Different forms of n-3 polyunsaturated fatty acids ameliorate myocardial function by accelerating ceramide catabolism

Whether different forms of n-3 polyunsaturated fatty acids (PUFA) have differential functions to improve cardiac damage remain elusive. The present study aimed to investigate different forms of n-3 PUFA intervention, namely eicosapentaenoic acid (C_{20:5 n-3}, EPA)/docosahexaenoic acid (C_{22:6 n-3}, DHA)-triglyceride (TAG), DHA/EPA-phospholipid (PL), and krill oil on high-fat/high-cholesterol diet (HFD)-induced myocardial injury. After 18 weeks of HFD feeding, the mice exhibited myocardial hypertrophy and disordered arrangement of cardiomyocytes. However, administration of the 3 forms of n-3 PUFA significantly led to alleviated myocardial hypertrophy and arrangement of myocardial cells in the C57BL/6J mice under HFD challenge. Meanwhile, administration of the 3 forms of n-3 PUFA ameliorated myocardial hypertrophy in low-density lipoprotein receptor knockout (LDLR^–/–) mice. However, n-3 PUFA intervention ameliorated HFD-induced cardiac dysfunction by increasing ejection fraction and fraction shortening levels, no significant difference was observed with respect to cardiac dysfunction between the 3 forms of n-3 PUFA groups. The lipidomics and targeted lipidomics analyses identified and confirmed that cardiac C_18:0-, C_20:0-, C_22:0-, and total ceramide concentrations in EPA/DHA-TAG and DHA/EPA-PL groups were significantly lower in comparison with the HFD group. Mechanistically, n-3 PUFA treatment significantly increased the protein expression levels of adiponectin and acid ceramidase, which accelerate ceramide catabolism. The reduced cardiac ceramide concentrations were associated with remodeling mitochondrial dynamics homeostasis and decreased dynamin-related protein 1 (Drp1) and mitochondrial fission factor (MFF) levels. Consequently, the protein expression levels of caspase 3 and recombinant tumor protein p53 (p53) were significantly decreased in the three n-3 PUFA groups compared with the HFD group. This work reveals that n-3 PUFA mitigate cardiac dysfunction through the adiponectin/ceramide/apoptosis axis, but there is no significant difference between the 3 forms of n-3 PUFA groups.