尿病学会 シンポジウム25「糖尿病・糖尿病合併症発症機序における臓器連関」
  • Invited
• [Presentation] 細胞死を起点とする炎症慢性化機構とメタボリックシンドローム (2020)
  • Author(s): 菅波孝祥
  • Organizer: 第41回日本炎症・再生医学会 シンポジウム8「免疫・炎症と代謝や神経との連関」
  • Invited
• [Presentation] イムノメタボリズムによるメタボリックシンドロームの制御機構 (2020)
  • Author(s): 菅波孝祥
  • Organizer: 第93回日本生化学会大会 シンポジウム2S01m「代謝と炎症・免疫の接点：イムノメタボリズム」
  • Invited
• [Presentation] 生活習慣病における慢性炎症と恒常性破綻のメカニズム (2020)
  • Author(s): 菅波孝祥
  • Organizer: 第48回日本臨床免疫学会総会 ワークショップ3：慢性炎症と恒常性の破綻
  • Invited
• [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] 東海国立大学機構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由来の肝細胞がんの予防又は治療剤 (2022)
  • Inventor(s): 菅波孝祥、田中都、浅原哲子、西村秀雄
  • Industrial Property Rights Holder: 東海国立大学機構/京都医療センター/神戸医療産業都市推進機構
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2022-100812
  • Filing Date: 2022
• [Patent(Industrial Property Rights)] 非アルコール性脂肪肝炎治療用医薬組成物 (2021)
  • Inventor(s): 田村篤志、由井伸彦、菅波孝祥、伊藤美智子
  • Industrial Property Rights Holder: 東海国立大学機構・東京医科歯科大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2021
  • Overseas
• [Patent(Industrial Property Rights)] 非アルコール性脂肪肝炎治療用医薬組成物 (2020)
  • Inventor(s): 田村篤志、由井伸彦、菅波孝祥、伊藤美智子
  • Industrial Property Rights Holder: 東京医科歯科大学/東海国立大学機構
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2020-139225
  • Filing Date: 2020