Elucidation of the role of secreted form and ectopic expression of fatty acid-binding proteins in cardiovascular and metabolic diseases

• Project/Area Number: 26461384
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Endocrinology
• Research Institution: Sapporo Medical University
• Principal Investigator: Furuhashi Masato 札幌医科大学, 医学部, 講師 (20563852)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 脂肪酸結合タンパク / 脂肪細胞 / 炎症 / インスリン抵抗性 / 動脈硬化 / アディポカイン

Outline of Final Research Achievements

Fatty acid-binding protein 4 (FABP4) is expressed in adipocytes and macrophages. Here we investigated the mechanism of secretion of FABP4 and its functions. FABP4 was secreted from adipocytes despite of the lack of signal peptides. Treatment with FABP4 promoted inflammation in a dose-dependent manner, leading to the development of atherosclerosis. FABP4 concentration was independently assocciated with not only insulin resistance and atherosclerosis but also cardiac diastolic dysfunction and PCSK9 level. Several drugs, including angiotensin II receptor blockers, a DPP-4 inhibitor, and EPA/DHA, significantly decreased FABP4 levels. Furthermore, ectopic expression of FABP4 was observed in wire-injured endothelial cells, which was associated with neointima formation.

Research Products

• [Journal Article] Serum FABP5 concentration is a potential biomarker for residual risk of atherosclerosis in relation to cholesterol efflux from macrophages. (2017)
  • Author(s): Furuhashi M, Ogura M, Matsumoto M, Yuda S, Muranaka A, Kawamukai M, Omori A, Tanaka M, Moniwa N, Ohnishi H, Saitoh S, Harada-Shiba M, Shimamoto K, Miura T.
  • Journal Title: Sci Rep Volume: 7 Issue: 1 Pages: 217-217
  • DOI: 10.1038/s41598-017-00177-w
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Reduction of circulating FABP4 level by treatment with omega-3 fatty acid ethyl esters. (2016)
  • Author(s): Furuhashi M, Hiramitsu S, Mita T, Omori A, Fuseya T, Ishimura S, Watanabe Y, Hoshina K, Matsumoto M, Tanaka M, Moniwa N, Yoshida H, Ishii J, Miura T.
  • Journal Title: Lipids Health Dis Volume: 15 Issue: 1 Pages: 15-15
  • DOI: 10.1186/s12944-016-0177-8
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Local production of fatty acid-binding protein 4 in epicardial/perivascular fat and macrophages is linked to coronary atherosclerosis. (2016)
  • Author(s): Furuhashi M, Fuseya T, Murata M, Hoshina K, Ishimura S, Mita T, Watanabe Y, Omori A, Matsumoto M, Sugaya T, Oikawa T, Nishida J, Kokubu N, Tanaka M, Moniwa N, Yoshida H, Sawada N, Shimamoto K, Miura T.
  • Journal Title: Arterioscler Thromb Vasc Biol Volume: 36 Issue: 5 Pages: 825-834
  • DOI: 10.1161/atvbaha.116.307225
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Possible increase in serum FABP4 level despite adiposity reduction by canagliflozin, an SGLT2 inhibitor. (2016)
  • Author(s): Furuhashi M, Matsumoto M, Hiramitsu S, Omori A, Tanaka M, Moniwa N, Yoshida H, Ishii J, Miura T.
  • Journal Title: PLoS ONE Volume: 11 Issue: 4 Pages: e0154482-e0154482
  • DOI: 10.1371/journal.pone.0154482
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Independent link between levels of proprotein convertase subtilisin/kexin type 9 and FABP4 in a general population without medication. (2016)
  • Author(s): Furuhashi M, Omori A, Matsumoto M, Kataoka Y, Tanaka M, Moniwa N, Ohnishi H, Yoshida H, Saitoh S, Shimamoto K, Miura T.
  • Journal Title: Am J Cardiol Volume: 118 Issue: 2 Pages: 198-203
  • DOI: 10.1016/j.amjcard.2016.04.037
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Transcriptome and metabolome analyses in exogenous FABP4- and FABP5-treated adipose-derived stem cells. (2016)
  • Author(s): Yamamoto T, Furuhashi M, Sugaya T, Oikawa T, Matsumoto M, Funahashi Y, Matsukawa N, Gotoh M, Miura T.
  • Journal Title: PLoS ONE Volume: 11 Issue: 12 Pages: 1-19
  • DOI: 10.1371/journal.pone.0167825
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Reduction of serum FABP4 level by sitagliptin, a DPP-4 inhibitor, in patients with type 2 diabetes mellitus. (2015)
  • Author(s): Furuhashi M, Hiramitsu S, Mita T, Fuseya T, Ishimura S, Omori A, Matsumoto M, Watanabe Y, Hoshina K, Tanaka M, Moniwa N, Yoshida H, Ishii J, Miura T.
  • Journal Title: J Lipid Res Volume: 56 Issue: 12 Pages: 2372-2380
  • DOI: 10.1194/jlr.m059469
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] FABP4 is secreted from adipocytes by adenyl cyclase-PKA- and guanylyl cyclase-PKG-dependent lipolytic mechanisms. (2015)
  • Author(s): Mita T, Furuhashi M, Hiramitsu S, Ishii J, Hoshina K, Ishimura S, Fuseya T, Watanabe Y, Tanaka M, Ohno K, Akasaka H, Ohnishi H, Yoshida H, Saitoh S, Shimamoto K, Miura T.
  • Journal Title: Obesity Volume: 23 Issue: 2 Pages: 359-367
  • DOI: 10.1002/oby.20954
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Angiotensin II receptor blockers decrease serum concentration of fatty acid-binding protein 4 in patients with hypertension. (2015)
  • Author(s): Furuhashi M, Mita T, Moniwa N, Hoshina K, Ishimura S, Fuseya T, Watanabe Y, Tanaka M, Yoshida H, Shimamoto K, Miura T.
  • Journal Title: Hypertens Res Volume: 38 Issue: 4 Pages: 252-259
  • DOI: 10.1038/hr.2015.2
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Elevation of circulating fatty acid-binding protein 4 is independently associated with left ventricular hypertrophy and diastolic dysfunction in a general population. (2014)
  • Author(s): Fuseya T, Furuhashi M, Yuda S, Muranaka A, Kawamukai M, Mita T, Ishimura S, Watanabe Y, Hoshina K, Tanaka M, Ohno K, Akasaka H, Ohnishi H, Yoshida H, Saitoh S, Shimamoto K, Miura T.
  • Journal Title: Cardiovasc Diabetol Volume: 13 Issue: 1 Pages: 126-126
  • DOI: 10.1186/s12933-014-0126-7
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Urinary excretion of fatty acid-binding protein 4 is associated with albuminuria and renal dysfunction. (2014)
  • Author(s): Okazaki Y, Furuhashi M, Tanaka M, Mita T, Fuseya T, Ishimura S, Watanabe Y, Hoshina K, Akasaka H, Ohnishi H, Yoshida H, Saitoh S, Miura T.
  • Journal Title: PLoS ONE Volume: 9 Issue: 12 Pages: e115429-e115429
  • DOI: 10.1371/journal.pone.0115429
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Ectopic expression of fatty acid-binding protein 4 in glomerulus is associated with proteinuria and renal dysfunction. (2014)
  • Author(s): Tanaka M, Furuhashi M, Okazaki Y, Mita T, Fuseya T, Ohno K, Ishimura S, Yoshida H, Miura T.
  • Journal Title: Nephron Clin Pract Volume: 128 Issue: 3-4 Pages: 345-351
  • DOI: 10.1159/000368412
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Fatty acid-binding protein 4 (FABP4): pathophysiological insights and potent clinical biomarker of metabolic and cardiovascular diseases. (2014)
  • Author(s): Furuhashi M, Saitoh S, Shimamoto K, Miura T.
  • Journal Title: Clin Med Insights Cardiol Volume: 8(S3) Pages: 23-33
  • DOI: 10.4137/cmc.s17067
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Emerging issues in radiogenic cataracts and cardiovascular disease. (2014)
  • Author(s): Hamada N, Fujimichi Y, Iwasaki T, Fujii N, Furuhashi M, Kubo E, Minamino T, Nomura T, Sato H.
  • Journal Title: J Radiat Res Volume: 55 Issue: 5 Pages: 831-846
  • DOI: 10.1093/jrr/rru036
  • Peer Reviewed / Open Access
• [Presentation] Serum FABP5 concentration, a Novel Determinant of Cholesterol Efflux from Macrophages, is a Potential Biomarker for Residual Risk of Atherosclerosis. (2017)
  • Author(s): Furuhashi M, Ogura M, Matsumoto M, Yuda S, Muranaka A, Tanaka M, Moniwa N, Ohnishi H, Saitoh S, Harada-Shiba M, Miura T.
  • Organizer: 第81回日本循環器学会
  • Place of Presentation: 石川県立音楽堂 (石川県金沢市)
  • Year and Date: 2017-03-17
• [Presentation] Serum FABP5 concentration, a Novel Determinant of Cholesterol Efflux from Macrophages, is a Potential Biomarker for Residual Risk of Atherosclerosis. (2016)
  • Author(s): Furuhashi M, Ogura M, Matsumoto M, Yuda S, Muranaka A, Tanaka M, Moniwa N, Ohnishi H, Saitoh S, Harada-Shiba M, Miura T.
  • Organizer: American Heart Association 2016
  • Place of Presentation: New Orleans, LA, U.S.A.
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] シンポジウム 「肥満と血管障害」 肥満と心血管・腎・代謝疾患をつなぐ新たな鍵因子：脂肪酸結合タンパク4 (FABP4) (2016)
  • Author(s): 古橋眞人、三浦哲嗣
  • Organizer: 第37回日本肥満学会
  • Place of Presentation: 東京ファッションタウン (東京都江東区)
  • Year and Date: 2016-10-07
  • Invited
• [Presentation] Independent link between levels of PCSK9 and FABP4 in a general population without medication. (2016)
  • Author(s): Furuhashi M, Omori A, Matsumoto M, Tanaka M, Moniwa N, Ohnishi H, Yoshida H, Saitoh S, Shimamoto K, Miura T.
  • Organizer: European Society of Cardiology Congress 2016
  • Place of Presentation: Rome, Italy.
  • Year and Date: 2016-08-27
  • Int'l Joint Research
• [Presentation] Independent link between levels of PCSK9 and FABP4 in a general population without medication. (2016)
  • Author(s): Furuhashi M, Omori A, Matsumoto M, Ohnishi H, Saitoh S, Miura T.
  • Organizer: 第48回日本動脈硬化学会
  • Place of Presentation: 京王プラザホテル (東京都新宿区)
  • Year and Date: 2016-07-14
• [Presentation] 家族性高コレステロール血症における残余リスクマーカーとしての脂肪酸結合蛋白 (2016)
  • Author(s): 小倉正恒、古橋眞人、森本めぐむ、松本めぐみ、三浦哲嗣、斯波真理子
  • Organizer: 第48回日本動脈硬化学会
  • Place of Presentation: 京王プラザホテル (東京都新宿区)
  • Year and Date: 2016-07-14
• [Presentation] SGLT2阻害薬であるカナグリフロジンによる新規アディポカイン脂肪酸結合タンパク4 (FABP4)の血中濃度への影響 (2016)
  • Author(s): 古橋眞人、松本めぐみ、平光伸也、大森晶奈、田中希尚、茂庭仁人、吉田英昭、石井潤一、三浦哲嗣
  • Organizer: 第59回日本糖尿病学会
  • Place of Presentation: 国立京都国際会館 (京都市左京区)
  • Year and Date: 2016-05-19
• [Presentation] シンポジウム 「エネルギー代謝と心血管病」 脂肪酸結合タンパク4 (FABP4) と心血管・代謝疾患 (2016)
  • Author(s): 古橋眞人、三浦哲嗣
  • Organizer: 第89回日本内分泌学会
  • Place of Presentation: 国立京都国際会館 (京都市左京区)
  • Year and Date: 2016-04-21
  • Invited
• [Presentation] シンポジウム「心腎脂肪連関と代謝異常」：心血管・腎・代謝疾患における脂肪酸結合タンパク4の役割 (2015)
  • Author(s): 古橋眞人
  • Organizer: 第38回日本高血圧学会
  • Place of Presentation: 愛媛県民文化会館（松山市）
  • Year and Date: 2015-10-09
  • Invited
• [Presentation] シンポジウム「高血圧を老化の観点から紐解く」：異所性発現型脂肪酸結合タンパク4と老化との関連 (2015)
  • Author(s): 古橋眞人
  • Organizer: 第38回日本高血圧学会
  • Place of Presentation: 愛媛県民文化会館（松山市）
  • Year and Date: 2015-10-09
  • Invited
• [Presentation] シタグリプチンは新規アディポカイン脂肪酸結合タンパク4 (FABP4) の血中濃度を低下させる (2015)
  • Author(s): 古橋眞人、平光伸也、石井潤一、美田知宏、大森晶奈、伏屋敬博、石村周太郎、渡邊 礼、松本めぐみ、田中希尚、茂庭仁人、吉田英昭、三浦哲嗣
  • Organizer: 第36回日本肥満学会
  • Place of Presentation: 名古屋国際会議場（名古屋市）
  • Year and Date: 2015-10-02
• [Presentation] Local production of fatty acid-binding protein 4 in the epicardial/perivascular fat and macrophage leads to coronary atherosclerosis. (2015)
  • Author(s): Furuhashi M, Fuseya T, Ishimura S, Mita T, Hoshina K, Watanabe Y, Omori A, Tanaka M, Yoshida H, Miura T.
  • Organizer: European Society of Cardiology Congress 2015
  • Place of Presentation: London, UK
  • Year and Date: 2015-08-29
  • Int'l Joint Research
• [Presentation] オメガ-3脂肪酸エチルは新規アディポカイン脂肪酸結合タンパク4の血中濃度を低下させる (2015)
  • Author(s): 古橋眞人、平光伸也、石井潤一、美田知宏、大森晶奈、伏屋敬博、石村周太郎、渡邊 礼、田中希尚、吉田英昭、三浦哲嗣
  • Organizer: 第58回日本糖尿病学会
  • Place of Presentation: 海峡メッセ下関（下関市）
  • Year and Date: 2015-05-21
• [Presentation] Angiotensin II Receptor Blockers Decrease Serum Concentration of Fatty Acid-Binding Protein 4 in Patients with Essential Hypertension. (2015)
  • Author(s): Ishimura S, Furuhashi M, Mita T, Fuseya T, Tanaka M, Moniwa N, Yoshida H, Shimamoto K, Miura T.
  • Organizer: 第79回日本循環器学会
  • Place of Presentation: 大阪国際会議場（大阪市）
  • Year and Date: 2015-04-24
• [Presentation] 「オルガネラストレスとエピジェネティクス」：2型糖尿病と血管傷害における小胞体ストレス (2014)
  • Author(s): 古橋眞人
  • Organizer: 第9回臨床ストレス応答学会
  • Place of Presentation: 岡山大学（岡山）
  • Year and Date: 2014-11-01
  • Invited
• [Presentation] 学術奨励賞受賞講演：肥満に関連する心血管・代謝疾患における各種アディポカインと慢性炎症の役割解明 (2014)
  • Author(s): 古橋眞人
  • Organizer: 第35回日本肥満学会
  • Place of Presentation: シーガイヤコンベンションセンター（宮崎）
  • Year and Date: 2014-10-25
  • Invited
• [Presentation] 脂肪酸結合タンパク4はAC-PKAおよびGC-PKG経路を介して脂肪分解と共に脂肪細胞から分泌される (2014)
  • Author(s): 美田知宏、古橋眞人、石村周太郎、伏屋敬博、保科京香、渡邊礼、大野紘平、田中希尚、吉田英昭、三浦哲嗣
  • Organizer: 第35回日本肥満学会
  • Place of Presentation: シーガイヤコンベンションセンター（宮崎）
  • Year and Date: 2014-10-24
• [Presentation] アンジオテンシンII受容体拮抗薬による新規アディポカイン脂肪酸結合タンパク4濃度の変化 (2014)
  • Author(s): 伏屋敬博、古橋眞人、美田知宏、茂庭仁人、渡邊 礼、大森晶奈、大野紘平、田中希尚、石村周太郎、吉田英昭、三浦哲嗣
  • Organizer: 第37回日本高血圧学会
  • Place of Presentation: パシフィコ横浜（横浜）
  • Year and Date: 2014-10-17
• [Presentation] Elevation of circulating fatty acid-binding protein 4 is associated with left ventricular diastolic dysfunction in a general population. (2014)
  • Author(s): Ishimura S, Furuhashi M, Yuda S, Muranaka A, Mita T, Fuseya T, Akasaka H, Yoshida H, Saitoh S, Miura T.
  • Organizer: European Society of Cardiology Congress 2014
  • Place of Presentation: Barcelona, Spain.
  • Year and Date: 2014-09-02
• [Presentation] Fatty Acid-Binding Protein 4 as a Key Molecule of Inter-Organ Network in Pathogenesis of Atherosclerosis (2014)
  • Author(s): Furuhashi M, Ishimura S, Miura T.
  • Organizer: 第46回日本動脈硬化学会
  • Place of Presentation: 京王プラザホテル（東京都、千代田区）
  • Year and Date: 2014-07-11
  • Invited
• [Presentation] 尿中FABP4濃度の臨床的意義の検討 (2014)
  • Author(s): 大野紘平、田中希尚、古橋眞人、赤坂憲、美田知宏、伏屋敬博、石村周太郎、大西浩文、吉田英昭、斉藤重幸、三浦哲嗣
  • Organizer: 第57回日本腎臓学会
  • Place of Presentation: パシフィコ横浜（横浜）
  • Year and Date: 2014-07-05
• [Presentation] Angiotensin II Receptor Blockers Decrease Serum Concentration of Fatty Acid-Binding Protein 4 in Patients with Essential Hypertension. (2014)
  • Author(s): Mita T, Furuhashi M, Ota H, Ishimura S, Fuseya T, Watanabe Y, Ohno K, Tanaka M, Moniwa N, Yoshida H, Shimamoto K, Miura T.
  • Organizer: The 25th Scientific Meeting of the International Society of Hypertension
  • Place of Presentation: Athens, Greece.
  • Year and Date: 2014-06-15
• [Presentation] 心血管・代謝疾患における脂肪酸結合タンパク4の臨床的役割の検討 (2014)
  • Author(s): 石村周太郎、古橋眞人、美田知宏、伏屋敬博、吉田英昭、三浦哲嗣
  • Organizer: 第87回日本内分泌学会
  • Place of Presentation: 福岡国際会議場（福岡）
  • Year and Date: 2014-04-25
• [Book] Handbook of Hydrocarbon and Lipid Microbiology: Biogenesis of Fatty Acids, Lipids and Membranes, (2017)
  • Author(s): Furuhashi M
  • Publisher: Springer
• [Book] The Lipid. 脂肪酸輸送と臓器障害～脂肪酸結合蛋白4 (FABP4)を中心に. (2016)
  • Author(s): 古橋眞人
  • Publisher: メディカルレビュー社
• [Book] 疾患モデルの作成と利用 &#8211; 脂質異常代謝と関連疾患 <<下巻>>. FABP4 (2015)
  • Author(s): 古橋眞人
  • Publisher: エル・アイ・シー
• [Remarks] 心血管・腎・代謝疾患における脂肪酸結合タンパク4 (FABP4)の役割解明
  • URL: http://web.sapmed.ac.jp/kikaku/degitalbook/research_seeds/FLASH/index.html
• [Remarks] Sapporo Medical University. Research Seeds.
  • URL: http://web.sapmed.ac.jp/kikaku/degitalbook/research_seeds/FLASH/index.html
• [Patent(Industrial Property Rights)] 糸球体障害の検査方法 (2015)
  • Inventor(s): 古橋眞人
  • Industrial Property Rights Holder: 古橋眞人
  • Industrial Property Rights Type: 特許
  • Filing Date: 2015-06-15
  • Acquisition Date: 2017-01-05
• [Patent(Industrial Property Rights)] 糸球体障害の検査方法 (2015)
  • Inventor(s): 古橋眞人
  • Industrial Property Rights Holder: 古橋眞人
  • Industrial Property Rights Type: 特許
  • Filing Date: 2015-06-15