Role of membrane-associated and cytoplasmic fatty acid-binding proteins in cellular fatty acid metabolism

Role of membrane-associated and cytoplasmic fatty acid-binding proteins in cellular fatty acid metabolism

Prostaglandins, Leukotrienes and Essential Fatty Acids (1997) 57(4 & 5), 373-378 © HarcourtBrace& Co Ltd 1997 Role of membrane-associated and cytopla...

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Prostaglandins, Leukotrienes and Essential Fatty Acids (1997) 57(4 & 5), 373-378 © HarcourtBrace& Co Ltd 1997

Role of membrane-associated and cytoplasmic fatty acid-binding proteins in cellular fatty acid metabolism J. F. C. Glatz, F. A. van Nieuwenhoven, J. J. F. P. Luiken, F. G. Schaap, G. J. van der Vusse Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht, The Netherlands

Summary A number of membrane-associated and cytoplasmic fatty acid-binding proteins (FABPs) are now being implicated in the cellular uptake and intracellular transport of long-chain fatty acids (FA). These proteins each have the capacity of non-covalent binding of FA, are present in tissues actively involved in FA metabolism, and are upregulated in conditions of increased cellular FA metabolism. To date, five distinct membrane FABPs have been described, ranging in mass from 22 to 88 kDa and each showing a characteristic tissue distribution. Evidence for involvement in cellular fatty acid uptake has been provided for several of them, because it was recently found that isolated cell lines transfected with 88-kDa putative fatty acid translocase (FAT; homologous to CD36) or with 63-kDa fatty acid-transport protein show an increased rate of FA uptake. The (at least nine) FABPs of cytoplasmic origin belong to a family of small (14-15 kDa) lipid binding proteins, all having a similar tertiairy structure but differing in binding properties and in tissue occurrence. The biological functions of the various FABPs, possibly exerted in a concerted action among them, comprise solubilization and compartmentalization of FA, facilitation of the cellular uptake and intracellular trafficking of FA, and modulation of mitosis, cell growth, and cell differentiation. In addition, the FABPs have been suggested to participate in and/or modulate FA-mediated signal transduction pathways and FA regulation of gene expression, and to prevent local high FA concentrations thereby contributing to the protection of cells against the toxic effects of FA. In conclusion, long-chain fatty acids are subject to continuous interaction with multiple proteins, which interplay influences their cellular metabolism.

INTRODUCTION

Each of the various biological functions served by long-chain fatty acids in mammalian cells requires the continuous supply or removal of sufficient varieties and quantities of these compounds. This relates to the production of cellular energy from fatty acid oxidation, the renewal of biological membranes for which fatty acids are incorporated into phospholipids forming the core of these membranes, and the role of specific fatty acids and metabolites in certain signal transduction pathways. The intracellular transport of fatty acids, which is hampered by their virtual insolubility in aqueous solutions, 1 is facilitated by the presence in the cytoplasm of so-called Correspondence to: Jan F. C. Glatz, Department of Physiology, CARIM, Maastricht University, PO Box 616, NL-6200 MD Maastricht, The Netherlands, Tel. 00 31 43 388 1200; Fax. 00 31 43 367 1028; Email: [email protected]

fatty acid-binding proteins (FABP),2 much like the occurrence of specific proteins for the intracellular translocation of other lipophflic substances such as retinol and steroid hormones. Strikingly, a total number of nine distinct types of cytoplasmic FABPs have now been identified? In the last decade, a number of proteins with the ability to non-covalently bind long-chain fatty acids have also been found in the plasma membrane of several cell types? Although fatty acids can readily pass phospholipid membranes by passive diffusion,3 these membraneassociated FABPs may assist in their membrane translocation and/or modulate the rate of cellular uptake or release of fatty acids. A schematic presentation of the tissue uptake, transport and utilization of fatty acids is given in Figure 1. Fatty acids are supplied as fatty acid-albumin complex and as fatty acyl residues incorporated in tfiacylglycerols of 373

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circulating lipoproteins from which they can be released by the enzyme lipoprotein lipase. In the absence of fenestrae in the endothelium, such as in muscle and kidney, fatty acids are transferred through the endothelial cells (Fig. 1, route 2), to bind to albumin in the interstitial space. In liver, however, the presence of endothelial fenestrae enable the vascular substances to directly reach the hepatocytes (Fig. 1, route 1). The release of fatty acids from albumin is most likely facilitated by specific albumin binding proteins present on the luminal membrane of endothelial cells and the plasma membrane of parenchymal cells. 4,s Transport across the latter membrane may be accomplished by diffusion through the lipid bilayer (Fig. 1, route 3), by a protein-mediated process (Fig. 1, route 4), or a combination of both. Intracellularly, the majority of fatty acids is bound to cytoplasmic FABP. In addition, a specific acyl-CoA binding protein has been identified in the cytoplasm of a variety of cells which is involved in channelling this fatty acyl derivative to its site of metabolic conversion? Hence, apart from the proteins already mentioned above, a number of other proteins are involved in the transport of fatty acids from the vascular space to and within the cytoplasm of parenchymal cells, i.e., albumin, membrane-associated albumin binding proteins, and acyl-CoA binding protein. In the present paper interstitial space

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we will focus on the current knowledge of the membraneassociated and cytoplasmic FABPs and discuss their roles in cellular fatty acid metabolism. Membrane-associated FABPs

The first indications for the existence of membraneassociated FABPs were obtained from experiments with isolated parenchymal cells in which the uptake of fatty acids was found to be saturable and subject to inhibition by fatty acid analogues. 7 Subsequently, a number of techniques were applied to identify the protein(s) involved in cellular fatty acid uptake. Using affinity chromatography Stremmel et al 8 purified a 40-43 kDa FABP from the plasma membrane of liver cells. This (peripherally bound) membrane protein, designated FAgPpm, o c c u r s also in several other tissues (Table) 9 and is closely related, if not identical, to mitochondrial aspartate aminotransferase (AAT).1° By labeling with fatty acid analogues, Abumrad and co-workers 11 found in rat adipocytes an 88 kDa integral membrane protein, called fatty acid translocase (FAT), which most likely is a species homologue of the human leukocyte differentiation antigen CD36. FAT is expressed in several tissues, but absent in liver (Table). More recently, Schaffer and Lodish 12reported the identifi-

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Fig. 1 Schematical overview of the route of fatty acid transport from the vascular space to the cytoplasm of parenchymal ceils. Note that passage of the albumin-fatty acid complex across the endothelial barrier (route 1) is negligible in tissues lacking fenestrae between endothelial cells, such as muscle and kidney. In those cases fatty acids most likely are transported across the endothelial cells (route 2) to bind to interstitial albumin. Transmembrane translocation of fatty acids could take place either by passive diffusion through the phospholipid bilayer (route 3), facilitated by membrane-associated proteins (route 4), or by a combination of both. Adapted from ref. 35. Abbreviations: FA, long-chain fatty acid; chylo's, chylomicrons; VLDL, very low-density lipoproteins; LPL, lipoprotein iipase; AIb.BP, albumin binding protein; FABP, fatty acid-binding protein; ACBP, acyI-CoA binding protein. Prostaglandins, Leukotrienes and Essential Fatty Acids (1997) 57(4 & 5), 373-378

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Cellular fatty acid-binding proteins

cation by expression cloning of a 63 kDa integral membrane protein, which they named fatty acid-transport protein (FATP). The existence of a 22 kDa membrane associated FABP in adipocytes, 13 possibly related to caveolin, ~4 and a 60kDa protein in heart and kidney ~ were also reported (Table), but these proteins have not yet been further characterized. Evidence for an involvement in cellular fatty acid uptake has been provided for both FABPpm/AAT, FATP and FAT/CD36. Thus, transfection of 3T3-L1 fibroblasts with a cDNA for AAT confers saturable and a lO-fold increased rate of fatty acid uptake to these cells. ~6 Likewise, transfected fibroblast cell lines expressing FATP exhibit a saturable and 3- to 4-fold increased rate of oleate uptake compared to control cells. ~2 Recently, we studied whether stable transfection of putative FAT/CD36 into a cell line derived from rat heart (H9c2 cells), normally lacking this protein, would increase cellular fatty acid uptake. In two transfected cell lines showing FAT expression levels (mRNA) of about 50% of that of rat heart, the rate of uptake of radiolabeled palmitate was ca. 2.5-fold higher than in transfected cell lines without FAT expressionY A similar increase in rate of fatty acid uptake was reported for mouse fibroblast cells after transfection with FAT cDNA. TM In rat heart and skeletal muscles the degree of FAT/CD36 expression is related to the oxidative capaci-

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ties of these muscles. 19Moreover, FAT/CD36 is markedly upregulated during differentiation of preadipocytes to adipocytes, ~1 in heart and skeletal muscles of diabetic animals, and in heart of animals fed a high fat diet,2 conditions in which cellular fatty acid uptake rates are also increased. These data further support the putative function of this protein in cellular fatty acid utilization. Despite the growing number of studies indicating the involvement of these membrane-associated FABPs in cellular fatty acid uptake, their precise mechanistic role in this process is not yet clear. Depending on their functioning in, for instance, the entrapping and/or transmembrane translocation of fatty acids, the names of the various proteins may have to be reconsidered. Cytoplasmic FABPs

The intracellular or cytoplasmic FABPs belong to a multigene family of 14-15kDa proteins capable of binding hydrophobic ligands with high affinity. This family of intracellular lipid binding proteins comprises (at least) 13 members, including four cellular refinoid binding proteins (Table). 2,2° Although these proteins show an amino acid sequence homology of only 15-70%, there is a striking similarity with respect to their tertiary structure, which features a clam shell-like structure with the lipid ligand bound ill between the two halves of the clam. 2° In

Table Overview of membrane-associated and cytoplasmic fatty acid-binding proteins of mammalian origin

Protein

Current designation

Molecular mass (kDa)*

Ligand(s)

Occurrence**

Membrane associated FABPs Membrane FABP Membrane FABP Plasma membrane FABP FABPpr, FA receptor FAR FA transport protein FATP

22 40-43 56-60 63

FA FA FA FA

FA translocase

FAT

88

FA

Adipose tissue Adipose tissue, heart, skeletal muscle, intestine, liver Heart, kidney Adipose tissue, heart, skeletal muscle, (brain, kidney, lung, liver) Adipose tissue, heart, skeletal muscle, intestine, spleen, (testis)

Cytoplasmic FABPs Epidermal FABP Heart FABP

E-FABP H-FABP (MDGI)

14.9 14.6

FA, eicosanoids FA

Brain FABP Testicular LBP Myelin LBP Adipocyte LBP Intestinal FABP Ileal LBP Liver FABP

B-FABP T-LBP M-LBP (mP2) A-LBP (aP2) I-FABP I-LBP L-FABP

14.7 15.0 14.8 14.5 15.0 14.4 14.1

FA n.d. FA, retinoids FA, retinoic acid FA FA, bile acids FA, heme, bilirubin, eicosanoids

Epidermis, endothelial cells, lens epithelial cell Heart, skeletal muscle, smooth muscle, brain, kidney, mammary gland, (lung, placenta, ovary) Brain Testis Peripheral nervous system Adipose tissue Small intestine Ileum, (ovary) Liver, small, intestine, kidney

Membrane associated FABPs are listed according to molecular mass, cytoplasmic FABPs according to presumed phylogenetic relation. Data were compiled from ref. 2. Not listed are the cellular retinol and retinoic acid-binding proteins (CRBP and CRABP), which also belong to the family of intracellular lipid binding proteins (2, 20). Abbreviations: FA, (long-chain) fatty acid; FABP, fatty acid-binding protein; LBP, lipid binding protein; MDGI, mammary-derived growth inhibitor; n.d., not determined. *Given for proteins from rat, except for FATP and M-LBP (mouse). **As far as tissues were studied; major occurrence is indicated, minor occurrence in parentheses. © Harcourt Brace & Co Ltd 1997

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general, the cytoplasmic FABPs show an affinity for long-chain fatty acid binding which is comparable to that of plasma albumin, the Ka ranging from 2 to 500 nM depending on the type of FABP and type of fatty acid studied.21,22For instance, the affinity of rat I-FABP is much higher for palmitate (Kd 30 riM) than for arachidonate (/~ 350riM), while rat H-FABP shows virtually similar affinities for these fatty acid species (Kd 15 and 39 nM, respectively). 21 Interestingly, some FABP types will bind exclusively long-chain fatty acids (I-FABP, H-FABP), whereas others will also bind eicosanoids (E-FABP,L-FABP) or even various amphiphflic ligands (L-FABP) (Table). The types of FABP each show a characteristic pattern of tissue expression (Table), and are relatively abundant in tissues with active fatty acid metabolism such as liver, adipose tissue and heart. The latter organs show a tissue content of ca. 1 mg/g FABP.2 Co-expression of more than one type of FABP in a single cell type is also seen. For example, intestinal enterocytes express I-FABP, L-FABP, I-LBP (and CRBP II), with the contents of these proteins showing a distinct regional and zonal pattern of expression. 23 Like the membrane-associated FABPs, the tissue and cellular expression of the cytoplasmic FABPs appears to be responsive to changes in lipid metabolic activity as induced by various (patho)physiological and pharmacological manipulations.2These include an increase in FABP contents: (i) of liver, intestine, heart and kidney by increasing the dietary fat content; (ii) of heart and skeletal muscles in diabetic animals; and (iii) of liver and intestine, but not heart, following treatment with the hypolipidemic drug clofibrate. More recent studies revealed that saturated and unsaturated fatty acids can also, as primary messengers, reversibly induce the expression of A-LBP in cultured adipose cells 24 and of H-FABP in neonatal rat cardiac myocytes.25 In adipocytes this effect is exerted by the unmetabolized fatty acid, a6 and presumably is mediated by a fatty acid-activated receptor (FAAR), a nuclear receptor protein which, after activation, modulates gene transcription. It remains to be elucidated whether the same mechanism also applies to other tissues. A number of biological functions have been established or are tentatively attributed to the cytoplasmic FABPs. The primary function is their involvement in the cytoplasmic translocation of long-chain fatty acids, for which role evidence has been presented. 2z FABP can thus be regarded as the intracellular counterpart of plasma albumin. Additional related functions may include: (i) the intracellular trapping of fatty acids or lipophilic substances to maintain a low intracellular concentration of non-protein bound fatty acids; (ii) a direct involvement in fatty acid metabolism by serving as a stimulatory or inhibitory cofactor for reactions in which fatty acids are substrates or regulators; and (iii) the selective binding of

specific types of fatty acids to influence their metabolic fate in the cell. Interestingly, the cytoplasmic FABPs were found to function also in cell growth and differentiation. In hepatocytes, the presence of L-FABP is required for induction of cell proliferation by carcinogens.28 Opposed to this intracellular function of L-FABPis the extracellular action of H-FABP, which is identical to mammary-derived growth inhibitor (MDGI), on the inhibition of DNA synthesis and the promotion of differentiation and milk protein synthesis in mammary epithelial cells,29 and the induction of hypertrophy in cardiac myocytes?° It has also been postulated31,32 that cytoplasmic FABP participates in signal transduction pathways and in fatty acid regulation of gene expression. For instance, cytoplasmic FABP could be involved in the synthesis of the lipophflic signalling compound by the signalling cell or that of the second messenger (e.g., arachidonic acid) by the target cell. Such involvement of FABP most likely occurs by enhancing product removal and thus preventing feedback inhibition. Additionally, FABP could carry and/or modulate the availability of the signalling compound or second messenger. The role of L-FABP as mediator of mitogenesis as induced by carcinogens that are bound by L-FABP (see above) may be explained by such mechanism. Finally, cytoplasmic FABPs have been suggested to possibly target transport of fatty acids to specific metabolic pathways, and to protect cells against the adverse effects of long-chain fatty acids, but at present available evidence for such roles remains inconclusive?,33 Concerted action of membrane-associated and cytoplasmic FABPs

The bulk transport of fatty acids between tissues and within tissue cells is facilitated by the presence in each compartment (and even in plasma membranes) of specific proteins which can reversibly and non-covalently bind these compounds. The fine-tuning of properties of these various proteins will be important for a proper handling of fatty acids, so as to have these compounds readily available for cellular utilization while keeping them from exerting their adverse affects on cellular function. The presence of FABPs in the plasma membrane may be vital for the controlled transmembrane translocation of fatty acids, whereby a direct interaction of the membrane protein with either albumin/albumin binding protein at the outer surface and/or cytoplasmic FABP at the inner surface of the plasma membrane may take place (Fig. 2). Indeed, Spitsberg et al34 recently reported evidence for protein-protein interaction between FAT/CD36 and HFABP. The abundance of the cytoplasmic FABPs, and their apparent presence in dependence on rates of cellular lipid utilization, would provide a large buffering capacity so as

Prostaglandins, Leukotrienes and Essential Fatty Acids (1997) 57(4 & 5), 373-378

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Cellular fatty acid-binding proteins

FA

Fi

Interstitial space 9.

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metabolism, signal transduction, etc. Fig. 2 Scheme of a hypothetical mechanism of cellular fatty acid uptake and the proposed role(s) of various proteins in this process. Abbreviations: FA, long-chain fatty acid; AIb.BP, albumin binding protein; membrane FABP, any membrane-associated fatty acidbinding protein (see Table), cytoplasmic FABP, any cytoplasmic fatty acid-binding protein (see Table). Dashed line, putative protein-protein interaction. tO p r e v e n t s u b s t a n t i a l f l u c t u a t i o n s i n n o n - p r o t e i n b o u n d fatty acid c o n c e n t r a t i o n s . I n s u m m a r y , t h e i m p o r t a n t n o t i o n arises t h a t l o n g c h a i n fatty acids are c o m i n u o u s l y e x p o s e d to specific p r o t e i n s w i t h w h i c h t h e y interact. This i n t e r a c t i o n n o t o n l y d r a m a t i c a l l y facilitates t h e t r a n s m e m b r a n e t r a n s l o c a t i o n ( m e m b r a n e - a s s o c i a t e d FABPs) of t h e s e fatty acids or t h e i r t r a n s p o r t i n a q u e o u s e n v i r o n m e n t s ( a l b u m i n , c y t o p l a s m i c FABPs), b u t m a y also m o d u l a t e t h e i r m e t a b o l i s m i n t h e cell. T h u s , w h e n e v a l u a t i n g t h e i n f l u e n c e s of fatty acids a n d m e t a b o l i t e s o n c e l l u l a r f u n c t i o n i n g , t h e s e i n t e r a c t i o n s h a v e to b e t a k e n i n t o a c c o u n t .

13.

14.

15.

16.

17.

18.

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