Fatty acid metabolism suppresses neonatal cardiomyocyte proliferation by increasing PDK4 and HMGCS2 expression through PPARδ.

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.