Intracellular channeling of fatty acids by acyl-CoA synthetases
Zusammenfassung der Projektergebnisse
Fatty acids are essential components of all cellular life. They are used for many different processes, including the biosynthesis of membranes and the generation of energy. Depending on nutrient supply, fatty acids may be efficiently stored as neutral lipids or mobilized by lipolysis. At the organismal level, uptake and metabolism of fatty acids are highly relevant for widespread and serious lipid associated diseases like diabetes type 2 and atherosclerosis. The overall direction of fatty acid metabolism is critical: Increased biosynthesis of neutral lipids causes adiposity whereas the ß-oxidation of fatty acids provides energy and actually removes lipids for good. Despite this obvious importance, the knowledge on how the fatty acids are distributed between these different pathways has remained fragmentary. The initial step of lipid metabolism is the activation of fatty acids to their acyl-CoA derivatives, which is catalyzed by the essential enzymes of the acyl-CoA synthetase (ACS) family. In mammals there are thirteen different long chain acyl-CoA synthetases which are expressed in a seemingly redundant way. Different subcellular localizations have been reported but it has been enigmatic what benefit this might have. Here, we tested the hypothesis that the subcellular localization of the acyl-CoA synthetases may be a key determinant in channeling fatty acids to specific metabolic fates. In this model, activated fatty acids would remain close to their subcellular site of origin, which allows preferential use by downstream enzymes at the same membrane system. This is in contrast to the current state of the art which presumes that activated fatty acids would equilibrate rapidly across the cytosol. The acyl-CoA synthetase ACSL4 was chosen as a model enzyme; this particular enzyme is clinically relevant for carcinogenesis and neuronal development. We characterized three different ACSL4 isoenzymes, which were localized to different intracellular compartments. All isoenzymes had the same specific activity, and increased fatty acid uptake after overexpression by metabolic trapping. The newly synthesized amount of the membrane lipid phosphatidylinositol (PI) correlated with the expression level of ACSL4. Remarkably, the biosynthesis of PI was also dependent on the subcellular localization of the ACSL4 isoenzyme. Our results suggest that the subcellular localization of acyl-CoA synthetases is indeed an important factor in determining the metabolic fate of fatty acids. In our particular case, the physiological function of ACSL4 may be to provide compartment specific metabolites for the biosynthesis of phosphatidylinositol, which itself is an important precursor for many signaling molecules. In a more general perspective, this newly uncovered mechanism may be exploited to drive fatty acid metabolism along desirable pathways. A new therapeutical approach for the treatment of obesity and associated metabolic diseases would be to increase the oxidation of fatty acids over their storage in adipose tissue by manipulating the corresponding acyl-CoA synthetases.
Projektbezogene Publikationen (Auswahl)
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(2009). Acyl-CoA synthetases: Fatty acid uptake and metabolic channeling. Mol Cell Biochem. 326 (1-2), 23-28
Digel, M., Ehehalt, R., Stremmel, W. and J. Füllekrug
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(2010). Lipid droplets lighting up: Insights from live microscopy. FEBS Lett. 584, 2168-2175
Digel, M., Ehehalt, R. and J. Füllekrug
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(2011). FATP4 contributes as an enzyme to the basal and insulin mediated fatty acid uptake of C2C12 muscle cells. Am J Physiol Endocr Metab. 301, 758-96
Digel, M., Staffer, S., Ehehalt, R., Stremmel, W. and J. Füllekrug
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(2011). Overexpression of CD36 and Acyl-CoA Synthetases FATP2, FATP4 and ACSL1 Increases Fatty Acid Uptake in Human Hepatoma Cells. Int J Med Sci. 8, 599-614
Krammer, J., Digel, M., Ehehalt, F., Stremmel, W., Füllekrug, J. and R. Ehehalt
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(2012). Enhanced fatty acid oxidation and FATP4 protein expression after endurance exercise training in human skeletal muscle. PLoS One 7, e29391
Jeppesen, J., Jordy, A.B., Sjoberg, K.A., Füllekrug, J., Stahl, A., Nybo, L. and B. Kiens
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(2012). Overexpressed FATP1, ACSVL4/FATP4 and ACSL1 Increase the Cellular Fatty Acid Uptake of 3T3-L1 Adipocytes but Are Localized on Intracellular Membranes. PLoS One 7(9), e45087
Zhan, T., Poppelreuther, M., Ehehalt, R. and J. Füllekrug
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(2012). The N-terminal region of acyl-CoA synthetase 3 is essential for both the localization on lipid droplets and the function in fatty acid uptake. J Lipid Res. 53(5), 888-900
Poppelreuther, M., Rudolph, B., Du, C., Großmann, R., Becker, M., Thiele, C., Ehehalt, R. and J. Füllekrug
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(2013). Differentially localized acyl-CoA synthetase 4 isoenzymes mediate the metabolic channeling of fatty acids towards phosphatidylinositol. BBA Mol Biol Cell Lipids
Küch, E., Vellaramkalayil, R., Zhang, I., Lehnen, D., Brügger, B., Stremmel, W., Ehehalt, R., Poppelreuther, M. and J. Füllekrug
