Elucidation of intracellular actions of fatty acid-binding protein family and application to clinical therapies

2022 Fiscal Year Annual Research Report

• Project/Area Number: 20K08913
• Research Institution: Sapporo Medical University
• Principal Investigator: 古橋 眞人 札幌医科大学, 医学部, 教授 (20563852)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 脂肪酸結合タンパク

Outline of Annual Research Achievements

1.ヒト脂肪組織由来幹細胞にリコンビナントFABP4を外因性に投与し、RNA-seqを行った。蛋白~蛋白相互作用カスケード解析から様々な転写因子および 各種キ ナーゼとの相互作用が認められた。 2.ヒト脂肪組織由来幹細胞にリコンビナントFABP4を外因性に投与し、CE-TOFMSおよびLC-TOFMSを用いてメタボローム解析を 行った。FABP4の外因性投与により、 様々な細胞内メタボライトの変化が認められ、FABP4が脂肪細胞由来の生理活性物質であるアディポカインとして働くこと が確認された。 3.リコンビナントFABP4に対する各種脂肪酸(パルミチン酸、パルミトレイン酸、ステアリン酸、オレイン酸、リノール酸、αリノレイン酸、ア ラキドン酸、エ イコサペンタエン酸、ドコサヘキサエン酸)に対する脂肪酸結合親和性を1,8 ANSを用いて行ったところ、通常状態で は脂肪酸結合親和性は必須脂肪酸で、多価不飽和脂肪酸であるリノール酸やαリノレイン酸に親和性が高く、飽和脂肪酸であるパルミチン酸と は親和性が低かった。また、酸化ストレスを模倣するフリーラジカルジェネレーターであるAAPHの存在下 ではパルミチン酸 以外の脂肪酸はKd値が上昇し、親和性が相対的に低くなったが、パルミチン酸とのKd値は変化がなかった。4. リコンビナントFABP4を各種細胞に投与して、炎症関連分子の変化を確認した。5.疫学調査 (端野・壮瞥町研究) でFABP4濃度を測定し、12年間のフォロー期間中の心血管死と関連することを見出した。 6.ヒトの心臓手術時に採取した心外膜脂肪組織や血管周囲脂肪組織の検討からFABP4の発現を確認した。

Research Products

• [Journal Article] Metabolic dysfunction-associated fatty liver disease predicts new onset of chronic kidney disease better than does fatty liver or nonalcoholic fatty liver disease. (2023)
  • Author(s): Tanaka M, Mori K, Takahashi S, Higashiura Y, Ohnishi H, Hanawa N, Furuhashi M.
  • Journal Title: Nephrol Dial Transplant Volume: 38 Pages: 700-711
  • DOI: 10.1093/ndt/gfac188
  • Peer Reviewed
• [Journal Article] Glomerular expression and urinary excretion of fatty acid-binding protein 4 in IgA nephropathy. (2023)
  • Author(s): Tanaka M, Moniwa N, Nogi C, Kano T, Matsumoto M, Sakai A, Maeda T, Takizawa H, Ogawa Y, Asanuma K, Suzuki Y, Furuhashi M.
  • Journal Title: J Nephrol Volume: 36 Pages: 385-395
  • DOI: 10.1007/s40620-022-01551-2
  • Peer Reviewed
• [Journal Article] Metabolic dysfunction-associated fatty liver disease is associated with an increase in systolic blood pressure over time: Linear mixed-effects model analyses. (2023)
  • Author(s): Mori K, Tanaka M, Hosaka I, Mikami T, Hanawa N, Ohnishi H, Furuhashi M.
  • Journal Title: Hypertens Res Volume: 46 Pages: 1110-1121
  • DOI: 10.1038/s41440-023-01179-0
  • Peer Reviewed
• [Journal Article] Comparison of phenotypes in subcutaneous fat and perivascular adipose tissue surrounding the saphenous vein in coronary artery bypass grafting. (2023)
  • Author(s): Mikami T, Furuhashi M, Numaguchi R, Hosaka I, Sakai A, Tanaka M, Ito T, Maeda T, Sakurada T, Muraki S, Yanase Y, Sato H, Fukada J, Tamiya Y, Iba Y, Kawaharada N.
  • Journal Title: Circ J Volume: 87 Pages: 791-798
  • DOI: 10.1253/circj.CJ-22-0740
  • Peer Reviewed / Open Access
• [Journal Article] Chlamydia pneumoniae Lung Infection in Mice Induces Fatty Acid-Binding Protein 4-Dependent White Adipose Tissue Pathology. (2023)
  • Author(s): Kurihara Y, Walenna NF, Ishii K, Soejima T, Chou B, Yoshimura M, Ozuru R, Shimizu A, Itoh R, Furuhashi M, Hotamisligil GS, Hiromatsu K.
  • Journal Title: J Immunol Volume: 210 Pages: 1086-1097
  • DOI: 10.4049/jimmunol.2200601
  • Peer Reviewed
• [Journal Article] Circulating level of fatty acid-binding protein 4 is an independent predictor of metabolic dysfunction-associated fatty liver disease in middle-aged and elderly individuals. (2022)
  • Author(s): Tanaka M, Takahashi S, Higashiura Y, Sakai A, Koyama M, Saitoh S, Shimamoto K, Ohnishi H, Furuhashi M.
  • Journal Title: J Diabetes Investig Volume: 13 Pages: 878-888
  • DOI: 10.1111/jdi.13735
  • Peer Reviewed / Open Access
• [Journal Article] STAT3 is the master regulator for the forming of 3D spheroids of 3T3-L1 preadipocytes. (2022)
  • Author(s): Ohguro H, Ida Y, Hikage F, Umetsu A, Ichioka H, Watanabe M, Furuhashi M*.
  • Journal Title: Cells Volume: 11 Pages: 300
  • DOI: 10.3390/cells11020300
  • Peer Reviewed / Open Access
• [Journal Article] Plasma Tsukushi concentration is associated with hepatokine, hyperinsulinemia and low total cholesterol level in a general population without medication. (2022)
  • Author(s): Furuhashi M, Higashiura Y, Sakai A, Koyama M, Tanaka M, Saitoh S, Shimamoto K, Ohnishi H.
  • Journal Title: Metabolites Volume: 12 Pages: 237
  • DOI: 10.3390/metabo12030237
  • Peer Reviewed / Open Access
• [Journal Article] Fatty acid-binding proteins 4 and 5 are involved in the pathogenesis of retinal vascular diseases in different manners (2022)
  • Author(s): Higashide M, Furuhashi M, Watanabe M, Itoh K, Suzuki S, Umetsu A, Tsugeno Y, Ida Y, Hikage F, Ohguro H.
  • Journal Title: Life Volume: 12 Pages: 467
  • DOI: 10.3390/life12040467
  • Peer Reviewed / Open Access
• [Journal Article] High fibrosis-4 index predicts ischemic heart disease during a 10-year period in a general population. (2022)
  • Author(s): Higashiura Y, Tanaka M, Mori K, Mikami T, Hosaka I, Ohnishi H, Hanawa N, Furuhashi M.
  • Journal Title: Eur Heart J Open Volume: 2 Pages: oeac030
  • DOI: 10.1093/ehjopen/oeac030
  • Peer Reviewed / Open Access
• [Journal Article] High fatty liver index is an independent predictor of ischemic heart disease during a 10-year period in a Japanese population. (2022)
  • Author(s): Mori K, Tanaka M, Higashiura Y, Hanawa N, Ohnishi H, Furuhashi M.
  • Journal Title: Hepatol Res Volume: 52 Pages: 687-698
  • DOI: 10.1111/hepr.13790
  • Peer Reviewed
• [Journal Article] Fatty acid metabolism is involved in both retinal physiology and the pathology of retinal vascular diseases. (2022)
  • Author(s): Umetsu A, Furuhashi M, Watanabe M, Ohkawa E, Tsugeno Y, Suzuki S, Itoh K, Ida Y, Hikage F, Ohguro H.
  • Journal Title: Prostaglandins Leukot Essent Fatty Acids Volume: 183 Pages: 102473
  • DOI: 10.1016/j.plefa.2022.102473
  • Peer Reviewed / Open Access
• [Presentation] Metabolic dysfunction-associated fatty liver disease predicts new onset of chronic kidney disease better than does fatty liver or nonalcoholic fatty liver disease. (2022)
  • Author(s): 57.Tanaka M, Mori K, Takahashi S, Higashiura Y, Ohnishi H, Hanawa N, Furuhashi M.
  • Organizer: The 29th Scientific Meeting of the International Society of Hypertension.
  • Int'l Joint Research
• [Presentation] Fatty Liver Index and FABP4 in Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) (2022)
  • Author(s): Furuhashi M.
  • Organizer: 第86回日本循環器学会学術集会
  • Invited
• [Presentation] MAFLDと動脈硬化関連疾患 新たなターゲットとしてのFABP4 (2022)
  • Author(s): 古橋眞人.
  • Organizer: 第54回日本動脈硬化学会学術集会
  • Invited