Fatty acid-binding proteins - Insights from genetic manipulations

Department of Biological Sciences, Simon Fraser University, 8888 University Drive, Burnaby, BC, Canada V5A 1S6.
Progress in Lipid Research (Impact Factor: 10.02). 08/2004; 43(4):328-49. DOI: 10.1016/j.plipres.2004.05.001
Source: PubMed


Fatty acid-binding proteins (FABPs) belong to the conserved multigene family of the intracellular lipid-binding proteins (iLBPs). These proteins are ubiquitously expressed in vertebrate tissues, with distinct expression patterns for the individual FABPs. Various functions have been proposed for these proteins, including the promotion of cellular uptake and transport of fatty acids, the targeting of fatty acids to specific metabolic pathways, and the participation in the regulation of gene expression and cell growth. Novel genetic tools that have become available in recent years, such as transgenic cell lines, animals, and knock-out mice, have provided the opportunity to test these concepts in physiological settings. Such studies have helped to define essential cellular functions of individual FABP-types or of combinations of several different FABPs. The deletion of particular FABP genes, however, has not led to gross phenotypical changes, most likely because of compensatory overexpression of other members of the iLBP gene family, or even of unrelated fatty acid transport proteins. This review summarizes the properties of the various FABPs expressed in mammalian tissues, and discusses the transgenic and ablation studies carried out to date in a functional context.

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Available from: Norbert Haunerland, Jul 02, 2014
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    • "However, the divergent sequences of the members confer subtle differences in their ligand-binding properties and may also indicate different protein–protein interaction partners depending on the cellular context. Indeed, it has been shown that intracellular adipocyte-, epithelial-, and heart-type FABPs interact with hormone-sensitive lipase , whereas the intestinal and liver isoforms do not [3] [4] [5] [6] [7]. It is also known that FABP4 interacts with Janus Kinase 2 in a fatty aciddependent manner, establishing a new role for FABP4 as a fatty acid sensor that affects cellular metabolism via protein–protein interactions [8]. "
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    ABSTRACT: Fatty acid-binding protein 4 (FABP4) is an adipose tissue-secreted adipokine that is involved in the regulation of energetic metabolism and inflammation. Increased levels of circulating FABP4 have been detected in individuals with cardiovascular risk factors. Recent studies have demonstrated that FABP4 has a direct effect on peripheral tissues, specifically promoting vascular dysfunction; however, its mechanism of action is unknown. The objective of this work was to assess the specific interactions between exogenous FABP4 and the plasma membranes of endothelial cells. Immunofluorescence assays showed that exogenous FABP4 localized along the plasma membranes of human umbilical vein endothelial cells (HUVECs), interacting specifically with plasma membrane proteins. Anti-FABP4 immunoblotting revealed two covalent protein complexes containing FABP4 and its putative receptor; these complexes were approximately 108 kDa and 77 kDa in size. Proteomics and mass spectrometry experiments revealed that cytokeratin 1 (CK1) was the FABP4-binding protein. An anti-CK1 immunoblot confirmed the presence of CK1. FABP4-CK1 complexes were also detected in HAECs, HCASMCs, HepG2 cells and THP-1 cells. Pharmacological FABP4 inhibition by BMS309403 results in a slight decrease in the formation of these complexes, indicating that fatty acids may play a role in FABP4 functionality. In addition, we demonstrated that exogenous FABP4 crosses the plasma membrane to enter the cytoplasm and nucleus in HUVECs. These findings indicate that exogenous FABP4 interacts with plasma membrane proteins, specifically CK1. These data contribute to our current knowledge regarding the mechanism of action of circulating FABP4.
    Biochimica et Biophysica Acta 09/2015; 1853(11). DOI:10.1016/j.bbamcr.2015.09.002 · 4.66 Impact Factor
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    • "IFABP has not been found to be involved with chylomicron formation [35] [57]; hence, IFABP has been proposed to be involved with uptake of FA from the lumen of the intestine, and with trafficking within the intestinal enterocyte to organelles [34]. It is also thought that both FABPs may serve as a cytosolic reservoir for FA required for various cellular functions, while also preventing accumulation of unesterified FA, which are known to modify membrane properties [4]. IFABP is typical among the members of the FABP family in that it has a single site where its FA ligand is bound. "
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    ABSTRACT: Fatty acid-binding proteins (FABP) are highly abundant cytosolic proteins that are expressed in most mammalian tissues. In the intestinal enterocyte, both liver- (LFABP; FABP1) and intestinal FABPs (IFABP; FABP2) are expressed. These proteins display high-affinity binding for long-chain fatty acids (FA) and other hydrophobic ligands; thus, they are believed to be involved with uptake and trafficking of lipids in the intestine. In vitro studies have identified differences in ligand-binding stoichiometry and specificity, and in mechanisms of FA transfer to membranes, and it has been hypothesized that LFABP and IFABP have different functions in the enterocyte. Studies directly comparing LFABP- and IFABP-null mice have revealed markedly different phenotypes, indicating that these proteins indeed have different functions in intestinal lipid metabolism and whole body energy homeostasis. In this review, we discuss the evolving knowledge of the functions of LFABP and IFABP in the intestinal enterocyte.
    Prostaglandins Leukotrienes and Essential Fatty Acids 10/2014; DOI:10.1016/j.plefa.2014.10.001 · 2.35 Impact Factor
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    • "Phylogenetic analysis divided the iLBP family into four subfamilies: subfamily I including CRBPs and CRABPs, subfamily II including BABPs and liver-FABP, subfamily III including intestinal-FABP and subfamily IV including all the remaining FABPs [9] (Fig. 1). "
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    ABSTRACT: Lipids are essential for many biological processes and crucial in the pathogenesis of several diseases. Intracellular lipid-binding proteins (iLBPs) provide mobile hydrophobic binding sites that allow hydrophobic or amphipathic lipid molecules to penetrate into and across aqueous layers. Thus iLBPs mediate the lipid transport within the cell and participate to a spectrum of tissue-specific pathways involved in lipid homeostasis. Structural studies have shown that iLBPs binding sites are inaccessible from the bulk, implying that substrate binding should involve a conformational change able to produce a ligand entry portal. Many studies have been reported in the last two decades on iLBPs indicating that their dynamics play a pivotal role in regulating ligand binding and targeted release. The ensemble of reported data has not been reviewed until today. This review is thus intended to summarise and possibly generalise the results up to now described, providing a picture which could help to identify the missing notions necessary to improve our understanding of the role of dynamics in iLBPs molecular recognition. Such notions would clarify the chemistry of lipid binding to iLBPs and set the basis for the development of new drugs.
    Biochimica et Biophysica Acta 04/2014; 1844(7). DOI:10.1016/j.bbapap.2014.04.011 · 4.66 Impact Factor
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