Department of Molecular Genetics, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands.
Department of Molecular Genetics, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands.
Prostaglandins Leukot Essent Fatty Acids. 2018 Sep;136:131-141. doi: 10.1016/j.plefa.2016.06.002. Epub 2016 Jun 13.
Long-chain fatty acids are the main cardiac substrates from which ATP is generated continually to serve the high energy demand and sustain the normal function of the heart. Under healthy conditions, fatty acid β-oxidation produces 50-70% of the energy demands with the remainder largely accounted for by glucose. Chronically increased dietary lipid supply often leads to excess lipid accumulation in the heart, which is linked to a variety of maladaptive phenomena, such as insulin resistance, cardiac hypertrophy and contractile dysfunction. CD36, the predominant cardiac fatty acid transporter, has a key role in setting the heart on a road to contractile dysfunction upon the onset of chronic lipid oversupply by translocating to the cell surface and opening the cellular 'doors' for fatty acids. The sequence of events after the CD36-mediated myocellular lipid accumulation is less understood, but in general it has been accepted that the excessively imported lipids cause insulin resistance, which in turn leads to contractile dysfunction. There are several gaps of knowledge in this proposed order of events which this review aims to discuss. First, the molecular mechanisms underlying lipid-induced insulin resistance are not yet completely disclosed. Specifically, several mediators have been proposed, such as diacylglycerols, ceramides, peroxisome proliferator-activated receptors (PPAR), inflammatory kinases and reactive oxygen species (ROS), but their relative contributions to the onset of insulin resistance and their putatively synergistic actions are topics of controversy. Second, there are also pieces of evidence that lipids can induce contractile dysfunction independently of insulin resistance. Perhaps, a more integrative view is needed, in which several lipid-induced pathways operate synergistically or in parallel to induce contractile dysfunction. Unraveling of these processes is expected to be important in designing effective therapeutic strategies to protect the lipid-overloaded heart.
长链脂肪酸是生成 ATP 的主要心脏基质，ATP 持续不断地为心脏提供高能量需求并维持其正常功能。在健康条件下，脂肪酸β氧化产生 50-70%的能量需求，其余大部分由葡萄糖提供。慢性增加膳食脂质供应通常会导致心脏内脂质过度积累，这与多种适应性不良现象有关，如胰岛素抵抗、心肌肥厚和收缩功能障碍。CD36 是主要的心脏脂肪酸转运体，在慢性脂质供应过剩时，它通过向细胞表面移位并为脂肪酸打开“细胞之门”，在心脏发生收缩功能障碍中起着关键作用。CD36 介导的肌细胞脂质积累后的一系列事件的了解较少，但一般认为，过多的脂质会导致胰岛素抵抗，进而导致收缩功能障碍。在这个提议的事件顺序中存在几个知识空白，这篇综述旨在讨论这些空白。首先，脂质诱导胰岛素抵抗的分子机制尚未完全揭示。具体来说，已经提出了几种介质，如二酰基甘油、神经酰胺、过氧化物酶体增殖物激活受体 (PPAR)、炎症激酶和活性氧 (ROS)，但它们对胰岛素抵抗的发生的相对贡献及其潜在的协同作用是有争议的。其次，也有证据表明，脂质可以独立于胰岛素抵抗诱导收缩功能障碍。也许，需要更综合的观点，其中几种脂质诱导的途径协同或平行作用以诱导收缩功能障碍。揭示这些过程对于设计有效的治疗策略以保护脂质超负荷的心脏将是重要的。
