van der Vusse Ger J, van Bilsen Marc, Glatz Jan F C, Hasselbaink Danny M, Luiken Joost J F P
Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.
Mol Cell Biochem. 2002 Oct;239(1-2):9-15. doi: 10.1007/978-1-4419-9270-3_2.
Despite decades of extensive research, the transport routes, mechanisms of uptake and points of flux control of long-chain fatty acids (FA) in mammalian organs are still incompletely understood. In non-fenestratred organs such as heart and skeletal muscle, membrane barriers for blood-borne FA are the luminal and abluminal membranes of endothelial cells, the sarcolemma and the mitochondrial membranes. Transport of FA through the phospholipid bilayer of the cellular membrane is most likely accomplished by diffusion of protonated FA. Evidence is accumulating that membrane-associated proteins, such as plasmalemmal fatty acid-binding protein (FABPpm) and fatty acid translocase (FAT/CD36), either alone or in conjunction with albumin binding protein (ABP), are instrumental in enhancing the delivery of FA to the cellular membrane. Inside the cell, cytoplasmic fatty acid-binding proteins (FABPc) are involved in diffusion of FA from the plasmalemma to the intracellular sites of conversion, such as the mitochondrial outer membrane. After conversion of FA to FACoA, the fatty acyl chain is transported across the mitochondrial inner membrane in a carnitine-mediated fashion. Uptake and utilization of FA by muscle cells are finely tuned, most likely to avoid the intracellular accumulation of FA, as these are cytotoxic at high concentrations. On a short-term basis, net uptake is, among others, regulated by intracellular translocation of FAT from intracellular stores to the sarcolemma and by the concentration gradient of FA across the sarcolemma. The latter implies that, among others, the rate of FA utilization determines the rate of uptake. The rate of utilization is governed by a variety of factors, including malonylCoA, the ratio acetylCoA/CoA and the availability of competing substrates such as glucose, lactate, and ketone bodies. Long-term regulation of uptake and utilization is accomplished by alterations in the rate of expression of genes, encoding for FA-handling proteins. Circumstantial evidence indicates that FA themselves are able to modulate the expression of FA-handling genes via nuclear transcription factors such as peroxisome proliferator-activated receptors (PPARs).
尽管经过了数十年的广泛研究，但哺乳动物器官中长链脂肪酸（FA）的运输途径、摄取机制和通量控制点仍未完全清楚。在心脏和骨骼肌等非窗孔性器官中，血源性FA的膜屏障是内皮细胞的管腔膜和基膜、肌膜和线粒体膜。FA通过细胞膜磷脂双分子层的运输很可能是通过质子化FA的扩散来完成的。越来越多的证据表明，膜相关蛋白，如质膜脂肪酸结合蛋白（FABPpm）和脂肪酸转运蛋白（FAT/CD36），单独或与白蛋白结合蛋白（ABP）一起，有助于增强FA向细胞膜的递送。在细胞内，细胞质脂肪酸结合蛋白（FABPc）参与FA从质膜向细胞内转化位点（如线粒体外膜）的扩散。FA转化为脂肪酰辅酶A后，脂肪酰链以肉碱介导的方式穿过线粒体内膜。肌肉细胞对FA的摄取和利用受到精细调节，很可能是为了避免FA在细胞内积累，因为高浓度的FA具有细胞毒性。在短期内，净摄取除其他因素外，受FAT从细胞内储存部位向肌膜的细胞内转运以及FA跨肌膜浓度梯度的调节。后者意味着，除其他因素外，FA的利用率决定摄取速率。利用率受多种因素控制，包括丙二酰辅酶A、乙酰辅酶A/辅酶A的比例以及葡萄糖、乳酸和酮体等竞争性底物的可用性。摄取和利用的长期调节是通过编码FA处理蛋白的基因表达速率的改变来实现的。间接证据表明，FA自身能够通过过氧化物酶体增殖物激活受体（PPARs）等核转录因子调节FA处理基因的表达。
