Liepinsh Edgars, Gukalova Baiba, Krims-Davis Kristaps, Kuka Janis, Leduskrasta Aiga, Korzh Stanislava, Vilskersts Reinis, Makrecka-Kuka Marina, Konrade Ilze, Dambrova Maija
Latvian Institute of Organic Synthesis, Riga, Latvia.
Riga Stradins University, Riga, Latvia.
Biofactors. 2025 Mar-Apr;51(2):e70014. doi: 10.1002/biof.70014.
Elevated levels of fatty acid-derived long-chain acylcarnitines are detrimental to cardiac health, primarily because of their adverse effects on mitochondrial function and key metabolic pathways in the heart. While trans-fatty acids are considered harmful and omega-3 polyunsaturated fatty acids (PUFAs) are considered beneficial, the specific properties of acylcarnitines derived from these types of fatty acids are not characterized. This study aimed to compare the effects of saturated palmitoylcarnitine (PC), monounsaturated cis-oleoylcarnitine (cis-OC), trans-elaidoylcarnitine (trans-EC), and polyunsaturated eicosapentaenoylcarnitine (EPAC) and docosahexaenoylcarnitine (DHAC) on heart function, cardiac cell viability, mitochondrial functionality, and insulin signaling pathways. Saturated and monounsaturated acylcarnitines, particularly trans-EC, significantly reduced cardiac contractility at concentrations of 8-12 μM, and trans-EC was identified as the most cardiotoxic acylcarnitine. Conversely, the presence of EPAC and DHAC in the perfusion buffer did not impair heart functionality. Saturated and monounsaturated acylcarnitines also drastically reduced H9C2 cell viability and suppressed mitochondrial OXPHOS by up to 70% at 25 μM, whereas PUFA-derived acylcarnitines caused only a 20%-25% reduction in OXPHOS and did not decrease cell viability. Furthermore, PC, cis-OC, and trans-EC significantly inhibited Akt phosphorylation, whereas EPAC and DHAC had a much weaker effect on insulin signaling. In conclusion, saturated and monounsaturated acylcarnitines, particularly trans-EC, exert significant cardiotoxic effects, primarily through the impairment of cardiac mitochondrial function. The omega-3 PUFA-derived acylcarnitines EPAC and DHAC are safe and less likely to damage cardiac mitochondria, cardiac cells, and the heart than other acylcarnitines. PUFA intake might be safer than other long-chain fatty acid-containing lipid sources in patients with FAODs and cardiometabolic diseases.
脂肪酸衍生的长链酰基肉碱水平升高对心脏健康有害，主要是因为它们对心脏线粒体功能和关键代谢途径有不利影响。虽然反式脂肪酸被认为有害，而ω-3多不饱和脂肪酸（PUFA）被认为有益，但源自这些类型脂肪酸的酰基肉碱的具体特性尚未得到表征。本研究旨在比较饱和棕榈酰肉碱（PC）、单不饱和顺式油酰肉碱（cis-OC）、反式elaidoyl肉碱（trans-EC）以及多不饱和二十碳五烯酰肉碱（EPAC）和二十二碳六烯酰肉碱（DHAC）对心脏功能、心肌细胞活力、线粒体功能和胰岛素信号通路的影响。饱和和单不饱和酰基肉碱，特别是trans-EC，在浓度为8-12μM时显著降低心脏收缩力，并且trans-EC被确定为最具心脏毒性的酰基肉碱。相反，灌注缓冲液中EPAC和DHAC的存在并未损害心脏功能。饱和和单不饱和酰基肉碱在25μM时也显著降低H9C2细胞活力，并使线粒体氧化磷酸化（OXPHOS）抑制高达70%，而PUFA衍生的酰基肉碱仅使OXPHOS降低20%-25%，且未降低细胞活力。此外，PC、cis-OC和trans-EC显著抑制Akt磷酸化，而EPAC和DHAC对胰岛素信号的影响则弱得多。总之，饱和和单不饱和酰基肉碱，特别是trans-EC，主要通过损害心脏线粒体功能发挥显著的心脏毒性作用。ω-3 PUFA衍生的酰基肉碱EPAC和DHAC是安全的，与其他酰基肉碱相比，对心脏线粒体、心肌细胞和心脏的损害可能性较小。在患有脂肪酸氧化障碍（FAOD）和心脏代谢疾病的患者中，摄入PUFA可能比其他含长链脂肪酸的脂质来源更安全。
