Musters Mark W J M, Bassingthwaighte James B, van Riel Natal A W, van der Vusse Ger J
Department of Electrical Engineering, Eindhoven University of Technology, 5612 AZ Eindhoven, The Netherlands.
Biochem J. 2006 Feb 1;393(Pt 3):669-78. doi: 10.1042/BJ20050869.
Long-chain fatty acids (FAs) are important substrates used by the heart to fulfil its energy requirements. Prior to mitochondrial oxidation, blood-borne FAs must pass through the cell membrane of the cardiac myocyte (sarcolemma). The mechanism underlying the sarcolemmal transport of FAs is incompletely understood. The aim of the present study was to estimate the trans-sarcolemmal FA uptake rate using a comprehensive computer model, in which the most relevant mechanisms proposed for cardiac FA uptake were incorporated. Our in silico findings show that diffusion of FA, present in its unbound form (uFA) in close proximity to the outer leaflet of the sarcolemma and serving as sole FA source, is insufficient to account for the physiological FA uptake rate. The inclusion of a hypothetical membrane-associated FA-TFPC (FA-transport-facilitating protein complex) in the model calculations substantially increased the FA uptake rate across the sarcolemma. The model requires that the biological properties of the FA-TFPC allow for increasing the rate of absorption of FA into the outer leaflet and the 'flip-flop' rate of FA from the outer to the inner leaflet of the sarcolemma. Experimental studies have identified various sarcolemma-associated proteins promoting cardiac FA uptake. It remains to be established whether these proteins possess the properties predicted by our model. Our findings also indicate that albumin receptors located on the outer leaflet of the sarcolemma facilitate the transfer of FA across the membrane to a significant extent. The outcomes of the computer simulations were verified with physiologically relevant FA uptake rates as assessed in the intact, beating heart in experimental studies.
长链脂肪酸（FAs）是心脏用于满足其能量需求的重要底物。在进行线粒体氧化之前，血液中的脂肪酸必须穿过心肌细胞的细胞膜（肌膜）。脂肪酸跨肌膜转运的机制尚未完全明确。本研究的目的是使用一个综合计算机模型来估计跨肌膜脂肪酸摄取率，该模型纳入了所提出的与心脏脂肪酸摄取最相关的机制。我们的计算机模拟结果表明，以未结合形式（游离脂肪酸，uFA）存在于肌膜外小叶附近并作为唯一脂肪酸来源的脂肪酸扩散，不足以解释生理状态下的脂肪酸摄取率。在模型计算中纳入一种假设的膜相关脂肪酸 - 转运促进蛋白复合物（FA - TFPC），显著提高了跨肌膜的脂肪酸摄取率。该模型要求FA - TFPC的生物学特性能够提高脂肪酸进入外小叶的吸收速率以及脂肪酸从肌膜外小叶到内小叶的“翻转”速率。实验研究已经确定了多种促进心脏脂肪酸摄取的肌膜相关蛋白。这些蛋白是否具有我们模型所预测的特性仍有待确定。我们的研究结果还表明，位于肌膜外小叶的白蛋白受体在很大程度上促进了脂肪酸跨膜转运。计算机模拟的结果通过实验研究中在完整跳动心脏中评估的生理相关脂肪酸摄取率进行了验证。
