Physiological properties and functions of intracellular fatty acid-binding proteins

Biochimica et Biophysica Acta 1391 Ž1998. 287–306

Review

Physiological properties and functions of intracellular fatty acid-binding proteins )

Natalie Ribarik Coe, David A. Bernlohr

Department of Biochemistry, UniÕersity of Minnesota, 1479 Gorter AÕe., St. Paul, MN 55108, USA Received 20 November 1997; accepted 27 November 1997

Contents 1. Historical perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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2. Structural characteristics of the fatty acid-binding proteins . . . . . . . . . . . . . . . . . . . . . . .

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3. Intracellular lipid trafficking and the roleŽs. of FABPs . . . . . . . . . . . . . . . . . . . . . . . . .

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290 292 293 294 297

4. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

299 299

3.1. 3.2. 3.3. 3.4. 3.5.

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Adipocyte lipid binding proteinraP2 . . . . . . . . Keratinocyte lipid binding protein . . . . . . . . . . Brain lipid binding protein . . . . . . . . . . . . . . Liver lipid binding protein . . . . . . . . . . . . . . Heartrskeletal muscle fatty acid-binding protein .

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Corresponding author. E-mail: [email protected]

0005-2760r98r$19.00 q 1998 Elsevier Science B.V. All rights reserved. PII S 0 0 0 5 - 2 7 6 0 Ž 9 7 . 0 0 2 0 5 - 1

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N.R. Coe, D.A. Bernlohrr Biochimica et Biophysica Acta 1391 (1998) 287–306

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1. Historical perspective Identified 25 years ago as cytoplasmic factors capable of high affinity association with long chain fatty acids w1x, the intracellular fatty acid-binding proteins ŽFABPs. are one of the best-studied classes of polypeptides used to analyze protein–lipid interactions. Biochemical and biophysical studies have extensively examined the physical forces which govern FABP–lipid interactions utilizing a combination of X-ray crystallography, microcalorimetry, nuclear magnetic resonance, electron paramagnetic resonance, fluorescence and infrared spectroscopy w2–14x. In addition to the elaborate biophysical experimentation, work has also progressed steadily through the application of molecular biology techniques to assess functional properties of the proteins. This review discusses studies with cultured cell lines, primary cultured cells and FABP null animals that have enhanced our understanding of the potential functionŽ s. of this large protein family. Many proteins are capable of associating with lipids. Examples of these include integral and peripheral membrane proteins, the apolipoproteins of the serum, phospholipid binding proteins w15,16x the acyl CoA binding proteins w17,18x and membrane associated proteins that translocate intracellularly. The key features which distinguish the FABPs from this group are a conserved b-barrel fold, a 4 exonr3 intron gene motif, and a generally unimolecular association with monoacyl lipids such as fatty acids. In order to provide a concise analysis of FABP functional characteristics, it is necessary to limit the scope of this review. The family of cellular retinoid binding proteins, members of which form complexes with Vitamin A and its derivatives, has been reviewed recently

w19x. Since the structural and molecular biophysical properties of the fatty acid-binding proteins have also recently been thoroughly discussed w11,20,21x this review will only briefly address these aspects. Since over 20 proteins of this family have been characterized, Žmany of them only on the basis of cloned cDNAs or genes., we have limited our comments to the metabolic aspects of five well-characterized systems in which themes have developed toward understanding FABP functionŽ s.. The initial identification, cloning and characterization of these LBP will provide a historical perspective and will be briefly discussed. This review will focus on recent data that addresses the metabolic roleŽ s. for intracellular fatty acid-binding proteins characterized by the adipocyte lipid binding protein ŽALBP, aP2., the keratinocyte lipid binding protein Ž KLBP., the brain lipid binding protein ŽB-LBP. , the liver fatty acid-binding protein ŽL-FABP. and the heart fatty acid-binding protein ŽH-FABP.. These five members, excluding ALBP, are found in various lipid active tissues, not simply that tissue from which its name was originally derived ŽTable 1.. It is anticipated that by examining these members in greater detail, general inferences concerning the family and the reason for its abundance and diverse tissue expression can be formed. Reviews that provide additional perspectives and information on these and other LBPs are also available w49–52x. 2. Structural characteristics of the fatty acidbinding proteins The basic structural motif which characterizes the FABPs is the b-barrel w7–13x. The FABP b-barrel is formed by an array of 10 b-strands referred to as A

Table 1 Tissue distribution of representative members of the LBP family LBP

Tissue

References

ALBP KLBP BLBP L-FABP H-FABP

adipose adipose, brain, dorsal root ganglia intestine, kidney, lens, liver, mammary gland, skin, tongue brain, dorsal root ganglia, liver intestine, kidney, liver, pancreas, stomach adrenal, brain, heart, kidney mammary gland, ovary, pancreas, testis, thymus

w22,23x w24–29x w30–32x w33–36x w37–48x

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Fig. 1. Ribbon diagram of ALBP with bound oleate. Helices Žtop. are denoted by a I and a II. The ten anti-parallel b-strands are labeled bA through b J. Oleate ligand is depicted as a van der Waals surface. This model was generated using Insight II molecular modeling system from Biosym.

through J, each arranged in an antiparallel manner in which the adjacent strands hydrogen bond to each other to form a contiguous b-sheet ŽFig. 1. . An interruption of the hydrogen bonding network occurs between b-strands E and F where the distance between the main chain atoms is too great for hydrogen bonding. In this case, side chains intercalate to form a closed system. In the FABP fold, the first and tenth strands hydrogen bond to each other, forming an uprdown b-cylinder with a characteristic twist. The ends of the cylinder are closed off, at one end by side chain packing, at the other by a helix-turn-helix motif formed between b-strands A and B. The helices are referred to as a I and a II. In most views of the protein, the helix-turn-helix is oriented towards the top as shown in Fig. 1, suggesting that the helixturn-helix caps the structure. The b-structure takes on the appearance of a b-barrel due to the closure of the ends and the concomitant formation of an interior cavity. A key feature of the FABP fold is the large, interior water-filled cavity. The interior surface of the

cavity is lined by both polar and hydrophobic amino acids whose sidechains extend into the cavity w11x. The large variability in amino acids which line the cavity is consistent with the wide variability in amino acid identity between FABPs Ž 20–70%. , and the large differences in interior cavity shape. The cavity volume of individual FABPs ranges from 300 to 700 ˚ 3. It should be stressed that although the cavity is A quite large, the volume it occupies is only about 5% the total volume of the protein. Hence, although FABPs are characterized as b-barrels, the accessible volume of their interior cavity is quite small. Ligand binding occurs within the cavity, where a typical ligand occupies one-half to one-third of the cavity volume. Aside from the liver FABP, most FABPs bind a single molecule of fatty acid per molecule of protein. Liver FABP, the family anomaly, is able to bind two ligands simultaneously w52x. For most FABPs, the fatty acid carboxylate is oriented inward, coordinated through electrostatic interactions with arginine and tyrosine residues. For the liver FABP, one bound fatty acid is oriented inward while

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the second is oriented with its carboxylate facing outwards w53x. X-ray analysis of apo- and holoprotein forms of several FABPs reveals crystallographically ordered water molecules within the cavity, some of which are in van der Waals contact with the bound fatty acid w11x. Ligand binding occurs coincidentally with the loss of disordered, but typically not ordered, water molecules from the cavity, although this point has not been rigorously examined. Ligand movement to and from the cavity occurs via a small opening, referred to as the portal, formed by helix a-II, and loops connecting b-strands CrD and ErF. The opening is small enough to accommodate some fatty acids, but not other lipids such as the anthroyloxy-derivatized fatty acids, which have been used to monitor ligand binding. In addition, large bulky lipids and sulfhydryl-directed reagents shown to rapidly modify cavity cysteine residues readily gain access to the cavity. These results suggest that the portal is dynamic in nature and exhibits conformational flexibility to allow ligand access to the cavity. Hodson and Cistola w12x have provided insight into such conformational flexibility by determining the solution structure of apo and holo IFABP using multidimensional NMR. Their results suggest a disordered ‘open’ portal in the apo structure in contrast to a more highly ordered ‘closed’ holo-structure portal. Similar conclusions have been drawn by Ory et al. w54x from an analysis of mutants of ALBPraP2 at the portal region. A careful comparison of the binding specificity and affinity of several FABPs has been carried out by Richieri et al. w13x. Using a fluorescence-based assay involving acrylodan-derivatized intestinal FABP ŽADIFAB., the thermodynamic parameters associated with lipid binding have been determined for several FABPs. Although experimental details vary from protein to protein, in general, the enthalpic considerations for binding far outweigh the entropic contributions w55x. Typically 60–80% of total binding energy is derived from enthalpic factors. These enthalpic factors arise from a combination of electrostatic interactions at the head group plus London forces along the acyl chain Žvan der Waals interactions.. However, in certain mutant FABPs, entropic effects can play a major role in affecting overall binding thermodynamics. In general, the FABPs associate most avidly with long chain polyunsaturated fatty acids with a 1:1

stoichiometry, yet L-FABP can bind two ligands simultaneously w53,56x. The measured dissociation constants vary between 50 nM and 5 m M w13,57–59x as the length of the lipid is shortened or the degree of unsaturation reduced, respectively. In addition, certain FABPs such as L-FABP, ALBP and KLBP, are capable of binding hydrophobic xenobiotics Žw60– 64x.. This observation is consistent with the hypothesis that the physiological function of FABPs may be broader than just fatty acid binding.

3. Intracellular lipid trafficking and the role(s) of FABPs 3.1. Adipocyte lipid binding proteinr aP2 The adipocyte lipid binding protein ŽALBP or aP2. cDNA was originally isolated from fat cell cDNA libraries by a number of laboratories in the mid 1980s w22,65x. Expression distribution studies showed that ALBPraP2 mRNA is confined almost exclusively to adipose tissue and adipogenic cell lines Ž Table 1. w22,23x. Estimates based on total cellular protein have indicated that ALBPraP2 is abundantly expressed in 3T3-L1 adipocytes and adipose tissue, constituting 1–3% of total soluble protein by mass. The ALBPraP2 gene has been localized by fluorescence in-situ hybridization techniques to murine chromosome 3, approximately 2.2 cM from the carbonic anhydrase gene w37x. The human ALBPraP2 gene localizes to chromosome 8 at position 8q21.3– q22.1 w66x. Interestingly, there exists an extended synteny between human chromosome 8 and murine chromosome 3 in this region. For example, human carbonic anhydrase is localized to chromosome 8q13–q22. Moreover, the human myelin P2 gene also localizes to this region Ž8q21.3–22.1. . Despite the similarity in chromosome position between human aP2 and P2, this does not appear to be the general case. The human genes encoding the liver, intestine, ileum, and heart lipid-binding proteins are found on chromosomes 2, 4, 5, and 1 respectively w67–71x. The ALBPraP2 basal promoter is characterized by a number of specific promoter elements including an AP-1 site w72–75x. Cook et al. w76x and Herrera et al. w77x have shown that the ALBPraP2 promoter Žre-

N.R. Coe, D.A. Bernlohrr Biochimica et Biophysica Acta 1391 (1998) 287–306

gion y248 to q21. which contains the AP-1 site, is responsive to cAMP and a mutation in the AP-1 sequence abolishes responsiveness to cyclic nucleotides. In addition to the AP-1 site, the ALBPraP2 basal promoter also includes a TATA box, CCAAT box and a CCAATr enhancer binding protein ŽCrEBP. site. CrEBP binds just upstream of the AP-1 site and is capable of transactivating the ALBPraP2 gene w78x. Insulin, through activation of CrEBPa , stimulates ALBPraP2 transcription. Fat specific expression of ALBPraP2 in terminally differentiated adipocytes requires the presence of an enhancer at y5.4 kb w79–81x. The 518 bp enhancer is necessary and sufficient to confer fatspecific expression to reporter genes in transgenic mice. Within this enhancer region reside several adipocyte response elements ŽAREs. which are bound by adipocyte regulatory factors Ž ARFs. w80,82x. Certain AREs have been characterized as peroxisome proliferator activated receptor responsive elements ŽPPREs. andror direct repeat ŽDR-1. sites. ARF 6 is a heterodimer comprised of a peroxisome proliferator activated receptor Ž PPARg . and retinoid X receptor ŽRXR a . w83x. PPARs constitute a family of transcription factors whose mammalian isoforms are a , d and g Žfor reviews see w84,85x.. PPAR a is most abundant in liver although also found in kidney, heart and brown adipose tissue. The d isoform ŽNUC-1 or fatty acid activated receptor, FAAR. is most widely distributed, found in a variety of tissues including heart, kidney, brain, intestine, muscle, spleen, lung and adrenals. The g isoform is the most highly restricted in its expression pattern. Alternate promoter usage coupled with differential mRNA splicing results in two closely related PPARg isoforms which differ by only 30 amino terminal amino acid residues. The g 1 isoform is found in adipose tissue and to a lesser extent in muscle, liver, kidney and heart. The g 2 isoform is found almost exclusively in white adipose tissue. Prostaglandins, metabolites of arachidonic acid, and other polyunsaturated fatty acids, have been suggested to serve as natural ligands for PPARs. For example, 15-deoxy D12,14-prostaglandin J2 , can activate the PPARg-RXR a complex to promote adipogenesis and elevate ALBPraP2 mRNA levels w86x. The reader is referred to excellent, detailed reviews describing the regulation of adipogenesis w87–89x.

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ALBPraP2 is able to bind 15-deoxy-D12,14-prostaglandin J2 and certain thiazolidinediones Že.g., LY171883. w64x. Under conditions of extremely high fatty acid levels or with certain xenobiotics, ALBPraP2 expression is upregulated. The resulting increase in ALBPraP2 protein level, as will be described below, is likely to lower the cellular free fatty acid level and indirectly decrease ALBPraP2 expression. To determine if ALBPraP2 is actively involved in fatty acid uptake or the intracellular solubilization of exogenous fatty acids, 3T3-L1 adipocytes were incubated with a radioactive photoactivatable fatty acid analog, flashed with ultraviolet light, and the crosslinked products analyzed. As shown by autoradiography and immunoprecipitation, ALBPraP2 binding to the probe was dependent on both time and temperature and mimicked the pattern of 3 H-oleic acid uptake by 3T3-L1 adipocytes, pointing to a functional link of ALBPraP2 to fatty acid trafficking w90x. These observations concomitantly suggest an autoregulatory loop exists in control of ALBPraP2 expression ŽFig. 2.. As generically depicted in Fig. 2, polyunsaturated fatty acids Ž PUFAs. are bound by LBP upon entering the cell. LBPs may direct fatty acids to appropriate cytosolic or membrane-bound proteinsrenzymes for metabolic activation. The sub-

Fig. 2. Polyunsaturated fatty acid control of gene expression. Lipid binding proteins ŽLBP. are depicted as binding a polyunsaturated fatty acid ŽPUFA. and facilitating their metabolism via an enzyme ŽE. to a lipophilic second messenger. Such second messengers associate with peroxisome proliferator activated receptors ŽPPAR. which allows for dimerization with retinoid X receptors ŽRXR. to activate LBP gene expression, thereby increasing cellular lipid binding protein levels.

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sequent activation of PPAR by the bioactive fatty acid results in the activation of gene expression. Unlike fatty acids, various exogenous ligands such as thiazolidinediones or fibrates do not require further modification and are likely to interact with and activate PPARs directly. Hotomisligil et al. w91x have constructed the first transgenic mice bearing a targeted gene disruption of a FABP allele. This line of mice, null for ALBPraP2, showed no obvious phenotype relative to their wildtype littermates when fed a standard lab chow diet containing 4% fat. The animals exhibit no anatomical or metabolic abnormalities and are fertile. At the molecular level, such null mice partially compensate for the loss of ALBPraP2 by increasing the expression of the mRNA and protein for the keratinocyte lipid binding protein Ž KLBP. . In contrast to results obtained in the above low fat Ž4%. studies, northern analysis of animals placed on a high fat Ž 40%. diet demonstrated a decrease in the expression of tumor necrosis factor-a ŽTNF-a . in the adipose tissue of ALBPraP2 disrupted mice compared to wildtype mice. One action of TNF-a in vivo is indirect inhibition of insulin receptor tyrosine kinase autophosphorylation and substrate phosphorylation. Furthermore, although all mice gain weight on this high fat diet, standard intraperitoneal insulin and glucose tolerance tests revealed that unlike the heterozygous and wildtype mice, aP2 disrupted mice did not become insulin resistant. Therefore, the lack of insulin resistance in null animals correlates with the absence of TNF-a expression. These results suggest that ALBPraP2 may mediate the transcriptional response of the adipocyte to lipid levels. Intracellular fatty acid-binding proteins may be cellular sensors of lipid levels, capable of affecting cellular metabolism in response to nutrient abundance or absence. Although northern analysis of various murine tissues revealed that ALBPraP2 is exclusively expressed in white adipose tissue, additional lipid binding proteins have been detected in brown adipose tissue. Two isoforms of a brown adipose lipid binding protein have recently been identified w92x. The primary roles of brown and white adipose tissue are quite different yet both cells actively synthesize triacylglycerols from fatty acids. White adipose acts as an energy depot and hydrolyzes its triacylglycerol stores in response to lipolytic stimuli, providing fatty

acids destined for metabolic use in other cell types. Brown adipose tissue responds similarly to epinephrine or norepinephrine stimulus, but hydrolyzed fatty acids are oxidized locally. It is interesting to speculate that brown fat lipid binding proteins may facilitate the delivery of fatty acids to the mitochondria for such oxidation. 3.2. Keratinocyte lipid binding protein The cDNA for the keratinocyte lipid binding protein ŽKLBP, mal-1. was originally isolated and cloned from phorbol ester treated murine skin in the mid 1980s w93x. The upregulation of KLBP mRNA in several murine papillomas and carcinomas was subsequently demonstrated w93x. Putatively initiated basal cells, induced by serum andror administration of a phorbol ester Ž12-O-tetradecanoylphorbol-13-acetate. upregulated KLBP mRNA and overexpression of KLBP appeared to be neoplasia-linked in these earlier studies. Northern analysis revealed low levels of KLBP mRNA in two growing keratinocyte lines ŽHEL30, HDII. w24x, normal epidermis, mammary gland, tongue epithelium, brain, intestine, liver, kidney and adipose ŽTable 1. w25x. The early 1990s brought documentation of two additional LBP isolated from human skin cells. The epidermal fatty acid binding protein ŽE-FABP., purified from human keratinocytes w26,94x, is the human homologue of murine derived KLBP. Additionally, Madsen et al. w95x cloned and isolated a LBP up-regulated in psoriatic skin cells Ž PA-FABP.. Immunohistological studies examining E-FABP expression in psoriatic skin, support the notion that E-FABP and PA-FABP are in fact the same protein w96x. Additional lipid binding proteins that are likely to be equivalents of KLBP have been isolated from rat lens ŽLELBP., bovine lens Ž LP2. and perhaps chick retina w27,28,97x. Evidence from various laboratories implicates an associative role between KLBP expression and cellular Žkeratinocytes, lens epithelial cells. differentiation w93,96,28x. KLBP is expressed at basal levels in 3T3-L1 preadipocytes, and similarly to ALBPraP2, its expression increases dramatically upon differentiation. Ibramhimi et al. w98x have shown that KLBP is upregulated in Ob 1771 preadipocytes upon thiazolidinedione or fatty acid treatment. Topical retinoic

N.R. Coe, D.A. Bernlohrr Biochimica et Biophysica Acta 1391 (1998) 287–306

acid treatment results in upregulation of PA-FABP in human skin w99x. KLBP also appears to be upregulated in response to cellular stress w29x. Recombinant KLBP was expressed and purified from Escherichia coli and its ligand binding properties assessed in vitro. Extensive ligand binding analysis established KLBP as a fatty acid-binding protein with minimal affinity for retinoic acid, retinol w57x, squalene or cholesterol w94x. KLBP has high affinity for medium to long chain fatty acids with various degrees of saturation w57,94x. The necessity of a lipid binding protein in keratinocytes may be directly related to maintenance of the skin-lipid barrier that is in place to prevent undue transepidermal loss of water. KLBP can also bind eicosanoids such as 5Ž S .- and 15Ž S .- hydroperoxyeicosatetraenoic acid Ž HPETE. with reasonable affinities w57x. 15-lipoxygenase, the rate limiting enzyme responsible for the conversion of arachidonic acid to 15-HPETE, was recently detected by northern analysis in human cultured keratinocytes w100x. Eicosanoids, such as hydroxyeicosatetraenoic acids ŽHETEs., thromboxanes and prostaglandins, are associated with the inflammatory and immune response systems, and KLBP may be involved in mediating this response in keratinocytes. Adipose tissue harbors two lipid binding proteins, ALBPraP2 and KLBP. ALBPraP2 is highly expressed while KLBP is expressed at barely detectable levels. A disruption in the structural gene of ALBPraP2 in C57Blr6J mice results in a marked increase in KLBP expression, partially compensating for the lack of the abundant ALBPraP2. The expression of KLBP is increased approximately 14-fold in ALBPraP2 disrupted mice when compared to their wildtype counterparts w101x. Although the null animals upregulate KLBP markedly, the total fatty acidbinding protein level Ž ALBPraP2 plus KLBP. in the fat from such animals is only 10% that of wildtype mice. In turn, the intracellular levels of free fatty acids increase in the ALBPraP2 disrupted mice compared to their wildtype counterparts. This implies an inverse proportionality between the level of LBP in adipose tissue and the intracellular fatty acid level. These observations support the hypothesis that LBPs are not simply buffers that prevent the high intracellular level of fatty acids in adipose tissue from disrupting cell membranes, but may in fact be shuttling fatty acids to specific targets within the cell.

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3.3. Brain lipid binding protein The search for a fatty acid-binding protein in the cytosol of brain was fueled by the observation of Rhoads et al. w102,103x that sodium-dependent uptake of neurotransmitter amino acids by synaptosomes can be inhibited by oleic or palmitic acid and that this inhibition can be abolished by bovine serum albumin ŽBSA. w104x. These results suggested that fatty acids could be neuromodulatory and that LBPs may regulate such processes. In 1984, Bass et al. w105x utilized gel-filtration chromatography to fractionate rat brain cytosolic proteins. The 12–15 kDa pool was able to bind w 14 Cxoleic acid and was capable of inhibiting Naq-dependent amino acid uptake of neurotransmitter amino acids. Furthermore, oleic, palmitic and stearic acids copurify in this fraction. These findings mirror the observed inhibitory effect of oleic acid on Naq-dependent amino acid uptake and the corresponding stimulation by a lipid binding protein. This suggests a regulatory role for brain lipid binding protein in amino acid uptake. Utilizing similar chromatographic techniques, Senjo et al. w106x also isolated and characterized a rat brain cytosolic FABP. Competitive displacement assays revealed that the isolated protein can bind palmitoyl-and oleoyl- CoA as well as fatty acids w106x. With the availability of clones and antibodies to various FABPs, recent studies have shown that brain lipid binding protein ŽBLBP. is one of three lipid binding proteins located in neural tissue w107x. In addition to BLBP, brain cytosol contains heart Ž H-FABP. and keratinocyte Ž KLBP. lipid binding proteins w107,108x. The level of BLBP in brain is 10-fold higher than that of H-FABP in brain and is estimated to constitute 0.1% of all the brain cytosolic proteins w108x. The BLBP cDNA and gene have been cloned from a number of rodent sources w30–32x. A 1.6 kb 5X fragment upstream of the transcription start site for BLBP is sufficient to drive cell specific expression of BLBP w109x. Notable features of the available promoter sequence are a TATA box Žy30. and a putative Pax gene site Žy548 to y565.. Feng and Heintz w109x have identified three cis acting elements that appear to drive expression of BLBP in specific cell types. A radial glial element ŽRGE. between y800 and y300 bp is necessary for expression in

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this tissue type. Similarly, a dorsal root ganglion element ŽDRGE. has been discovered to lie between y800 and y1200 bp. In addition to these apparently positive regulatory elements, a negative regulatory element, located between y1.2 and y1.6 kb, appears to prevent the premature expression of BLBP in dorsal spinal cord w109x. The availability of BLBP cDNA facilitated extensive expression distribution studies. In addition to brain, high levels of rat BLBP mRNA have been shown to be expressed in liver and the MOCH-1 murine oligodendrite Žglial subclass. cell line w30x. In-situ hybridization histochemistry revealed high levels of BLBP in fiber tracts of day 11 rat brain. Specifically, the optic nerve, corpus callosum, external and internal capsule, fimbria, cingulum and lateral olfactory tract were labeled by the BLBP antisense probe w30x. Expression of BLBP protein and its mRNA was also verified in the ganglia of spinal cord and cranium as well as the olfactory nerve layer ensheathing cells in embryonic day 11 and adult mice w104x. BLBP mRNA is highly expressed in the subependymal layer of the rat infant forebrain, which further supports a role for BLBP in glial and neuronal development w30x. BLBP, in addition to its high expression in the developing cerebellum, is also associated with the initial steps in neuron differentiation in the cortex and in radial glial cells of the developing spinal cord w110x. Studies by Kurtz et al. w32x found that BLBP is expressed in radial glial cells as well as immature astrocytes. Incubation of granule and astroglial cells with anti-BLBP antibodies had no impact on reaggregation of the cells but did prevent the normal extension of glial fascicles. The anti-BLBP antibodies effectively interfered with neuronal glial extension w110x. This work, accompanied by elaborate expression studies, clearly shows that BLBP is involved in the differentiation of glial cells, allowing for proper neuronal migration w32,110x. High concentrations of docosahexaenoic acid ŽDHA; C22:6. localized to the brain are associated with, and necessary for, proper neuronal development w111,112x. The concentration of DHA in rat brain phospholipids is substantially higher than that of plasma lipids w113x, implying that a brain specific mechanism may be in place to selectively internalize

andror retain DHA. BLBP may be central to this process as the recombinant protein binds DHA very tightly Žapproximate K d , 10 nM. and has lower affinities for oleic and arachidonic acids, 440 and 250 nM respectively w114x. 3.4. LiÕer lipid binding protein L-FABP was initially isolated from rat liver cytosol through a combination of gel filtration and affinity chromatography w33x and has since been identified in a variety of cell and tissue types including stomach, pancreas w34x, intestine w35x and kidney w36x ŽTable 1.. Cloning of the gene encoding L-FABP allowed for extensive genetic analysis of its promoter w115,116x. Proper tissue expression distribution of L-FABP is conferred by nucleotides y4000 to q21 w117x. More specifically, the region spanning nucleotides y132 to q21 allows for proper expression in certain but not all specific cellular regions of the intestine, liver and kidney. Overall L-FABP expression is decreased in fasted rats w35x. Cis-acting suppressors and activators of L-FABP in the kidney and colon are located in the regions from y4000 to y1600 and y596 to y351, respectively. Additional sequence is required for proper suppression of L-FABP expression in specific epithelial cells of the intestine and kidney. The LFABP promoter contains a peroxisome proliferator response element ŽPPRE. which is located at nucleotides y75 to y66 w117x. L-FABP mRNA levels also increase in the presence of fatty acids, dicarboxylic acids and retinoic acid as well as the mitochondrial b-oxidation inhibitor, 2-tetradecylglycidic Ž TDGA . w118 – 121 x. Similar to BLBP and ALBPraP2, the promoter region of L-FABP contains three CrEBPa domains w117x. Extensive ligand binding analysis of native and recombinantly expressed L-FABP has closely accompanied the search for a functional role of this well characterized lipid binding protein. A number of potential ligands have been tested and documented ŽTable 2., including heme, acyl- CoAs, fatty acids, lysophospholipids, peroxisome proliferators and eicosanoids w56,60–63,122–126x. Unlike other members of the fatty acid-binding protein family, L-FABP is capable of binding two ligands simultaneously w53,56x. In addition to the aforementioned ligand

N.R. Coe, D.A. Bernlohrr Biochimica et Biophysica Acta 1391 (1998) 287–306 Table 2 Ligands and correlative functions of the liver lipid binding protein

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classes, L-FABP can interact with a variety of synthetic ligands such as Bexafibrat, WY-14,643, tiadenol, and warfarin as well as certain carcinogens w60,127x. L-FABP does not bind retinol, retinoic acid, clofibric acid w124x or cholesterol w56,128x. Current research continues to focus on the binding properties of L-FABP and its ability to deliver ligands to cellular enzymes or membranes. L-FABP may aid acyl-CoA synthetase by allowing the substrate to become more accessible to the enzyme w129x. The effective fatty acid diffusion rate constant, as measured by fluorescence recovery after photobleaching, was 65% greater in female than in male hepatocytes w130x which reflects the 20% increase in L-FABP expression in female versus male rat livers w33,130x. A time and temperature dependent labeling and solubilization by L-FABP of a fatty acid analog mimicked the uptake pattern of 3 H-oleic acid by hepatocytes w131x. To help further elucidate L-FABP function, many laboratories have assessed the effects of L-FABP on enzyme function and overall lipid composition. LFABP can stimulate the synthesis of phosphatidic acid ŽPA. from its precursor, sn-glycerol 3-phosphate, in rat liver microsomes w132x and the addition of L-FABP to rat liver mitochondrial preparations will enhance lysophosphatidic acid ŽLPA. release from this cellular compartment w133x. Interestingly, L-FABP promotes the production of PA from LPA in microsomes but greatly reduces the amount of PA formed in mitochondria w133x. Incubation of L-FABP with either mitochondria or microsomes will result in an increase in glycerophosphate acyltransferase activity in these compartments. L-FABP may act to modulate enzyme activity by causing alterations in lipid levels. In vitro transfections of L-FABP into fibroblasts doubled the levels of unesterified fatty acid, esterified neutral lipids and esterified phospholipids w134x. L-FABP expression correlates with an increase in esterification of cholesterol and synthesis of phospholipids which will in turn, cause an increase in membrane fluidity w135x. The changes in membrane composition andror fluidity, as seen in L-FABP transfection studies, may directly affect certain hepatic enzymes. A significant drop in NarK-ATPase activity occurred in liver cells transfected with L-FABP cDNA. As argued by the authors, this decrease may be due to a change in the

cholesterolrphospholipid ratio in membranes isolated from control and transfected cells as well as an increase in the fluidity of the membranes from transfected cells as measured by fluorescence polarization w136x. Similar transfections will also cause re-distribution of sterol in the exo- and cytofacial leaflets of the plasma membrane and the percentage of sterol in the exofacial leaflet doubles in the transfected cells w137x. This doubling is accompanied by an increase Žapproximately 20%. in lipid uptake. Transfection studies have also been used extensively to examine the relationship between L-FABP expression and mitogenesis in liver cells. Mitogenesis can be induced by peroxisome proliferators Ž e.g., WY-14,643. in rat hepatocytes expressing L-FABP sense DNA, but not in cells transfected with L-FABP antisense DNA w138x. The mitogenic properties of peroxisome proliferators in these studies were dependent on L-FABP expression. DNA synthesis could be stimulated more intensely in L-FABP expressing cells as compared to non-expressing control cells and this stimulation was enhanced by unsaturated but not saturated fatty acids w139x. An extensive review of L-FABP and its functional implications in mitogenesis is available w140x. The intracellular distribution and level of L-FABP is affected by physical growth stages. Hypophysectomy of male rats caused a decrease in L-FABP expression that can be counteracted by injection of growth hormone and both sexes have a higher expression of L-FABP during growth stages, specifically 4–6 months, than at 12–13 months w141x. LFABP is expressed at high levels in fetal liver but much lower in newborns, infants, and adults. Pregnancy and lactation, however, will result in a doubling of L-FABP in rats w142x. L-FABP, isolated from adult tissue, occurs in several forms that are characterized by their respective isoelectric points Žp I s 5.0, 6.0, 7.0, 7.1.. The p I of a particular L-FABP species is affected by 1. glutathione modification of Cys 69, 2. cysteinylation of Cys 69 or 3. identity of amino acid Asp or Asn 105 w143x. Glutathione modification of L-FABP Ž LFABP-SSG. negatively effects the ability of the protein to bind unsaturated fatty acids. The K d values of oleic, linoleic, and arachidonic acid increase approximately 40% for L-FABP-SSG compared to the unmodified form. This S-thiolation appears to have no

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effect on the dissociation constants for saturated fatty acids w144x. The authors estimate that 20% of L-FABP has a mixed disulfide cysteine ŽCys 69. form. This subspecies is more susceptible to degradation. The authors speculate that proteolysis of this modified form may be responsible for the diurnal fluctuations in L-FABP levels. L-FABP levels peak at 7 mgrg liver in the middle of the dark cycle and drop to 1 mgrg liver as the light stage begins w145x but evidence against the existence of diurnal fluctuation has also been documented w146x. 3.5. Heart r skeletal muscle fatty acid-binding protein Heart skeletal muscle fatty acid-binding protein ŽH-FABP., as its name projects, has been purified and in some cases, sequenced, from several sources including heart w38,39x and skeletal muscle w39,40x, as well as kidney, brain, testes, ovaries, pancreas, thymus and adrenal tissue w67,40,42–44x. Unlike certain LBPs that are expressed in either one or a small number of tissue types, H-FABP is widely distributed ŽTable 1. . It should also be noted that H-FABP has been documented as a nuclear, as well as a cytosolic protein w147x. Modifications of H-FABP include dimerization through a disulfide bond linkage w148x and tyrosine phosphorylation upon insulin treatment w149,150x. Recent advances have shown striking similarities between H-FABP and the mammary-derived growth inhibitor Ž MDGI. protein. Both proteins are highly expressed in the mammary glands of lactating micerrats w45,46x and eventual sequence alignment showed 95% similarity between the two w47x. MGDI is in fact a mixture of two LBPs, heart and adipocyte w151x. Common convention treats MGDI and H-FABP as interchangeable proteins. Two isoforms of cardiac H-FABP, varying by one amino acid, are coded by different mRNAs w152x. The human H-FABP gene has been localized to chromosome 1p32–1p33 w153x. The mammary derived growth inhibitor protein, as its name implies, is involved in cell growth, or lack thereof. Incubation of carcinoma cells with MDGI will result in growth inhibition from the stationary stage and is accompanied by a decrease in thymidine incorporation w47x and mRNA expression of certain transcription factors such as c-fos, c-myc, and c-ras w154x. As would be expected, similar results were

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seen with H-FABP. Incubation of H-FABP with primary culture mammary cells led to an inhibition of DNA synthesis in alveoli, ducts, and ductules. Interestingly, this inhibition was accompanied by an increase Ž over 250%. in the mRNA levels of the differentiation markers b-casein and whey acidic protein w155x. As experiments documented with MDGI would elucidate, endogenous H-FABP expression increases 60-fold upon differentiation of C 2 C 12 myoblasts to myotubes w156x. Incubation of myocytes with exogenous H-FABP will cause an increase in cellular surface area and nearly a 120% increase in protein synthesis with a corresponding increase in c-jun protein levels w157x. Immunohistochemical comparisons of fetal, postnatal, and adult brain H-FABP expression support a role for H-FABP in development w48x. Analysis of H-FABP expression in the pre- and post-natal rat ovaries revealed a positive correlation between protein and steroid hormone levels w158x. Expression levels of H-FABP mRNA throughout pre- and postnatal development vary in the different tissues in which it is expressed w37,40x. For example, in heart tissue, H-FABP increases steadily from prenatal day 19 until birth and then continues to rise until postnatal day 14. Certain tissues Ž e.g., red skeletal muscle, pancreas, thymus, ovaries. express H-FABP exclusively in the adult Ž not fetal. tissue w44x. Extensive analysis of H-FABP distribution in specific cells has allowed for the classification of tissue types in which H-FABP is expressed. Zschiesche et al. w159x identify H-FABP expression with cells that 1. carry out extensive b-oxidation Ž e.g., myocardium muscle, red vastus., 2. maintain synthesis of steroids Že.g., adrenal cortex. andror are involved in 3. resorption Že.g., salivary gland ducts. . In support of a direct relationship between active b-oxidation and H-FABP levels, Vork et al. w160x have compiled evidence from several laboratories and provided theoretical calculations implicating H-FABP as a critical component of fatty acid transport in the cardiomyocyte, specifically from the sarcolemma to the inner mitochondria. H-FABP can bind acylcarnitines and appears to modulate acylcarnitine movement from the cytosol to the outer mitochondrial membrane for subsequent b-oxidation w161x. In conjunction, a strong positive correlation exists between exercise and H-FABP expression. H-FABP increases

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when b-oxidation increases: during flight in locust muscle w162x, upon electrostimulation in the rat anterior tibialis muscle, and after 6 weeks of treadmill running in rat plantaris muscle w163x. H-FABP is expressed at higher levels in red than in white gastrocnemius muscle w40,42x and there is an increase of H-FABP in the outer layer of the heart ventricle Ž5–15%. compared to that expressed in the inner layer w164x. Endurance and administration of testosterone increased the levels of H-FABP in heart approximately 30%. Simultaneous training and testosterone treatment resulted in a 53% increase in HFABP in heart w165x. The role of H-FABP in ‘energy production’ and oxidation levels are often interconnected w166x. A correlative relationship between HFABP and b-adrenergic receptor supersensitivity reduction has also been drawn w167x. Experiments have been completed to assess the ability of H-FABP to modulate fatty acid trafficking. An increase in the oleate diffusion coefficient was measured in cytosol containing H-FABP compared to control cytosol containing no LBP w168x although this data has been challenged on the basis of technical considerations w169,170x. It can be argued that the low endogenous expression of H-FABP in endothelial cells implies that it may not be a major constituent in fatty acid uptake across the plasma membrane w171x, but H-FABP promotes an increase in incorporation of oleoly-CoA and palmitoyl-CoA into phosphatidylcholine and lysophosphatidic acid, respectively, correlating with an increase in Vmax of monoacylglycerophosphorylcholine and glycerol acyltransferase w172x. These data further support the speculation that LBPs are involved in lipid trafficking and modulateraffect specific target enzymes involved in lipid metabolism. The expression pattern of a fatty acid translocase ŽFAT. speculated to be involved in fatty acid transport is similar to that for H-FABP in muscle Žextensor digitorum longus, soleus. and heart Žadult, fetal, cardiomyocytes. w173x. Developmental expression of both H-FABP and FAT in heart is also quite similar w173x and a heart homologue to the adipose FAT has recently been isolated from heart membranes w174x. H-FABP and heart-FAT may synergistically modulate fatty acid uptake andror transport. H-FABP expression has been assessed during stress-related states Ž e.g., dietary, diabetic, ischemic. .

In animals fed a high fat diet, H-FABP expression will increase in mammary tissue, but not in heart or gastrocnemius muscle w46,163x. H-FABP expression has also been shown to increase during fasting with a corresponding increase in its rate of transcription w175x. Several laboratories have examined the role or connectivity of LBPs, specifically H-FABP and ALBP Žpreviously reviewed. , with the diabetic state. Type I diabetes is commonly mimicked in laboratory animals by streptozotocin treatment. H-FABP mRNA and protein increase in streptozotocin-induced diabetes is not due to an increase in the transcriptional rate but perhaps to an increase in mRNA stability w175x, whereas aortic H-FABP mRNA levels, like ALBP, decrease in response to streptozotocin-induced diabetes w176x. Similarly to ALBP, aortic HFABP levels will then return to normal upon insulin treatment w176x. A streptozotocin-induced increase in H-FABP expression in heart tissue does not effect local fatty acid oxidation capacity w177x. Rats with non-insulin-dependent diabetes Ž compromised glucose oxidation., have a significant increase in HFABP levels compared to normal rats that is accompanied by an increase in 3-hydroxylacyl-CoA dehydrogenase activity and a decrease in fructose-6-phosphate kinase activity w178x. This data provides yet another example of the inter-relationship between FABPs and subsequent modification of a subset of enzymes directly involved in lipid metabolism. In addition to dietary and diabetic states, the potential effectrrole of H-FABP in the ischemic state has also been examined. Interestingly, H-FABP is very effective at ‘scavenging’ free radicals, specifically Oy 2, and hydroxyl and hypochlorite radicals w179x. This scavenging ability of H-FABP may be important in situations in which harmful free radicals are prevalent, such as the ischemic state w177x. H-FABP retains 86% or 73% of its fatty acid binding capacity after pre-incubation with Oy 2 or hydroxyl radicals, respectively w180x.

4. Concluding remarks The number of intracellular fatty acid-binding protein multigene family members now numbers nearly 20. This review has focused on a small number of well characterized members of the family. An exami-

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nation of the putative roleŽ s. of the various members reveals certain themes that are common to most members of the family, including: high abundance in the cytosol of many cell types, regulated expression patterns confined to cell types with active fatty acid flux, and up-regulation of expression under conditions of high metabolic activity and demand. The abundance of intracellular fatty acid-binding proteins has almost exclusively been determined by immunochemical methods. Surprisingly, despite the high degree of primary sequence and tertiary structure conservation, polyclonal antibodies to individual family members are remarkably specific with little overlap in specificity. Using such antibodies, intracellular FABPs are most abundantly found in the cytosolic fraction of cells. However, due to their small size, FABPs are clearly capable of being located within the nucleus. In fact, several reports of L-FABP translocation to the nucleus suggest that the FABPs may be more dynamic carriers of hydrophobic ligands than previously considered. The intracellular flux of metabolites between intracellular locales, including the nucleus, is clearly a function for FABPs that needs to be carefully considered. The high concentration of FABPs, coupled with their strong affinities for fatty acid, implies that most, if not all, free fatty acids within the cell are in equilibrium with a FABP binding site. This speaks directly to the metabolic roles for FABPs as either buffers or shuttles. Examination of a number of different FABPs suggests that different proteins may play different roles. For example, L-FABP may buffer fatty acids while the H-FABP may function as a shuttle of hydrophobic ligands between locales. Docking partners for those proteins that function as shuttles, whether intracellular proteins or membranes, remain unidentified. The regulated expression patterns of FABP genes is a matter of considerable scrutiny. While the gene structures for FABPs imply convergent evolutionary origin, the tissue and cell-specific transcriptional elements which control their expression are just beginning to be characterized. The roleŽ s. of PPARs and CrEBPs in regulation of the expression of FABP genes appears to be a common theme. Such results suggest that the FABPs, as a class, may be targeted for metabolic activation through the concerted interplay of these transcription factors and the ligands

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which activate them. A feedback loop appears to exist for many FABP genes, whereby a hydrophobic ligand bound by an FABP may be a prohormone stimulus for a transcription factor, which then activates FABP expression ŽFig. 2. . FABPs may therefore be either positive or negative factors in FABP expression, depending upon the ligand, the cellular context of expression, and cell-specific transcription factors. This will be particularly important for understanding the developmental expression of many FABP types. Although this review did not focus on structural aspects of FABPs it is clear that advances in FABP research must continue to integrate structural information with metabolic data from laboratories examining FABP function. It is likely that within the next few years our understanding of these proteins, their structure-function relationships, and relationships to metabolic disease will increase markedly.

Acknowledgements The authors would like to thank the members of the Bernlohr laboratory, particularly Melanie Simpson, for critical reading and commentary of this review. This work was supported by grants from the National Institutes of Health ŽDK49807. and the National Science Foundation Ž MCB 9506088. to D.A.B.

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