Do Long-Chain Acyl-CoA Synthetases Regulate Fatty Acid Entry into Synthetic Versus Degradative Pathways?

Recent studies suggest that the long-chain acyl-CoA synthetases (ACS) may play a role in channeling fatty acids either toward complex lipid synthesis and storage or toward oxidation. Each of the five members of the ACS family that has been cloned has a distinct tissue distribution and subcellular location, and is regulated independently during cellular differentiation and by diverse hormones and nuclear transcription factors including adrenocorticotropic hormone (ACTH), peroxisomal proliferator-activated receptor-α (PPARα) and sterol regulatory element binding protein. Taken as a whole, these features suggest that in liver, ACS1 and ACS5 may provide acyl-CoA destined primarily for triacylglycerol synthesis or for mitochondrial oxidation, respectively. ACS4 may provide acyl-CoA for both synthesis and peroxisomal oxidation, depending on whether the enzyme is associated with the mitochondrial-associated membrane or with peroxisomes. It should be emphasized that although the data for acyl-CoA channeling are strong, they are indirect. Rigorous testing of these predictions will be required.