Brody School of Medicine at East Carolina University, Department of Physiology, and East Carolina Diabetes and Obesity Institute, Greenville, NC, USA.
Department of Biochemistry, Purdue University, West Lafayette, IN, USA.
J Lipid Res. 2021;62:100069. doi: 10.1016/j.jlr.2021.100069. Epub 2021 Mar 20.
Long-chain fatty acid oxidation is frequently impaired in primary and systemic metabolic diseases affecting the heart; thus, therapeutically increasing reliance on normally minor energetic substrates, such as ketones and medium-chain fatty acids, could benefit cardiac health. However, the molecular fundamentals of this therapy are not fully known. Here, we explored the ability of octanoate, an eight-carbon medium-chain fatty acid known as an unregulated mitochondrial energetic substrate, to ameliorate cardiac hypertrophy in long-chain fatty acid oxidation-deficient hearts because of carnitine palmitoyltransferase 2 deletion (Cpt2). CPT2 converts acylcarnitines to acyl-CoAs in the mitochondrial matrix for oxidative bioenergetic metabolism. In Cpt2 mice, high octanoate-ketogenic diet failed to alleviate myocardial hypertrophy, dysfunction, and acylcarnitine accumulation suggesting that this alternative substrate is not sufficiently compensatory for energy provision. Aligning this outcome, we identified a major metabolic distinction between muscles and liver, wherein heart and skeletal muscle mitochondria were unable to oxidize free octanoate, but liver was able to oxidize free octanoate. Liver mitochondria, but not heart or muscle, highly expressed medium-chain acyl-CoA synthetases, potentially enabling octanoate activation for oxidation and circumventing acylcarnitine shuttling. Conversely, octanoylcarnitine was oxidized by liver, skeletal muscle, and heart, with rates in heart 4-fold greater than liver and, in muscles, was not dependent upon CPT2. Together, these data suggest that dietary octanoate cannot rescue CPT2-deficient cardiac disease. These data also suggest the existence of tissue-specific mechanisms for octanoate oxidative metabolism, with liver being independent of free carnitine availability, whereas cardiac and skeletal muscles depend on carnitine but not on CPT2.
长链脂肪酸氧化在影响心脏的原发性和全身性代谢疾病中经常受到损害；因此，通过治疗增加对通常较小的能量底物（如酮体和中链脂肪酸）的依赖，可能有益于心脏健康。然而，这种治疗的分子基础尚不完全清楚。在这里，我们研究了作为不受调节的线粒体能量底物的辛酸（一种八碳中链脂肪酸）改善由于肉碱棕榈酰转移酶 2 缺失（Cpt2）而导致的长链脂肪酸氧化缺陷心脏的心肌肥大的能力。Cpt2 将酰基辅酶 A 转化为线粒体基质中的酰基辅酶 A，用于氧化生物能量代谢。在 Cpt2 小鼠中，高辛酸生酮饮食未能缓解心肌肥大、功能障碍和酰基辅酶 A 积累，这表明这种替代底物在能量供应方面没有足够的补偿作用。与这一结果一致，我们在肌肉和肝脏之间发现了一个主要的代谢区别，其中心脏和骨骼肌线粒体不能氧化游离辛酸，但肝脏能够氧化游离辛酸。肝脏线粒体，但不是心脏或肌肉，高度表达中链酰基辅酶 A 合成酶，可能使辛酸能够进行氧化并避免酰基辅酶 A 的转运。相反，游离辛酸可以被肝脏、骨骼肌和心脏氧化，心脏的氧化速率比肝脏高 4 倍，而且在肌肉中，它不依赖于 Cpt2。综上所述，这些数据表明，饮食中的辛酸不能挽救 Cpt2 缺陷型心脏病。这些数据还表明，存在组织特异性的辛酸氧化代谢机制，肝脏独立于游离肉碱的可用性，而心脏和骨骼肌依赖肉碱但不依赖 Cpt2。
