Intracellular channeling of fatty acids by acyl-CoA synthetases

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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.