Fatty acid-binding proteins (FABPs) are members of a superfamily of lipid-binding proteins, and occur intracellularly in vertebrates and invertebrates. This review presents recent findings on the diversity of these FABPs and their proposed roles in fatty acid (FA) metabolism and other cellular processes. Special attention is paid to the structural features of the different mammalian FABP types and the physiological role of these proteins in FA transport, cell growth and differentiation, cellular signalling, gene transcription and cytoprotection. Additionally, data on FABP knockout mice and the implication of FABP in medicine are discussed.

IntroductionThe interaction between a T cell and an antigen-presenting cell (APC) is the central event in the induction of an adaptive immune response and involves different and sequential cellular events. Initially, the T cell transiently adheres to the APC and scans its surface for the presence of specific peptide-major histocompatibility (MHC) complexes in an antigen-independent manner. Several receptor-ligand pairs such as CD2/lymphocyte function-associated antigen-3 (LFA-3), LFA-1/intercellular adhesion molecule-1 (ICAM-1) and ICAM-3, and ICAM-3/dendritic cell (DC)-specific ICAM-3-grabbing nonintegrin (DC-SIGN) have been implicated in these early T-cell-APC interactions. 1 In particular, ICAM-1 and -3 play a key role in mediating the initial, antigen-independent adhesion of T cells and APC. 1,2 Once the initial contact has been generated, the contact interface is stabilized by molecular reorganization of antigen receptors, adhesion molecules, costimulatory molecules, and the actin cytoskeleton. This highly organized supramolecular structure is known as the immunological synapse. 3 Adhesion molecules and T-cell-receptor (TCR)-associated components are segregated into 2 major areas within the immunological synapse: the central supramolecular activation cluster (SMAC), which is enriched in TCR/CD3 complexes, costimulatory molecules (CD4, CD2, CD28), and kinases (protein kinase C-[PKC-], Lck, and Fyn), and the peripheral SMAC, including LFA-1 and talin. 4,5 Synapse formation is accompanied by cytoskeletal rearrangements, induction of tyrosine phosphorylation and an increase in intracellular free Ca 2ϩ . Upon Ca 2ϩ mobilization, the nuclear factor of activated T cells (NFAT) is dephosphorylated and translocates to the nucleus, where it acts as a transcriptional regulator of interleukin-2 (IL-2) expression. 6 Activated leukocyte cell adhesion molecule (ALCAM; CD166) is a member of the immunoglobulin (Ig) superfamily of proteins. 7 Although ALCAM is expressed on a wide variety of cells, within the leukocyte population its expression is particularly high on DC. In addition, monocytic cells in synovium from patients with rheumatoid arthritis show strongly increased ALCAM levels compared with resting monocytes, suggesting that ALCAM is involved in regulating immunologic processes such as inflammation. 8 However, the precise role of ALCAM in the immune system is as yet unclear. Similar to several other Ig-like adhesion molecules (NCAM, CEA), ALCAM mediates homotypic ALCAM-ALCAM interactions, 7,9,10 but also heterotypic interactions with the T-cell antigen CD6 have been described. 7 CD6 is a surface receptor expressed by T lymphocytes, thymocytes, and a subset of B cells. [11][12][13] 18 It has been suggested that CD6 fine-tunes CD5 tyrosine phosphorylation by recruiting specific kinases of different families, such as Itk and Lck. 19 CD6 physically associates with the TCR/CD3 complex, it relocalizes upon T-cell activation at the central SMAC (cSMAC) and it modulates immunological synapse maturation in a Jurkat-Raji mo...

Fatty acid binding proteins (FABP) form a family of proteins displaying tissue-specific expression. These proteins are involved in fatty acid (FA) transport and metabolism by mechanisms that also appear to be tissue-specific. Cellular retinoid binding proteins are related proteins with unknown roles in FA transport and metabolism. To better understand the origin of these tissue-specific differences we report new measurements, using the acrylodated intestinal fatty acid binding protein (ADIFAB) method, of the binding of fatty acids (FA) to human fatty acid binding proteins (FABP) from brain, heart, intestine, liver, and myelin. We also measured binding of FA to a retinoic acid (CRABP-I) and a retinol (CRBP-II) binding protein and we have extended to 19 different FA our characterization of the FA-ADIFAB and FA-rat intestinal FABP interactions. These studies extend our previous analyses of human FABP from adipocyte and rat FABPs from heart, intestine, and liver. Binding affinities varied according to the order brain approximately myelin approximately heart > liver > intestine > CRABP > CRBP. In contrast to previous studies, no protein revealed a high degree of selectivity for particular FA. The results indicate that FA solubility (hydrophobicity) plays a major role in governing binding affinities; affinities tend to increase with increasing hydrophobicity (decreasing solubility) of the FA. However, our results also reveal that, with the exception of the intestinal protein, FABPs exhibit an additional attractive interaction for unsaturated FA that partially compensates for their trend toward lower affinities due to their higher aqueous solubilities. Thermodynamic potentials were determined for oleate and arachidonate binding to a subset of the FABP and retinoid binding proteins. FA binding to all FABPs was enthalpically driven. The DeltaH degrees values for paralogous FABPs, proteins from the same species but different tissues, reveal an exceptionally wide range of values, from -22 kcal/mol (myelin) to -7 kcal/mol (adipocyte). For orthologous FABPs from the same tissue but different species, DeltaH degrees values were similar. In contrast to the enthalpic dominance of FA binding to FABP, binding of FA to CRABP-I was entropically driven. This is consistent with the notion that FA specificity for FABP is determined by the enthalpy of binding. Proteins from different tissues also revealed considerable heterogeneity in heat capacity changes upon FA binding, DeltaC(p) values ranged between 0 and -1.3 kcal mol(-1) K(-1). The results demonstrate that thermodynamic parameters are quite different for paralogous but are quite similar for orthologous FABP, suggesting tissue-specific differences in FABP function that may be conserved across species.