Fatty acid-binding proteins (FABPs) are members of the superfamily of lipid-binding proteins (LBP). So far 9 different FABPs, with tissue-specific distribution, have been identified: L (liver), I (intestinal), H (muscle and heart), A (adipocyte), E (epidermal), Il (ileal), B (brain), M (myelin) and T (testis). The primary role of all the FABP family members is regulation of fatty acid uptake and intracellular transport. The structure of all FABPs is similar — the basic motif characterizing these proteins is β-barrel, and a single ligand (e.g. a fatty acid, cholesterol, or retinoid) is bound in its internal water-filled cavity. Despite the wide variance in the protein sequence, the gene structure is identical. The FABP genes consist of 4 exons and 3 introns and a few of them are located in the same chromosomal region. For example,A-FABP, E-FABP andM-FABP create a gene cluster. Because of their physiological properties some FABP genes were tested in order to identify mutations altering lipid metabolism. Furthermore, the porcineA-FABP andH-FABP were studied as candidate genes with major effect on fatness traits.

The multigene family of fatty acid-binding proteins (FABPs): function, structure and polymorphism.

Recent insights into hepatic lipid metabolism in non-alcoholic fatty liver disease (NAFLD).

The fatty acid transport function of fatty acid-binding proteins.

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.

New insights into the structure and function of fatty acid-binding proteins.

Fatty acid-binding proteins (FABPs) are abundant intracellular proteins that bind long-chain fatty acids with high affinity. Nine separate mammalian FABPs have been identified, and their tertiary structures are highly conserved. The FABPs have unique tissue-specific distributions that have long suggested functional differences among them. In the last decade, considerable progress has been made in understanding the specific functions of the FABPs and, in some cases, their mechanisms of action at the molecular level. The FABPs appear to be involved in the extranuclear compartments of the cell by trafficking their ligands within the cytosol via interactions with organelle membranes and specific proteins. Several members of the FABP family have been shown to function directly in the regulation of cognate nuclear transcription factor activity via ligand-dependent translocation to the nucleus. This review will focus on these emerging functions and mechanisms of the FABPs, highlighting the unique functional properties of each as well as the similarities among them.

The emerging functions and mechanisms of mammalian fatty acid-binding proteins

Intestinal fatty acid binding protein (IFABP) and liver FABP (LFABP), homologous proteins expressed at high levels in intestinal absorptive cells, employ markedly different mechanisms for the transfer of fatty acids (FAs) to acceptor membranes. Transfer from IFABP occurs during protein−membrane collisional interactions, while for LFABP, transfer occurs by diffusion through the aqueous phase. Earlier, we had shown that the helical domain of IFABP is critical in determining its collisional FA transfer mechanism. In the study presented here, we have engineered a pair of chimeric proteins, one with the “body” (ligand binding domain) of IFABP and the α-helical region of LFABP (αLβIFABP) and the other with the ligand binding pocket of LFABP and the helical domain of IFABP (αIβLFABP). The objective of this work was to determine whether the change in the α-helical domain of each FABP would alter the rate and mechanism of transfer of FA from the chimeric proteins in comparison with those of the wild-type proteins....

The α-Helical Domain of Liver Fatty Acid Binding Protein Is Responsible for the Diffusion-Mediated Transfer of Fatty Acids to Phospholipid Membranes†

Role of the helical domain in fatty acid transfer from adipocyte and heart fatty acid-binding proteins to membranes: Analysis of chimeric proteins

The path of a small hydrophobic molecule through the aqueous cytoplasm is not linear. Partition may favor membrane binding by several orders of magnitude; thus significant membrane association will markedly decrease the cytosolic transport rate. The presence of high concentrations of soluble binding proteins for these hydrophobic molecules would compete with membrane association and thereby increase transport rate. For long chain fatty acid molecules, a family of cytosolic binding proteins collectively known as the fatty acid-binding proteins (FABP), are thought to act as intracellular transport proteins. This paper examines the mechanism of transfer of fluorescent anthroyloxy-labeled fatty acids (AOFA) from purified FABP's to phospholipid vesicles. With the exception of the liver FABP, AOFA is transferred from FABP by collisional interaction of the protein with an acceptor membrane. The rate of transfer increased markedly when membranes contain anionic phospholipids; this suggests that positively charged residues on the surface of the FABP may interact with the membranes. Neutralization of surface lysine residues of adipocyte and heart-type FABPs decreased the AOFA transfer rate, and transfer was then found to proceed via aqueous diffusion rather than collisional interaction. Site-specific mutagenesis has further shown that the helix-turn-helix domain of the FABPs is critical for interaction with anionic acceptor membranes. In addition, direct interaction of adipocyte FABPs with anionic membranes has been demonstrated. Thus “cytosolic” FABP may function in. intracellular transport of fatty acids to decrease their membrane association, as well as to target fatty acids to specific subcellular sites of utilization.

The role of membranes and intracellular binding proteins in cytoplasmic transport of hydrophobic molecules: Fatty acid-binding proteins

The family of mammalian fatty acid-binding proteins (FABP) includes at least ten distinct gene products, and additional homologues continue to be reported. The FABP were first discovered in the early 1970’s as abundant cytoplasmic proteins which bound long chain fatty acids (FA) in vitro 11-3. In the ensuing years, a great deal of information has been obtained about their tissue distributions, ligand binding affinities and specificities, developmental regulation and, more recently, their tertiary structures 3-5 Their functions, however, remain largely undefined. Among the first members of the FABP family to be purified were those from intestine 1,6, liver 1,2 and heart7. In all these tissues, fatty acid flux is considerable, and thus it was proposed that the FABP are necessary for large-scale intracellular binding of fatty acids. More recently, FABP family members have been identified in other tissues that are generally considered to be lipid-active, e.g. adipose tissue 8, as well as other tissues, e.g. brain 9,10. In addition, the FABP have been suggested as modulators not only of lipid metabolism and cellular FA flux, but also of gene expression, cell growth and differentiation, etc.11-13 It is also of interest that a number of cell types, most notably intestinal enterocytes, express high and approximately equivalent levels of two separate FABP’s 14 suggesting a functional specificity for different family members. In all of these tissues and for all of these putative functions, a role for FABP in cytoplasmic transport of FA from sites of entry and/or synthesis to sites of utilization and function, is implied.

Heng Ling Liou

Papers

The α-Helical Domain of Liver Fatty Acid Binding Protein Is Responsible for the Diffusion-Mediated Transfer of Fatty Acids to Phospholipid Membranes†

Role of the helical domain in fatty acid transfer from adipocyte and heart fatty acid-binding proteins to membranes: Analysis of chimeric proteins

The role of membranes and intracellular binding proteins in cytoplasmic transport of hydrophobic molecules: Fatty acid-binding proteins

The Role of Intracellular Fatty Acid-Binding Proteins in Cellular Transport of Fatty Acids