Department of Genetics & Cell Biology, Faculty of Health, Medicine and Life Sciences, Maastricht University, P.O. Box 616, 6200 MD Maastricht, the Netherlands.
Department of Genetics & Cell Biology, Faculty of Health, Medicine and Life Sciences, Maastricht University, P.O. Box 616, 6200 MD Maastricht, the Netherlands; Department of Clinical Genetics, Faculty of Health, Medicine and Life Sciences, Maastricht University Medical Centre, 6211 LK Maastricht, the Netherlands.
Biochim Biophys Acta Mol Basis Dis. 2020 Jul 1;1866(7):165775. doi: 10.1016/j.bbadis.2020.165775. Epub 2020 Mar 21.
CD36 and GLUT4 are the main cardiac trans-sarcolemmal transporters for long-chain fatty acids and glucose, respectively. Together they secure the majority of cardiac energy demands. Moreover, these transporters each represent key governing kinetic steps in cardiac fatty acid and glucose fluxes, thereby offering major sites of regulation. The underlying mechanism of this regulation involves a perpetual vesicle-mediated trafficking (recycling) of both transporters between intracellular stores (endosomes) and the cell surface. In the healthy heart, CD36 and GLUT4 translocation to the cell surface is under short-term control of the same physiological stimuli, most notably increased contraction and insulin secretion. However, under chronic lipid overload, a condition that accompanies a Western lifestyle, CD36 and GLUT4 recycling are affected distinctly, with CD36 being expelled to the sarcolemma while GLUT4 is imprisoned within the endosomes. Moreover, the increased CD36 translocation towards the cell surface is a key early step, setting the heart on a route towards insulin resistance and subsequent contractile dysfunction. Therefore, the proteins making up the trafficking machinery of CD36 need to be identified with special focus to the differences with the protein composition of the GLUT4 trafficking machinery. These proteins that are uniquely dedicated to either CD36 or GLUT4 traffic may offer targets to rectify aberrant substrate uptake seen in the lipid-overloaded heart. Specifically, CD36-dedicated trafficking regulators should be inhibited, whereas such GLUT4-dedicated proteins would need to be activated. Recent advances in the identification of CD36-dedicated trafficking proteins have disclosed the involvement of vacuolar-type H-ATPase and of specific vesicle-associated membrane proteins (VAMPs). In this review, we summarize these recent findings and sketch a roadmap of CD36 and GLUT4 trafficking compatible with experimental findings.
CD36 和 GLUT4 分别是心脏长链脂肪酸和葡萄糖的主要跨肌膜转运蛋白。它们共同确保了心脏的大部分能量需求。此外，这些转运蛋白各自代表了心脏脂肪酸和葡萄糖通量的关键调节动力学步骤，因此是主要的调节位点。这种调节的潜在机制涉及两种转运蛋白在细胞内储存（内体）和细胞表面之间的持续囊泡介导的运输（再循环）。在健康的心脏中，CD36 和 GLUT4 向细胞表面的易位受相同的生理刺激的短期控制，最显著的是收缩增加和胰岛素分泌。然而，在慢性脂质过载的情况下，即伴随西方生活方式的情况，CD36 和 GLUT4 的再循环受到明显影响，CD36 被驱逐到肌膜，而 GLUT4 则被囚禁在内体中。此外，CD36 向细胞表面的增加易位是一个关键的早期步骤，使心脏走上胰岛素抵抗和随后的收缩功能障碍的途径。因此，需要特别关注 CD36 运输机制中的蛋白质组成与 GLUT4 运输机制的差异，以确定构成 CD36 运输机制的蛋白质。这些专门用于 CD36 或 GLUT4 运输的蛋白质可能为纠正脂质过载心脏中异常的底物摄取提供靶点。具体来说，应该抑制专门用于 CD36 的转运调节剂，而需要激活这些专门用于 GLUT4 的蛋白质。最近在鉴定 CD36 专用转运蛋白方面的进展揭示了液泡型 H+-ATP 酶和特定囊泡相关膜蛋白（VAMPs）的参与。在这篇综述中，我们总结了这些最近的发现，并勾勒出与实验结果一致的 CD36 和 GLUT4 转运路线图。
