Acyl-CoA synthetases: fatty acid uptake and metabolic channeling
Acyl-CoA synthetases: fatty acid uptake and metabolic channeling
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DOI：
10.1007/s11010-008-0003-3
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发表时间：
2009-06-01
影响因子：
4.3
通讯作者：
Fuellekrug, Joachim
中科院分区：
文献类型：
--
作者：
Digel, Margarete;Ehehalt, Robert;Fuellekrug, Joachim
脂肪酸摄取和利用的分子机制对肥胖、糖尿病和心血管疾病的治疗具有很高的医学意义。神经元过程、激素和转录因子是这些基本过程的主要调节器，而它们的微调是通过调节酶的活性和数量来实现的。参与脂肪酸摄取和代谢的蛋白质是重要的药物靶点。只有对这些分子的基础研究才能带来新的治疗策略。从概念上讲，长链脂肪酸在细胞内的利用可分为三个步骤：跨质膜摄取、与辅酶A的酯化活化和随后的代谢。长链酰辅酶A合成酶(ACSLs)激活脂肪酸的细胞内代谢，但也参与摄取的调节。脂肪酸的主要途径是储存、膜生物合成和转化为能量。在分子水平上，活化的脂肪酸是如何被引导到一条特定的代谢途径上的还不是很清楚。我们以前已经证明，ACSLs定位于内质网或线粒体，可以调节脂肪酸摄取的程度。多种不同的长链ACSLs在同一细胞类型中同时表达，但其亚细胞定位不同。我们在这里提出的假设暗示，ACSL活性的空间组织是引导脂肪酸走向特定代谢命运的关键因素。
The molecular mechanism of fatty acid uptake and utilization is of high medical relevance for the treatment of obesity, diabetes, and cardiovascular disease. Neuronal processes, hormones, and transcription factors are master regulators of these essential processes while their fine-tuning is achieved by modulating the activity and amount of enzymes. Proteins involved in fatty acid uptake and metabolism are important pharmaceutical targets. Only basic research on these molecules will lead to new strategies for therapy. Conceptionally, the intracellular utilization of long chain fatty acids may be subdivided into three steps: uptake across the plasma membrane, activation by esterification with coenzyme A, and subsequent metabolism. Long chain acyl-CoA synthetases (ACSLs) activate fatty acids for intracellular metabolism but are also involved in the regulation of uptake. The predominant pathways for fatty acids are their storage, membrane biosynthesis, and conversion to energy. How activated fatty acids are channeled toward one particular metabolic pathway is not well understood on the molecular level. We have previously shown that ACSLs localized to either the endoplasmic reticulum or to mitochondria can regulate the extent of fatty acid uptake. Multiple different long chain ACSLs are expressed simultaneously in the same cell type but differ in their subcellular localization. The hypothesis we put forward here implies that the spatial organization of ACSL activity is a key factor in channeling fatty acids toward a particular metabolic fate.