Regulatory mechanisms of fatty acids synthesis and breadown in pressure-overloaded heart

2022 Fiscal Year Final Research Report

• Project/Area Number: 20H03671
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Gunma University
• Principal Investigator: Kurabayashi Masahiko 群馬大学, その他部局等, 名誉教授 (00215047)
• Co-Investigator(Kenkyū-buntansha): 磯 達也 群馬大学, 大学院医学系研究科, 非常勤講師 (10400756)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: エネルギー代謝 / 脂肪酸 / 遺伝子発現 / ケトン体 / 酸化ストレス

Outline of Final Research Achievements

The heart is the most energy-demanding and metabolically omnivorous organ which uses ketone bodies as well as fatty acids and glucose as fuel source. It is a growing appreciation that circulating ketone body (bOHB) is not just used during fasting and exercise, but also has important cellular signaling roles to regulate gene expression. Stimulation of neonatal rat cardiomyocytes with bOHB and FGF21 induced peroxisome proliferator-activated receptor-a(PPARa and PGC1a expression along with the phosphorylation of LKB1 and AMPK. bOHB and FGF21 induced transcription of peroxisome proliferator-activated receptor response element (PPRE)-containing genes through an activation of PPARa. Additionally,bOHB and FGF21 induced the expression of Nrf2, a master regulator for oxidative stress response, and catalase and Ucp2 genes.These findings suggest that bOHB and circulating FGF21 coordinately regulate oxidative stress response gene expression in the heart.

Free Research Field

循環器内科

Academic Significance and Societal Importance of the Research Achievements

心臓は生体で最もエネルギー産生が活発な臓器であり、脂肪酸酸化によるATP産生が全ATP産生の70％を占める。そのため、脂肪酸の酸化と合成は心臓の機能を維持する上で重要である。私たちは脂肪酸伸長酵素が細胞膜のリン脂質中の脂肪酸組成の決定に大きな役割を持つことを明らかにした。また、エネルギー枯渇に対する適応として肝臓で産生されるケトン体が、脂肪酸の燃焼・酸化を調節するかを検討した結果、ケトン体およびFGF21が脂肪酸酸化に重要な転写因子PPARaと転写コファクタPGC-1aの発現を増加し、抗酸化機能を増強させることを示した。ケトン体とFGF21が心不全治療における新たな治療方法になる可能性がある。