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Intracellular channeling of fatty acids by acyl-CoA synthetases

酰基辅酶A合成酶对脂肪酸的细胞内通道

基本信息

批准号：
53551550
负责人：
Professor Dr. Joachim Füllekrug
金额：
--
依托单位：
Klinik für Gastroenterologie, Infektionskrankheiten, Vergiftungen
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2007
资助国家：
德国
起止时间：
2006-12-31 至 2011-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/53551550?language=en
关键词：
Intracellular channeling fatty acids acyl

项目摘要

Conceptionally, the intracellular utilization of long chain fatty acids can be subdivided into three steps: Cellular uptake across the plasma membrane, activation by esterification with coenzyme A, and subsequent metabolism. Acyl-CoA synthetases activate fatty acids for intracellular metabolism but are also involved in uptake. The predominant pathways for fatty acids are storage, membrane biosynthesis and conversion to energy. How activated fatty acids are channeled towards one particular metabolic pathway is not well understood on the molecular level. We previously showed that acyl-CoA synthetases localized to either the ER or to mitochondria can regulate the extent of fatty acid uptake. Recent data are consistent with the idea that multiple different long chain acyl-CoA synthetases are expressed simultaneously at the same time in the same cell type but differ in their subcellular localization. Strikingly, the initial subcellular localization of fatty acids taken up is dependent on the type and localization of the acyl-CoA synthetase being expressed. The hypothesis derived from our findings implies that the spatial organization of acyl-CoA synthetase activity is a key factor in channeling fatty acids towards a particular metabolic fate. The major experimental strategy aims at providing solid evidence for this idea. The model systems are tissue culture cells expressing either different acyl-CoA synthetases or the same acyl-CoA synthetase engineered to be localized to different subcellular compartments. The metabolism and trafficking of both physiological and fluorescent fatty acids will be analyzed by thin layer chromatography, subcellular fractionation and microscopy. Proteins involved in fatty acid uptake and metabolism are important pharmaceutical targets for the treatment of adipositas and associated diseases. Only basic research on these molecules will enable new strategies for therapy.

从概念上讲，长链脂肪酸的细胞内利用可以细分为三个步骤：细胞跨质膜摄取，通过与辅酶A酯化活化，以及随后的代谢。酰基辅酶A合成酶激活脂肪酸用于细胞内代谢，但也参与摄取。脂肪酸的主要途径是储存、膜生物合成和转化为能量。如何激活脂肪酸被引导到一个特定的代谢途径是不是在分子水平上很好地理解。我们以前表明，位于ER或线粒体的酰基辅酶A合成酶可以调节脂肪酸摄取的程度。最近的数据是一致的想法，多个不同的长链酰基辅酶A合成酶同时在同一时间在相同的细胞类型中表达，但不同的亚细胞定位。引人注目的是，所摄取的脂肪酸的初始亚细胞定位依赖于所表达的酰基辅酶A合成酶的类型和定位。从我们的研究结果中得出的假设意味着酰基辅酶A合成酶活性的空间组织是引导脂肪酸朝向特定代谢命运的关键因素。主要的实验策略旨在为这一想法提供坚实的证据。模型系统是表达不同酰基辅酶A合成酶或相同酰基辅酶A合成酶的组织培养细胞，所述酰基辅酶A合成酶被工程化以定位于不同亚细胞区室。生理和荧光脂肪酸的代谢和运输将通过薄层色谱法、亚细胞分级分离和显微镜进行分析。参与脂肪酸摄取和代谢的蛋白质是治疗肥胖症和相关疾病的重要药物靶标。只有对这些分子的基础研究才能实现新的治疗策略。