Long-chain acyl-CoA synthetases and fatty acid channeling

Abstract

Thirteen homologous proteins comprise the long-chain acyl-CoA synthetase (ACSL), fatty acid transport protein (FATP), and bubblegum (ACSBG) subfamilies that activate long-chain and very-long-chain fatty acids to form acyl-CoAs. Gain- and loss-of-function studies show marked differences in the ability of these enzymes to channel fatty acids into different pathways of complex lipid synthesis. Further, the ability of the ACSLs and FATPs to enhance cellular FA uptake does not always require these proteins to be present on the plasma membrane; instead, FA uptake can be increased by enhancing its conversion to acyl-CoA and its metabolism in downstream pathways. Since altered fatty acid metabolism is a hallmark of numerous metabolic diseases and pathological conditions, the ACSL, FATP and ACSBG isoforms are likely to play important roles in disease etiology.

Fig. 1

Pathways initiated by ACSL, FATP, and ACSBG isoforms. In addition to initiating the synthesis of triacylglycerol (TAG) and all the glycerophospholipids, acyl-CoAs are required for the synthesis of cholesterol esters, ceramide and sphingolipids, for fatty acid (FA) degradation pathways and for FA modification pathways of elongation and desaturation. Intermediates in the glycerolipid synthetic pathway, lysophosphatidic acid (LPA), phosphatidic acid (PA), and diacylglycerol (DAG) are intracellular signals. Both FA and acyl-CoAs are also intracellular signals and regulators of cellular physiology as well as purported ligands for PPAR and HNF4α transcription factors. G-3-P, glycerol-3-phosphate; PI, phosphatidylinositol; PG, phosphatidylglycerol; CL, cardiolipin; PE phosphatidylethanolamine; PC, phosphatidylcholine; PS, phosphatidylserine.