Mechanisms of cellular uptake of long chain free fatty acids.
Mechanisms of cellular uptake of long chain free fatty acids.
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DOI：
10.1007/978-1-4615-4929-1_3
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发表时间：
1999-02
影响因子：
4.3
通讯作者：
P. Berk;D. Stump
中科院分区：
文献类型：
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作者：
P. Berk;D. Stump
细胞在体内从细胞外液和血浆中的非蛋白结合配体池中摄取长链游离脂肪酸（FFA），这些配体池分别含有约100和600 μM白蛋白。传统上，此类液体中未结合FFA浓度的生理范围计算为< 1 μM。肝细胞、脂肪细胞、心肌细胞和其他细胞类型对[3 H]-油酸盐摄取的研究表明，FFA在此范围内的摄取是饱和的，并显示出许多其他动力学特性，表明易化转运。在此范围内，酸性（pKa = 0.5）FFA类似物α2，β2，ω3-七氟硬脂酸酯的摄取动力学与硬脂酸酯相似。因此，摄取生理浓度的FFA涉及促进FFA阴离子（FA-）的转运。在更宽的游离FFA浓度范围内，肝细胞[3 H]-油酸盐摄取表现出饱和和非饱和组分。油酸盐与肝质膜（LPM）的结合也证明了这些成分。比较FFA摄取的两个组成部分与相应的结合组成部分，可以估计跨膜转运速率。可饱和摄取的T1/2（0.1秒）小于非饱和摄取的T1/2（0.14秒）。其他人已经确定了质子化FFA（FAH）穿过小和大单层囊泡（SUV，LUV）和穿过细胞质膜的翻转率。这些报道的触发器率，测量的pH值的降低所造成的伴随质子通量，表现出非常显着的负相关性与细胞和囊泡直径（r = 0.99）。虽然囊泡中的T1/2在毫秒范围内，但细胞中的T1/2> 10秒，因此与我们确定的非饱和摄取速率相当。因此，在生理条件下，细胞FFA摄取的主要机制是促进FA-的转运;在高得多的非生理FFA浓度下，FAH的被动触发占主导地位。几种质膜蛋白已被确定为促进FFA转运的潜在介质。在肥胖和非胰岛素依赖型糖尿病动物模型中的研究表明，促进FFA转运的组织特异性调节具有重要的病理生理后果。(Mol Cell Biochem 192：17-31，1999）
Cells take up long chain free fatty acids (FFA)in vivofrom the non-protein bound ligand pools in extracellular fluid and plasma, which contain ∼100 and 600 μM albumin, respectively. The physiologic range of unbound FFA concentrations in such fluids has traditionally been calculated at < 1 μM. Studies of [3H]-oleate uptake by hepatocytes, adipocytes, cardiac myocytes and other cell types demonstrate that FFA uptake within this range is saturable, and exhibits many other kinetic properties indicative of facilitated transport. Within this range, the uptake kinetics of the acidic (pKa = 0.5) FFA analog α2, β2, ω3-heptafluorostearate are similar to those of stearate. Thus, uptake of physiologic concentrations of FFA involves facilitated transport of the FFA anion (FA-). Over a much wider range of unbound FFA concentrations hepatocellular [3H]-oleate uptake exhibits both saturable and non-saturable components. Oleate binding to liver plasma membranes (LPM) also demonstrates such components. Comparing the two components of FFA uptake to the corresponding components of binding permits estimates of trans-membrane transport rates. T1/2for saturable uptake (∼ 1 sec) is less than for non-saturable uptake (∼ 14 sec). Others have determined the flip-flop rates of protonated FFA (FAH) across small and large unilamellar vesicles (SUV, LUV) and across cellular plasma membranes. These reported flip-flop rates, measured by the decrease in pH resulting from the accompanying proton flux, exhibit a highly significant inverse correlation with cell and vesicle diameter (r = 0.99). Although T1/2’s in vesicles are in the msec range, those in cells are > 10 sec, and thus comparable to the rates of non-saturable uptake we determined. Thus, under physiologic conditions, the predominant mechanism of cellular FFA uptake is facilitated transport of FA-; at much higher, non-physiologic FFA concentrations, passive flip-flop of FAH predominates. Several plasma membrane proteins have been identified as potential mediators of facilitated FFA transport. Studies in animal models of obesity and non-insulin dependent diabetes mellitus demonstrate that tissue-specific regulation of facilitated FFA transport has important pathophysiologic consequences. (Mol Cell Biochem 192: 17–31, 1999)