The physiological role of long-chain fatty acyl-CoA is thought to be primarily in intermediary metabolism of fatty acids. However, recent data show that nM to microM levels of these lipophilic molecules are potent regulators of cell functions in vitro. Although long-chain fatty acyl-CoA are present at several hundred microM concentration in the cell, very little long-chain fatty acyl-CoA actually exists as free or unbound molecules, but rather is bound with high affinity to membrane lipids and/or proteins. Recently, there is growing awareness that cytosol contains nonenzymatic proteins also capable of binding long-chain fatty acyl-CoA with high affinity. Although the identity of the cytosolic long-chain fatty acyl-CoA binding protein(s) has been the subject of some controversy, there is growing evidence that several diverse nonenzymatic cytosolic proteins will bind long-chain fatty acyl-CoA. Not only does acyl-CoA binding protein specifically bind medium and long-chain fatty acyl-CoA (LCFA-CoA), but ubiquitous proteins with multiple ligand specificities such as the fatty acid binding proteins and sterol carrier protein-2 also bind LCFA-CoA with high affinity. The potential of these acyl-CoA binding proteins to influence the level of free LCFA-CoA and thereby the amount of LCFA-CoA bound to regulatory sites in proteins and enzymes is only now being examined in detail. The purpose of this article is to explore the identity, nature, function, and pathobiology of these fascinating newly discovered long-chain fatty acyl-CoA binding proteins. The relative contributions of these three different protein families to LCFA-CoA utilization and/or regulation of cellular activities are the focus of new directions in this field.

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Rat liver fatty acid binding protein (L-FABP) and rat intestine fatty acid binding protein (I-FABP) are homologous proteins which are both found in intestinal epithelial cells. It was once well accepted that liver fatty acid binding protein bound fatty acyl-CoAs, but the recent finding of a novel acyl-CoA binding protein (ACBP) in preparations of L-FABP has challenged the role of FABPs in acyl-CoA metabolism. Prior to the discovery of ACBP, L-FABP preparations from liver were shown to modulate the rate of fatty acyl-CoA synthesis (Burrier et al., 1987) and their conversion to phospholipids (Bordewick et al., 1989). Studies using FABPs free of ACBP are needed to determine the role of I-FABP and L-FABP in fatty acyl-CoA metabolism. In this study, highly pure recombinant L-FABP and I-FABP were used first to establish binding to fatty acyl-CoAs and then to examine the effects of these FABPs on microsomal phosphatidic acid synthesis. The standard Lipidex-1000 binding assay using [14C]oleoyl-CoA and a new fluorescence binding assay using the fluorescent fatty acyl-CoA cis-parinaroyl-CoA were used to determine binding. The results of these assays indicate that L-FABP binds fatty acyl-CoAs at two sites with a high-affinity Kd = 3-14 microM. These binding assays showed that I-FABP has a much lower affinity for fatty acyl-CoAs than does L-FABP. Furthermore, in vitro only L-FABP significantly increases the rate of incorporation of oleoyl-CoA into lysophosphatidic acid and phosphatidic acid.