Odd chain fatty acids suppress RANKL-induced osteoclast differentiation via Keap1/Nrf2 pathway

• Project/Area Number: 20K11635
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 59040:Nutrition science and health science-related
• Research Institution: Aichi Medical University
• Principal Investigator: Tomono Susumu 愛知医科大学, 医学部, 助教 (60554011)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2022: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 奇数鎖脂肪酸 / 機能性脂質 / 破骨細胞 / 機能性脂肪酸 / 抗炎症作用

Outline of Research at the Start

最近、申請者は乳製品や魚類に多く含まれる長鎖奇数鎖脂肪酸であるヘプタデカン酸（C17:0）やペンタデカン酸（C15:0）が抗炎症作用を示す機能性脂肪酸であることを見出した。本研究では、生活習慣病と密接に関係し、近年、我が国で増加の一途をたどっている骨粗鬆症に着目し、申請者が得た奇数鎖脂肪酸の抗炎症・抗生活習慣病作用に関する知見を基盤に、免疫細胞を中心とした骨代謝に対する影響を明らかとすることを目的とする。本研究を行うことで、奇数鎖脂肪酸の新規機能性脂質としての有用性の確立および進行する高齢化社会における健康寿命延伸への貢献を目指す。

Outline of Final Research Achievements

Recently, some large-scale epidemiological studies reported an inverse association between chronic inflammatory diseases risk and odd-chain saturated fatty acids (OCFAs). However, the molecular mechanism by which OCFAs suppress inflammation remains unclear. In this study, we found that the addition of heptadecanoic acid and pentadecanoic acid inhibited RANKL-induced osteoclast differentiation in bone marrow-derived cells and RAW264.7. Furthermore, the inhibitory mechanism of RANKL-induced osteoclast differentiation was suggested to be due to activation of the Keap1/Nrf2 pathway.

Academic Significance and Societal Importance of the Research Achievements

骨粗鬆症はQOL（quality of life：生活の質）を低下させるだけではなく、高齢者の生命にも関わる重大な疾患である。また、我が国の医療費は2018年度には42.5兆円と国家予算の約半分となり、国民の生活を圧迫する大きな要因ともなっており、骨粗鬆症予防が喫緊の課題となっている。奇数鎖脂肪酸（C15:0, C17:0）の破骨細胞分化抑制効果と骨の代謝メカニズムとの関連性を明らかとすることは、生体内に存在する脂質バランスと骨粗鬆症発症機序との関連性の解明や脂質に着目した食と栄養学的な骨粗鬆症発症予防に有用な知見となると考えられる。

Research Products

• [Journal Article] The anti‐TLR4 monoclonal antibody Sa15‐21 enhances inflammatory cytokine production in LPS‐stimulated macrophages (2023)
  • Author(s): Chowdhury Sajid Iftekhar、Inui Masanori、Yamazaki Tatsuya、Tomono Susumu、Takagi Hidekazu、Biswas Mrityunjoy、Saitoh Shin‐Ichiroh、Miyake Kensuke、Akashi‐Takamura Sachiko
  • Journal Title: FEBS Letters Volume: - Issue: 9 Pages: 1-15
  • DOI: 10.1002/1873-3468.14619
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Cell surface expression of human<scp>RP105</scp>depends on<i>N</i>‐glycosylation of<scp>MD</scp>‐1 (2022)
  • Author(s): Biswas Mrityunjoy、Yamazaki Tatsuya、Tomono Susumu、Karnan Sivasundaram、Takagi Hidekazu、Ichimonji Isao、Inui Masanori、Nagaoka Fumiaki、Hosokawa Yoshitaka、Akashi‐Takamura Sachiko
  • Journal Title: FEBS Letters Volume: 596 Issue: 24 Pages: 3211-3231
  • DOI: 10.1002/1873-3468.14452
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Assessment of the toxicity and carcinogenicity of double-walled carbon nanotubes in the rat lung after intratracheal instillation: a two-year study. (2022)
  • Author(s): Saleh, D.M., Luo, S., Ahmed, O.H.M., Alexander, D.B., Alexander, W.T., Gunasekaran, S., El-Gazzar, A.M., Abdelgied, M., Numano, T., Takase, H., Ohnishi, M., Tomono, S., El Hadi, R.H.A., Fukamachi, K., Kanno, J., Hirose, A., Xu, J., Suzuki, S., Naiki-Ito, A., Takahashi, S., Tsuda, H.
  • Journal Title: Particle abd Fibre Toxicology Volume: 19 Issue: 1 Pages: 1-21
  • DOI: 10.1186/s12989-022-00469-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The combination of cigarette smoking and alcohol consumption synergistically increases reactive carbonyl species in human male plasma (2021)
  • Author(s): Mure K, Tomono S, Mure M, Horinaka M, Mutoh M, Sakai T, Ishikawa H, Wakabayashi K
  • Journal Title: International Journal of Molecular Sciences Volume: 22 Issue: 16 Pages: 9043-9043
  • DOI: 10.3390/ijms22169043
  • Peer Reviewed / Open Access
• [Journal Article] Clostridium butyricum MIYAIRI 588 Modifies Bacterial Composition under Antibiotic-Induced Dysbiosis for the Activation of Interactions via Lipid Metabolism between the Gut Microbiome and the Host (2021)
  • Author(s): Ariyoshi Tadashi、Hagihara Mao、Tomono Susumu、Eguchi Shuhei、Minemura Ayaka、Miura Daiki、Oka Kentaro、Takahashi Motomichi、Yamagishi Yuka、Mikamo Hiroshige
  • Journal Title: Biomedicines Volume: 9 Issue: 8 Pages: 1065-1065
  • DOI: 10.3390/biomedicines9081065
  • Peer Reviewed / Open Access
• [Journal Article] A Novel Gene Delivery Vector of Agonistic Anti-Radioprotective 105 Expressed on Cell Membranes Shows Adjuvant Effect for DNA Immunization Against Influenza (2020)
  • Author(s): Yamazaki Tatsuya、Biswas Mrityunjoy、Kosugi Kouyu、Nagashima Maria、Inui Masanori、Tomono Susumu、Takagi Hidekazu、Ichimonji Isao、Nagaoka Fumiaki、Ainai Akira、Hasegawa Hideki、Chiba Joe、Akashi-Takamura Sachiko
  • Journal Title: Frontiers in Immunology Volume: 11 Pages: 606518-606518
  • DOI: 10.3389/fimmu.2020.606518
  • Peer Reviewed / Open Access / Int'l Joint Research