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: 12.96). 08/2004; 43(4):328-49. DOI: 10.1016/j.plipres.2004.05.001
Source: PubMed

ABSTRACT 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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    ABSTRACT: Reversible association of soluble proteins to lipid membranes is fundamental for a wide variety of cellular functions, showing an important role in conformational modulation. The present work was intended to study the binding of two peripheral proteins members of the FABPs family (Fatty Acid Binding Proteins) to lipid membranes, from a structural and thermodynamic approach. These proteins are hydrophobic ligand transporters, so their physiological function is closely related to the interaction with membranes. The ligand uptake/release takes place trough a conformational change which is modulated by the interphase. Two alternative mechanisms have been proposed for the ligand transfer: collisional and diffusional. These mechanisms require specific orientations in the membrane, which are key in determining the selectivity for any mechanism. The conformational modulation process of these proteins in the lipid interphase was studied by spectroscopic techniques such as fluorescence and Fourier Transform Infrarred Spectroscopy (FTIR). Results were analyzed qualitatively in terms of conformational equilibria which describe the population of diverse states in the local minima of the protein folding potential funnel. These proteins exhibit selectivity towards anionic interphases. Thus, a special attention was invested in elucidating electrostatic main contribution in the interaction process. This analysis was addressed through the establishment of correlations between lipid affinity or spectroscopic characteristics reflecting protein degree of unfolding, and electric properties of the membranes. Together with previous work in the group, it was evidenced that the orientation of these proteins at the interphase is determined primarily by interaction between the macrodipole and the electric field of the membrane. The orientation was obtained from molecular dynamics simulations and experimentally validated through experimental filtration assays and Fluorescence Resonant Energy Transfer (FRET) between Trp residues in the protein and acceptors anchored in the membrane surface. The dipolar character of the interaction was reflected through association and orientation studies of these proteins in cationic membranes. They resulted selectively associated to charged membranes, either anionic or cationic, irrespective of the net charge of the protein. Its interphasial orientation is according to the interaction of the macrodipole with the electric field of the membrane.
    03/2013, Degree: PhD Chemistry, Supervisor: Dr. Guillermo G. Montich
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    ABSTRACT: Myostatin (MSTN) is a secreted protein belonging to the transforming growth factor-β (TGF-β) family that is primarily expressed in skeletal muscle and also functions in adipocyte maturation. Studies have shown that MSTN can inhibit adipogenesis in muscle satellite cells (MSCs) but not in adipose-derived stem cells (ADSCs). However, the mechanism by which MSTN differently regulates adipogenesis in these two cell types remains unknown. Peroxisome proliferator-activated receptor-γ (PPARγ) and myogenic differentiation factor (MyoD) are two key transcription factors in fat and muscle cell development that influence adipogenesis. To investigate whether MSTN differentially regulates PPARγ and MyoD, we analyzed PPARγ and MyoD expression by assessing mRNA, protein and methylation levels in ADSCs and MSCs after treatment with 100 ng/mL MSTN for 0, 24, and 48 h. PPARγ mRNA levels were downregulated after 24 h and upregulated after 48 h of treatment in ADSCs, whereas in MSCs, PPARγ levels were downregulated at both time points. MyoD expression was significantly increased in ADSCs and decreased in MSCs. PPARγ and MyoD protein levels were upregulated in ADSCs and downregulated in MSCs. The CpG methylation levels of the PPARγ and MyoD promoters were decreased in ADSCs and increased in MSCs. Therefore, this study demonstrated that the different regulatory adipogenic roles of MSTN in ADSCs and MSCs act by differentially regulating PPARγ and MyoD expression.
    Biochemical and Biophysical Research Communications 01/2015; DOI:10.1016/j.bbrc.2015.01.120 · 2.28 Impact Factor
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    ABSTRACT: Over the past decade, evidences of an integration of metabolic and inflammatory pathways, referred to as metaflammation in several aspects of metabolic syndrome, have been accumulating. Fatty acid-binding protein 4 (FABP4), also known as adipocyte FABP (A-FABP) or aP2, is mainly expressed in adipocytes and macrophages and plays an important role in the development of insulin resistance and atherosclerosis in relation to metaflammation. Despite lack of a typical secretory signal peptide, FABP4 has been shown to be released from adipocytes in a non-classical pathway associated with lipolysis, possibly acting as an adipokine. Elevation of circulating FABP4 levels is associated with obesity, insulin resistance, diabetes mellitus, hypertension, cardiac dysfunction, atherosclerosis, and cardiovascular events. Furthermore, ectopic expression and function of FABP4 in several types of cells and tissues have been recently demonstrated. Here, we discuss both the significant role of FABP4 in pathophysiological insights and its usefulness as a biomarker of metabolic and cardiovascular diseases.
    01/2014; 8(Suppl 3):23-33. DOI:10.4137/CMC.S17067

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