Tanaka Shota, Hirota Akane, Okada Yoshiaki, Obana Masanori, Fujio Yasushi
Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka, Japan.
PLoS One. 2025 May 8;20(5):e0318178. doi: 10.1371/journal.pone.0318178. eCollection 2025.
Cardiomyocytes lose their capacity to regenerate immediately after birth. Simultaneously, cardiomyocytes change energy metabolism from glycolysis to oxidative phosphorylation, especially using fatty acids. Accumulating evidence has revealed that fatty acid metabolism weakens the proliferative ability of cardiomyocytes. However, its underlying molecular mechanism remains unclear. In this study, we investigated how fatty acid metabolism contributes to cell cycle regulation in neonatal cardiomyocytes. Cultured neonatal rat cardiomyocytes (NRCMs) were treated with a fatty acid mixture (FA) consisting of palmitic and oleic acids containing L-carnitine. The FA treatment increased not only β-oxidation-related enzymes but also pyruvate dehydrogenase kinase 4 (PDK4), a fatty acid metabolism regulator, and HMG-CoA synthase 2 (HMGCS2), a ketogenic factor. Moreover, Ki67-positive proliferative NRCMs were reduced by the FA, indicating that fatty acids suppress the NRCM cell cycle. GW501516, a peroxisome proliferator-activated receptor δ (PPARδ) activator, also upregulated fatty acid metabolism genes and disturbed NRCM proliferation, whereas GSK3787, a PPARδ inhibitor, recovered FA-induced the cell cycle arrest. Furthermore, overexpression of PDK4 or HMGCS2 using a lentiviral vector suppressed cell cycle activity in NRCMs, and silencing either gene regained cell cycle even in FA-rich condition. In conclusion, fatty acid metabolism increased PDK4 and HMGCS2 via PPARδ activation and suppressed NRCM proliferation.
心肌细胞在出生后立即失去再生能力。与此同时，心肌细胞的能量代谢从糖酵解转变为氧化磷酸化，尤其是利用脂肪酸。越来越多的证据表明，脂肪酸代谢会削弱心肌细胞的增殖能力。然而，其潜在的分子机制仍不清楚。在本研究中，我们研究了脂肪酸代谢如何影响新生心肌细胞的细胞周期调控。用含有L-肉碱的棕榈酸和油酸组成的脂肪酸混合物（FA）处理培养的新生大鼠心肌细胞（NRCMs）。FA处理不仅增加了与β-氧化相关的酶，还增加了脂肪酸代谢调节因子丙酮酸脱氢酶激酶4（PDK4）和生酮因子HMG-CoA合酶2（HMGCS2）。此外，FA使Ki67阳性增殖的NRCMs减少，表明脂肪酸抑制NRCM细胞周期。过氧化物酶体增殖物激活受体δ（PPARδ）激活剂GW501516也上调脂肪酸代谢基因并干扰NRCM增殖，而PPARδ抑制剂GSK3787可恢复FA诱导的细胞周期停滞。此外，使用慢病毒载体过表达PDK4或HMGCS2可抑制NRCMs中的细胞周期活性，即使在富含FA的条件下沉默任一基因也可恢复细胞周期。总之，脂肪酸代谢通过激活PPARδ增加PDK4和HMGCS2并抑制NRCM增殖。
