The function and therapeutic application of macrophage-specific H-ferritin in chronic inflammation of obese adipose tissue

• Project/Area Number: 18K08480
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: The University of Tokushima
• Principal Investigator: IKEDA Yasumasa 徳島大学, 大学院医歯薬学研究部(医学域), 教授 (60432754)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: 鉄 / マクロファージ / フェリチン / 肥満 / 糖尿病 / 鉄保持タンパク / 炎症

Outline of Final Research Achievements

We investigated the role of macrophage H-ferritin in obesity and diabetes using conditional macrophage-specific H-ferritin knockout (LysM-Cre Fth KO) mice. Iron concentration reduced, and mRNA expression of ferroportin increased, in macrophages from KO mice. HFD-induced obesity was lower in KO mice with the reduced mRNA expression of inflammatory cytokines, infiltrated macrophages and oxidative stress in the adipose tissue than WT mice. WT mice fed HFD had elevated iron concentration in fat and spleen, which was not observed in KO mice fed an HFD. Impaired both glucose tolerance and insulin sensitivity by HFD was alleviated in KO mice. Additionally, energy expenditure, mRNA expression of thermogenic genes, and body temperature were higher in KO mice with HFD than WT mice with HFD. The findings from this study highlight macrophage iron levels involves in the development of obesity and diabetes through regulating inflammatory response and energy metabolism in adipose tissue.

Academic Significance and Societal Importance of the Research Achievements

健康長寿のための栄養素の重要性、特に微量元素についての研究が進展するにつれて新しい知見が次々と明らかにされている。鉄摂取量や生体内鉄量が多いと様々な疾患のリスクが高まることが報告されており、鉄摂取が病態をむしろ悪化させることが危惧される。その一方で、生体内鉄量を減らすことで病態の改善が得られるも、従来の除鉄は非特異的あり限界があった。本研究によって、マクロファージ鉄が慢性炎症制御の標的であること、FTHが新規の鉄制御標的遺伝子であることが明らかとなり、マクロファージ特異的に鉄除去可能な新たな治療法の創出へと応用・展開につながると考えられる。

Research Products

• [Journal Article] Investigation of drugs affecting hypertension in bevacizumab‐treated patients and examination of the impact on the therapeutic effect (2020)
  • Author(s): Yagi Kenta、Mitstui Marin、Zamami Yoshito、Niimura Takahiro、Izawa‐Ishizawa Yuki、Goda Mitsuhiro、Chuma Masayuki、Fukunaga Kimiko、Shibata Takahiro、Ishida Shunsuke、Sakurada Takumi、Okada Naoto、Hamano Hirofumi、Horinouchi Yuya、Ikeda Yasumasa、Yanagawa Hiroaki、Ishizawa Keisuke
  • Journal Title: Cancer Medicine Volume: 10 Issue: 1 Pages: 164-172
  • DOI: 10.1002/cam4.3587
  • NAID: 120007147667
  • Peer Reviewed / Open Access
• [Journal Article] Deletion of H-ferritin in macrophages alleviates obesity and diabetes induced by high-fat diet in mice (2020)
  • Author(s): Ikeda Yasumasa、Watanabe Hiroaki、Shiuchi Tetsuya、Hamano Hirofumi、Horinouchi Yuya、Imanishi Masaki、Goda Mitsuhiro、Zamami Yoshito、Takechi Kenshi、Izawa-Ishizawa Yuki、Miyamoto Licht、Ishizawa Keisuke、Aihara Ken-ichi、Tsuchiya Koichiro、Tamaki Toshiaki
  • Journal Title: Diabetologia Volume: 63 Issue: 8 Pages: 1588-1602
  • DOI: 10.1007/s00125-020-05153-0
  • NAID: 120007039998
  • Peer Reviewed
• [Journal Article] Fibroblast-specific ERK5 deficiency changes tumor vasculature and exacerbates tumor progression in a mouse model. (2020)
  • Author(s): Masaki Imanishi, Yusuke Yamakawa, Keijo Fukushima, Raiki Ikuto, Akiko Maegawa, Yuki Izawa-Ishizawa, Yuya Horinouchi, Masateru Kondo, Masatoshi Kishuku, Mitsuhiro Goda, Yoshito Zamami, Kenshi Takechi, Masayuki Chuma, Yasumasa Ikeda, Koichiro Tsuchiya, Hiromichi Fujino, Koichi Tsuneyama, Keisuke Ishizawa
  • Journal Title: Naunyn-Schmiedeberg's Archives of Pharmacology Volume: - Issue: 7 Pages: 1239-1250
  • DOI: 10.1007/s00210-020-01859-5
  • Peer Reviewed / Open Access
• [Journal Article] Novel Hydrophilic Camptothecin Derivatives Conjugated to Branched Glycerol Trimer Suppress Tumor Growth without Causing Diarrhea in Murine Xenograft Models of Human Lung Cancer (2020)
  • Author(s): Tsuchihashi Yuki、Abe Shinji、Miyamoto Licht、Tsunematsu Honoka、Izumi Toshihiro、Hatano Aya、Okuno Hiroko、Yamane Megumi、Yasuoka Takashi、Ikeda Yasumasa、Tsuchiya Koichiro
  • Journal Title: Molecular Pharmaceutics Volume: 17 Issue: 4 Pages: 1049-1058
  • DOI: 10.1021/acs.molpharmaceut.9b00249
  • Peer Reviewed / Open Access
• [Journal Article] Proton pump inhibitors block iron absorption through direct regulation of hepcidin via the aryl hydrocarbon receptor-mediated pathway (2020)
  • Author(s): Hamano Hirofumi、Niimura Takahiro、Horinouchi Yuya、Zamami Yoshito、Takechi Kenshi、Goda Mitsuhiro、Imanishi Masaki、Chuma Masayuki、Izawa-Ishizawa Yuki、Miyamoto Licht、Fukushima Keijo、Fujino Hiromichi、Tsuchiya Koichiro、Ishizawa Keisuke、Tamaki Toshiaki、Ikeda Yasumasa
  • Journal Title: Toxicology Letters Volume: 318 Pages: 86-91
  • DOI: 10.1016/j.toxlet.2019.10.016
  • NAID: 120006894295
  • Peer Reviewed / Open Access
• [Journal Article] 鉄と腎：腎疾患と鉄代謝異常 (2020)
  • Author(s): 池田 康将
  • Journal Title: 腎臓内科 Volume: 11 Pages: 146-152
• [Journal Article] Body iron accumulation in obesity, diabetes and its complications, and the possibility of therapeutic application by iron regulation (2019)
  • Author(s): Horinouchi Yuya、Ikeda Yasumasa、Tamaki Toshiaki
  • Journal Title: Folia Pharmacologica Japonica Volume: 154 Issue: 6 Pages: 316-321
  • DOI: 10.1254/fpj.154.316
  • NAID: 130007754372
  • ISSN: 0015-5691, 1347-8397
  • Peer Reviewed
• [Journal Article] Iron accumulation causes impaired myogenesis correlated with MAPK signaling pathway inhibition by oxidative stress (2019)
  • Author(s): Ikeda Yasumasa、Satoh Akiho、Horinouchi Yuya、Hamano Hirofumi、Watanabe Hiroaki、Imao Mizuki、Imanishi Masaki、Zamami Yoshito、Takechi Kenshi、Izawa‐Ishizawa Yuki、Miyamoto Licht、Hirayama Tasuku、Nagasawa Hideko、Ishizawa Keisuke、Aihara Ken‐Ichi、Tsuchiya Koichiro、Tamaki Toshiaki
  • Journal Title: The FASEB Journal Volume: 33 Issue: 8 Pages: 9551-9564
  • DOI: 10.1096/fj.201802724rr
  • NAID: 120006847086
  • Peer Reviewed / Open Access
• [Journal Article] Development of a novel aortic dissection mouse model and evaluation of drug efficacy using in-vivo assays and database analyses (2019)
  • Author(s): Izawa-Ishizawa Yuki、Imanishi Masaki、Zamami Yoshito、Toya Hiroki、Nagao Tomoko、Morishita Marin、Tsuneyama Koichi、Horinouchi Yuya、Kihira Yoshitaka、Takechi Kenshi、Ikeda Yasumasa、Tsuchiya Koichiro、Yoshizumi Masanori、Tamaki Toshiaki、Ishizawa Keisuke
  • Journal Title: Journal of Hypertension Volume: 37 Issue: 1 Pages: 73-83
  • DOI: 10.1097/hjh.0000000000001898
  • NAID: 120006627861
  • Peer Reviewed / Open Access
• [Journal Article] Mechanisms of the pH- and Oxygen-Dependent Oxidation Activities of Artesunate (2018)
  • Author(s): Tsuda K, Miyamoto L, Hamano S, Morimoto Y, Kangawa Y, Fukue C, Kagawa Y, Horinouchi Y, Xu W, Ikeda Y, Tamaki T, Tsuchiya K
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 41 Issue: 4 Pages: 555-563
  • DOI: 10.1248/bpb.b17-00855
  • NAID: 130006602520
  • ISSN: 0918-6158, 1347-5215
  • Peer Reviewed / Open Access
• [Journal Article] Renoprotective effects of a factor Xa inhibitor: fusion of basic research and a database analysis (2018)
  • Author(s): Horinouchi Yuya、Ikeda Yasumasa、Fukushima Keijo、Imanishi Masaki、Hamano Hirofumi、Izawa-Ishizawa Yuki、Zamami Yoshito、Takechi Kenshi、Miyamoto Licht、Fujino Hiromichi、Ishizawa Keisuke、Tsuchiya Koichiro、Tamaki Toshiaki
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 10858-10858
  • DOI: 10.1038/s41598-018-29008-2
  • NAID: 120006535061
  • Peer Reviewed / Open Access
• [Journal Article] Irinotecan-induced neutropenia is reduced by oral alkalization drugs: analysis using retrospective chart reviews and the spontaneous reporting database (2018)
  • Author(s): Hamano Hirofumi、Mitsui Marin、Zamami Yoshito、Takechi Kenshi、Nimura Takahiro、Okada Naoto、Fukushima Keijo、Imanishi Masaki、Chuma Masayuki、Horinouchi Yuya、Izawa-Ishizawa Yuki、Kirino Yasushi、Nakamura Toshimi、Teraoka Kazuhiko、Ikeda Yasumasa、Fujino Hiromichi、Yanagawa Hiroaki、Tamaki Toshiaki、Ishizawa Keisuke
  • Journal Title: Supportive Care in Cancer Volume: 27 Issue: 3 Pages: 849-856
  • DOI: 10.1007/s00520-018-4367-y
  • Peer Reviewed / Open Access
• [Journal Article] Nitrosonifedipine, a photodegradation product of nifedipine, suppresses pharmacologically induced aortic aneurysm formation (2018)
  • Author(s): Imanishi Masaki、Izawa-Ishizawa Yuki、Sakurada Takumi、Kohara Yusuke、Horinouchi Yuya、Sairyo Eriko、Zamami Yoshito、Takechi Kenshi、Chuma Masayuki、Fukushima Keijo、Ikeda Yasumasa、Fujino Hiromichi、Yoshizumi Masanori、Tsuchiya Koichiro、Tamaki Toshiaki、Ishizawa Keisuke
  • Journal Title: Pharmacology Volume: 102 Issue: 5-6 Pages: 287-299
  • DOI: 10.1159/000492577
  • Peer Reviewed / Open Access
• [Journal Article] Methanol extraction fraction from Citrus Sudachi peel exerts lipid reducing effects in cultured cells (2018)
  • Author(s): Xu Wenting、Miyamoto Licht、Aihara Haruna、Yamaoka Tomomi、Tanaka Naonobu、Tsuchihashi Yuki、Ikeda Yasumasa、Tamaki Toshiaki、Kashiwada Yoshiki、Tsuchiya Koichiro
  • Journal Title: The Journal of Medical Investigation Volume: 65 Issue: 3.4 Pages: 225-230
  • DOI: 10.2152/jmi.65.225
  • NAID: 130007495803
  • ISSN: 1343-1420, 1349-6867
  • Peer Reviewed / Open Access
• [Journal Article] Xanthine oxidase inhibition by febuxostat in macrophages suppresses angiotensin II-induced aortic fibrosis (2018)
  • Author(s): Kondo Masateru、Imanishi Masaki、Fukushima Keijo、Ikuto Raiki、Murai Yoichi、Horinouchi Yuya、Izawa-Ishizawa Yuki、Goda Mitsuhiro、Zamami Yoshito、Takechi Kenshi、Chuma Masayuki、Ikeda Yasumasa、Fujino Hiromichi、Tsuchiya Koichiro、Ishizawa Keisuke
  • Journal Title: American Journal of Hypertension Volume: 32 Issue: 3 Pages: 249-256
  • DOI: 10.1093/ajh/hpy157
  • Peer Reviewed / Open Access
• [Journal Article] 糖尿病における微量栄養素「鉄」の役割 (2018)
  • Author(s): 池田康将
  • Journal Title: 四国医学雑誌 Volume: 74 Pages: 13-20
• [Journal Article] The uremic toxin indoxyl sulfate interferes with iron metabolism by regulating hepcidin in chronic kidney disease (2017)
  • Author(s): Hirofumi Hamano, Yasumasa Ikeda, Hiroaki Watanabe, Yuya Horinouchi, Yuki Izawa-Ishizawa, Masaki Imanishi, Yoshito Zamami, Kenshi Takechi, Licht Miyamoto, Keisuke Ishizawa, Koichiro Tsuchiya, Toshiaki Tamaki
  • Journal Title: Nephrology Dialysis Transplantation Volume: - Issue: 4 Pages: 586-597
  • DOI: 10.1093/ndt/gfx252
  • Peer Reviewed / Open Access
• [Presentation] シスプラチン起因性腎障害の予防薬の探索・同定 (2021)
  • Author(s): 池田 康将, 濱野 裕章, 合田 光寛, 福島 圭穣, 岸 誠司, 中馬 真幸, 座間味 義人, 宮本 理人, 石澤啓介 , 藤野 裕道, 粟飯原 賢一, 土屋 浩一郎, 玉置 俊晃
  • Organizer: 第94回日本薬理学会年会
• [Presentation] シスプラチン起因性腎障害を予防する既存薬の同定 (2020)
  • Author(s): 池田 康将, 濱野 裕章, 合田 光寛, 福島 圭穣, 岸 誠司, 石澤啓介, 土屋 浩一郎, 玉置 俊晃
  • Organizer: 第63回日本腎臓学会学術総会
• [Presentation] シスプラチン腎障害における鉄依存性細胞死の検討 (2020)
  • Author(s): 池田 康将, 濱野 裕章, 堀ノ内 裕也, 合田 光寛, 座間味 義人, 宮本 理人, 石澤 啓介, 土屋 浩一郎
  • Organizer: 第93回日本薬理学会年会
• [Presentation] シスプラチン腎障害における鉄依存性細胞死の役割の検討 (2019)
  • Author(s): 池田 康将, 堀ノ内 裕也
  • Organizer: 第23回日本心血管内分泌代謝学会学術総会【CVMW2019 心血管代謝週間 】
• [Presentation] 心血管病におけるアンドロゲン受容体の意義 (2019)
  • Author(s): 吉田 守美子, 池田 康将, 粟飯原 賢一, 安倍 正博
  • Organizer: 第30回 日本性機能学会学術総会 シンポジウム
  • Invited
• [Presentation] 心血管病における性機能障害と男性ホルモンの心血管保護作用 (2019)
  • Author(s): 八木 秀介, 粟飯原 賢一, 吉田 守美子, 池田 康将, 赤池 雅史, 佐田 政隆
  • Organizer: 日本性機能学会第30回学術集会 シンポジウム
  • Invited
• [Presentation] プロトンポンプ阻害剤はヘプシジンを介して鉄代謝異常に関与する (2019)
  • Author(s): 濱野 裕章, 池田 康将, 堀ノ内 裕也, 合田 光寛, 座間味 義人, 桐野 靖, 中村 敏己, 寺岡 和彦, 石澤 啓介
  • Organizer: 第29回日本医療薬学会年会
• [Presentation] 慢性腎不全関連骨格筋萎縮における鉄代謝異常 (2019)
  • Author(s): 堀ノ内 裕也、池田 康将、濱野 裕章、今西 正樹、福島 圭穣、合田 光寛、武智 研志、宮本 理人、石澤 有紀、座間味 義人、藤野 裕道、石澤 啓介、土屋 浩一郎、玉置 俊晃
  • Organizer: 第92回日本薬理学会年会
• [Presentation] 鉄蓄積は骨格筋分化を抑制する (2019)
  • Author(s): 池田 康将，佐藤 明穂，堀ノ内 裕也，石澤 有紀，宮本 理人，石澤 啓介，土屋 浩一郎，玉置 俊晃
  • Organizer: 第92回日本薬理学会年会
• [Presentation] シンポジウム2「必須微量金属研究のパラダイムシフト」疾患における鉄の意義と治療応用 (2019)
  • Author(s): 堀ノ内 裕也，池田 康将，玉置 俊晃
  • Organizer: 第92回日本薬理学会年会
• [Presentation] シンポジウム4「心疾患腎代謝疾患の制御因子としての微量金属栄養素「鉄」の新たな展開 」肥満・糖尿病における鉄制御の意義 (2019)
  • Author(s): 堀ノ内 裕也，池田 康将，玉置 俊晃
  • Organizer: 第48回日本心脈管作動物質学会
• [Presentation] Utilizing Real-World Big Data in the Search for New Renoprotective Drugs (2018)
  • Author(s): Yuya Horinouchi, Yasumasa Ikeda, Keijo Fukushima, Masaki Imanishi, Hirofumi Hamano, Yuki Izawa-Ishizawa, Yoshito Zamami, Hiromichi Fujino, Keisuke Ishizawa, Koichiro Tsuchiya, Toshiaki Tamaki
  • Organizer: HBPR 2018 AHA Scientific Sessions
  • Int'l Joint Research
• [Presentation] Renoprotective effects of edoxaban, a factor Xa inhibitor (2018)
  • Author(s): Yuya Horinouchi, Yasumasa Ikeda, Keijo Fukushima, Masaki Imanishi, Yuki Izawa-Ishizawa, Yoshito Zamami, Hiromichi Fujino, Keisuke Ishizawa, Koichiro Tsuchiya and Toshiaki Tamaki
  • Organizer: 18th World Congress of Basic and Clinical Pharmacology
  • Int'l Joint Research
• [Presentation] Proton Pump Inhibitor Involves Abnormality of Iron Metabolism through Hepcidin Regulation (2018)
  • Author(s): Hirofumi Hamano, Yasumasa Ikeda, Yuya Horinouchi, Yoshito Zamami, Masaki Imanishi, Yuki Izawa-ishizawa, Licht Miyamoto, Koichiro Tsuchiya, Keisuke Ishizawa,Toshiaki Tamaki
  • Organizer: 18th World Congress of Basic and Clinical Pharmacology
  • Int'l Joint Research
• [Presentation] シンポジウム1「腎疾患(CKD)の治療と研究の最前線」慢性腎臓病における鉄代謝の意義と治療応用 (2018)
  • Author(s): 池田 康将, 玉置 俊晃
  • Organizer: 第48回日本腎臓学会西部学術大会
• [Presentation] シンポジウム2:「心血管系のNO/活性酸素と臨床応用展開」心腎血管代謝疾患における鉄の新たな知見 (2018)
  • Author(s): 池田 康将
  • Organizer: 第18回日本NO学会学術集会・第71回日本酸化ストレス学会学術集会合同大会
• [Presentation] マクロファージフェリチン欠損は肥満・糖尿病における脂肪炎症を抑制する (2018)
  • Author(s): 堀ノ内 裕也，池田 康将，渡邉 大晃，濱野 裕章，石澤 有紀，今西 正樹，座間味 義人，武智 研志，宮本 理人，石澤 啓介，土屋 浩一郎，玉置 俊晃
  • Organizer: 第48回日本心脈管作動物質学会
• [Presentation] マクロファージ鉄の肥満・糖尿病における役割 (2018)
  • Author(s): 堀ノ内 裕也, 池田 康将, 渡邉 大晃, 濱野 裕章, 石澤 有紀, 今西 正樹, 座間味 義人, 武智 研志，宮本 理人, 石澤 啓介, 土屋 浩一郎, 玉置 俊晃
  • Organizer: 第42回日本鉄バイオサイエンス学会学術集会
• [Remarks] 徳島大学 教育研究者総覧
  • URL: http://pub2.db.tokushima-u.ac.jp/ERD/person/219499/work-ja.html
• [Remarks] 徳島大学大学院医歯薬学研究部薬理学分野HP
  • URL: https://yasuike2.wixsite.com/website
• [Remarks] 徳島大学大学院医歯薬学研究部薬理学分野HP
  • URL: http://www.tuyakuri.umin.jp/