Showing papers on "Fatty acid-binding protein published in 2002"

Selective Cooperation between Fatty Acid Binding Proteins and Peroxisome Proliferator-Activated Receptors in Regulating Transcription

Abstract: Lipophilic compounds such as retinoic acid and long-chain fatty acids regulate gene transcription by activating nuclear receptors such as retinoic acid receptors (RARs) and peroxisome proliferator-activated receptors (PPARs). These compounds also bind in cells to members of the family of intracellular lipid binding proteins, which includes cellular retinoic acid-binding proteins (CRABPs) and fatty acid binding proteins (FABPs). We previously reported that CRABP-II enhances the transcriptional activity of RAR by directly targeting retinoic acid to the receptor. Here, potential functional cooperation between FABPs and PPARs in regulating the transcriptional activities of their common ligands was investigated. We show that adipocyte FABP and keratinocyte FABP (A-FABP and K-FABP, respectively) selectively enhance the activities of PPARγ and PPARβ, respectively, and that these FABPs massively relocate to the nucleus in response to selective ligands for the PPAR isotype which they activate. We show further that A-FABP and K-FABP interact directly with PPARγ and PPARβ and that they do so in a receptor- and ligand-selective manner. Finally, the data demonstrate that the presence of high levels of K-FABP in keratinocytes is essential for PPARβ-mediated induction of differentiation of these cells. Taken together, the data establish that A-FABP and K-FABP govern the transcriptional activities of their ligands by targeting them to cognate PPARs in the nucleus, thereby enabling PPARs to exert their biological functions.

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

Abstract: 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.

Exercise training increases lipid metabolism gene expression in human skeletal muscle.

Abstract: The effects of a single bout of exercise and exercise training on the expression of genes necessary for the transport and β-oxidation of fatty acids (FA), together with the gene expression of trans...

Insights into binding of fatty acids by fatty acid binding proteins.

Abstract: Members of the phylogenetically related intracellular lipid binding protein (iLBP) are characterized by a highly conserved tertiary structure, but reveal distinct binding preferences with regard to ligand structure and conformation, when binding is assessed by the Lipidex method (removal of unbound ligand by hydrophobic polymer) or by isothermal titration calorimetry, a true equilibrium method. Subfamily proteins bind retinoids, subfamily II proteins bind bulky ligands, examples are intestinal bile acid binding protein (I-BABP) and liver fatty acid binding protein (L-FABP) which binds 2 ligand molecules, preferably monounsaturated and n-3 fatty acids. Subfamily III intestinal fatty acid binding protein (I-FABP) binds fatty acid in a bent conformation. The fatty acid bound by subfamily IV FABPs has a U-shaped conformation; here heart (H-) FABP preferably binds n-6, brain (B-) FABP n-3 fatty acids. The ADIFAB-method is a fluorescent test for fatty acid in equilibrium with iLBP and reveals some correlation of binding affinity to fatty acid solubility in the aqueous phase; these data are often at variance with those obtained by the other methods. Thus, in this review published binding data are critically discussed, taking into account on the one hand binding increments calculated for fatty acid double bonds on the basis of the 'solubility' hypothesis, on the other hand the interpretation of calorimetric data on the basis of crystallographic and solution structures of iLBPs.

Cytoplasmic fatty acid-binding proteins: emerging roles in metabolism and atherosclerosis.

Abstract: Cytoplasmic fatty acid-binding proteins (FABPs) are a family of proteins, expressed in a tissue-specific manner, that bind fatty acid ligands and are involved in shuttling fatty acids to cellular compartments, modulating intracellular lipid metabolism, and regulating gene expression. Several members of the FABP family have been shown to have important roles in regulating metabolism and have links to the development of insulin resistance and the metabolic syndrome. Recent studies demonstrate a role for intestinal FABP in the control of dietary fatty acid absorption and chylomicron secretion. Heart FABP is essential for normal myocardial fatty acid oxidation and modulates fatty acid uptake in skeletal muscle. Liver FABP is directly involved in fatty acid ligand signaling to the nucleus and interacts with peroxisome proliferator-activated receptors in hepatocytes. The adipocyte FABP (aP2) has been shown to affect insulin sensitivity, lipid metabolism and lipolysis, and has recently been shown to play an important role in atherosclerosis. Interestingly, expression of aP2 by the macrophage promotes atherogenesis, thus providing a link between insulin resistance, intracellular fatty acid disposition, and foam cell formation. The FABPs are promising targets for the treatment of dyslipidemia, insulin resistance, and atherosclerosis in humans.

Evolution of the family of intracellular lipid binding proteins in vertebrates.

Abstract: Members of the family of intracellular lipid binding proteins (iLBPs) have been implicated in cytoplasmic transport of lipophilic ligands, such as long-chain fatty acids and retinoids. iLBPs are low molecular mass proteins (14-16 kDa) sharing a common structural fold. The iLBP family likely arose through duplication and diversification of an ancestral iLBP gene. Phylogenetic analysis undertaken in the present study indicates that the ancestral iLBP gene arose after divergence of animals from fungi and plants. The first gene duplication was dated around 930 millions of years ago, and subsequent duplications in the succeeding 550 millions of years gave rise to the 16 iLBP types currently recognized in vertebrates. Four clusters of proteins, each binding a characteristic range of ligands, are evident from the phylogenetic tree. Evolution of different binding properties probably allowed cytoplasmic trafficking of distinct ligands. It is speculated that recruitment of an iLBP during evolution of animals enabled the mitochondrial oxidation of long-chain fatty acids.

Seasonal dynamics of flight muscle fatty acid binding protein and catabolic enzymes in a migratory shorebird.

Abstract: We developed an ELISA to measure heart-type fatty acid binding protein (H-FABP) in muscles of the western sandpiper (Calidris mauri), a long-distance migrant shorebird. H-FABP accounted for almost 11% of cytosolic protein in the heart. Pectoralis H-FABP levels were highest during migration (10%) and declined to 6% in tropically wintering female sandpipers. Premigratory birds increased body fat, but not pectoralis H-FABP, indicating that endurance flight training may be required to stimulate H-FABP expression. Juveniles making their first migration had lower pectoralis H-FABP than adults, further supporting a role for flight training. Aerobic capacity, measured by citrate synthase activity, and fatty acid oxidation capacity, measured by 3-hydroxyacyl-CoA-dehydrogenase and carnitine palmitoyl transferase activities, did not change during premigration but increased during migration by 6, 12, and 13%, respectively. The greater relative induction of H-FABP (+70%) with migration than of catabolic enzymes suggests that elevated H-FABP is related to the enhancement of uptake of fatty acids from the circulation. Citrate synthase, 3-hydroxyacyl-CoA-dehydrogenase, and carnitine palmitoyl transferase were positively correlated within individuals, suggesting coexpression, but enzyme activities were unrelated to H-FABP levels.

Changes in fatty acid transport and transporters are related to the severity of insulin deficiency

Abstract: We have examined the effects of streptozotocin (STZ)-induced diabetes (moderate and severe) on fatty acid transport and fatty acid transporter (FAT/CD36) and plasma membrane-bound fatty acid binding protein (FABPpm) expression, at the mRNA and protein level, as well as their plasmalemmal localization. These studies have shown that, with STZ-induced diabetes, 1) fatty acid transport across the plasma membrane is increased in heart, skeletal muscle, and adipose tissue and is reduced in liver; 2) changes in fatty acid transport are generally not associated with changes in fatty acid transporter mRNAs, except in the heart; 3) increases in fatty acid transport in heart and skeletal muscle occurred with concomitant increases in plasma membrane FAT/CD36, whereas in contrast, the increase and decrease in fatty acid transport in adipose tissue and liver, respectively, were accompanied by concomitant increments and reductions in plasma membrane FABPpm; and finally, 4) the increases in plasma membrane transporters (FAT/CD36 in heart and skeletal muscle; FABPpm in adipose tissue) were attributable to their increased expression, whereas in liver, the reduced plasma membrane FABPpm appeared to be due to its relocation within the cell in the face of slightly increased expression. Taken together, STZ-induced changes in fatty acid uptake demonstrate a complex and tissue-specific pattern, involving different fatty acid transporters in different tissues, in combination with different underlying mechanisms to alter their surface abundance.

New insights into the fatty acid-binding protein (FABP) family in the small intestine

Abstract: The fatty acid-binding protein (FABP) superfamily is constituted by 14-15 kDa soluble proteins which bind with a high affinity either long-chain fatty acids (LCFAs), bile acids (BAs) or retinoids. In the small intestine, three different FABP isoforms exhibiting a high affinity for LCFAs and/or BAs are expressed: the intestinal and the liver-type (I-FABP and L-FABP) and the ileal bile acid-binding protein (I-BABP). Despite of extensive investigations, their respective physiological function(s) are not clearly established. In contrast to the I-FABP, L-FABP and I-BABP share several common structural features (shape, size and volume of the hydrophobic pocket). Moreover, L-FABP and I-BABP genes are also specifically regulated by their respective preferential ligands through a very similar molecular mechanism. Although, they exhibit differences in their binding specificities and location along the small intestine supporting a specialization, it is likely that L-FABP and I-BABP genes exert the same type of basic function(s) in the enterocyte, in contrast to I-FABP.

Mechanism of cellular uptake of long-chain fatty acids: Do we need cellular proteins?

Abstract: Defining the mechanism(s) of long-chain fatty acid movement through membranes is vital to understanding whether or not entry of fatty acids into cells can be controlled at the plasma membrane of a typical cell Is there a protein that acts as gatekeeper, regulating the amount, and possibly the type, of fatty acid that can enter the cell for metabolism? Is the lipid bilayer of the membrane highly permeable to fatty acids, and is the rate of simple diffusion on the time scale of metabolism? We will briefly review efforts to study diffusion in model lipid membranes that are devoid of proteins We also present new results using dual fluorescence approaches showing that fatty acids diffuse very rapidly across the plasma membrane of the adipocyte

Fatty acid binding protein-2 gene variants and insulin resistance: gene and gene-environment interaction effects

Abstract: The intestinal fatty acid binding protein (FABP2) gene is proposed as a candidate gene for diabetes because the protein it codes is involved in fatty acid (FA) absorption and metabolism and may, th...

Critical steps in cellular fatty acid uptake and utilization.

Abstract: Despite decades of extensive research, the transport routes, mechanisms of uptake and points of flux control of long-chain fatty acids (FA) in mammalian organs are still incompletely understood. In non-fenestratred organs such as heart and skeletal muscle, membrane barriers for blood-borne FA are the luminal and abluminal membranes of endothelial cells, the sarcolemma and the mitochondrial membranes. Transport of FA through the phospholipid bilayer of the cellular membrane is most likely accomplished by diffusion of protonated FA. Evidence is accumulating that membrane-associated proteins, such as plasmalemmal fatty acid-binding protein (FABPpm) and fatty acid translocase (FAT/CD36), either alone or in conjunction with albumin binding protein (ABP), are instrumental in enhancing the delivery of FA to the cellular membrane. Inside the cell, cytoplasmic fatty acid-binding proteins (FABPc) are involved in diffusion of FA from the plasmalemma to the intracellular sites of conversion, such as the mitochondrial outer membrane. After conversion of FA to FACoA, the fatty acyl chain is transported across the mitochondrial inner membrane in a carnitine-mediated fashion. Uptake and utilization of FA by muscle cells are finely tuned, most likely to avoid the intracellular accumulation of FA, as these are cytotoxic at high concentrations. On a short-term basis, net uptake is, among others, regulated by intracellular translocation of FAT from intracellular stores to the sarcolemma and by the concentration gradient of FA across the sarcolemma. The latter implies that, among others, the rate of FA utilization determines the rate of uptake. The rate of utilization is governed by a variety of factors, including malonylCoA, the ratio acetylCoA/CoA and the availability of competing substrates such as glucose, lactate, and ketone bodies. Long-term regulation of uptake and utilization is accomplished by alterations in the rate of expression of genes, encoding for FA-handling proteins. Circumstantial evidence indicates that FA themselves are able to modulate the expression of FA-handling genes via nuclear transcription factors such as peroxisome proliferator-activated receptors (PPARs).

Regulation of fatty acid transport and membrane transporters in health and disease.

Abstract: Long chain fatty acid uptake across the plasma membrane occurs, in part, via a protein-mediated process involving a number of fatty acid binding proteins known as fatty acid transporters. A critical step in furthering the understandings of fatty acid transport was the discovery that giant vesicles, prepared from tissues such as muscle and heart, provided a suitable system for measuring fatty acid uptake. These vesicles are large ( 10–15 μm diameter), are oriented fully right side out, and contain cytosolic FABP in the lumen, which acts as a fatty acid sink, while none of the fatty acid taken up is metabolized or associated with the plasma membrane. The key fatty acid transporters FAT/CD36 and FABPpm arc expressed in muscle and heart and their plasma membrane content is positively correlated with rates of fatty acid transport. These transporters are regulated acutely (within minutes) and chronically (days). For instance, both muscle contraction and insulin can translocate FAT/CD36 from an intracellular pool to the plasma membrane, thereby increasing fatty acid transport. With obesity, fatty acid transport is increased along with a concomitant increase in plasmalemmal FAT/CD36 (heart, muscle) and FABPpm (heart only), but without change in the expression of these transporters. This latter observation suggests that some of the fatty acid transporters are permanently relocated to the plasma membrane. In other studies it also appears that fatty acid transport rates are altered in a reciprocal manner to glucose transport. Since disorders in lipid metabolism appear to be an important factor contributing to the etiology of a number of common human diseases such as diabetes and obesity, our evidence that protein-mediated fatty acid transport is a key step in lipid metabolism allows the speculation that malfunctioning of the fatty acid transport process could be a common critical factor in the pathogenesis of these diseases. (Mol Cell Biochem 239: 181–192, 2002)

Expression of fatty acid binding proteins inhibits lipid accumulation and alters toxicity in L cell fibroblasts.

Abstract: High levels of saturated, branched-chain fatty acids are deleterious to cells and animals, resulting in lipid accumulation and cytotoxicity. Although fatty acid binding proteins (FABPs) are thought...

Cytosolic fatty acid binding proteins catalyze two distinct steps in intracellular transport of their ligands.

Abstract: Cytosolic long-chain fatty acid binding proteins (FABPs) are found in tissues that metabolize fatty acids Like most lipid binding proteins, their specific functions remain unclear Two classes have been described Membrane-active FABPs interact directly with membranes during exchange of fatty acids between the protein binding site and the membrane, while membrane-inactive FABPs bind only to fatty acids that are already in aqueous solution Despite these binding proteins, most fatty acids in cell cytoplasm appear to be bound to membranes This paper reviews data suggesting that FABPs catalyze transfer of fatty acids between intracellular membranes, often across considerable intracellular distances This process occurs in three distinct steps: dissociation of the fatty acid from a ‘donor’ membrane, diffusion of the fatty acid across the intervening water layer, and binding to an ‘acceptor’ membrane Membrane-active FABPs catalyze dissociation of the fatty acid from the donor membrane and binding to the acceptor membrane, while membrane-inactive FABPs catalyze diffusion of fatty acids across the aqueous cytosol Thus, FABPs catalyze all three steps in intracellular transport A simple quantitative model has been developed that predicts the rate of intracellular transport as a function of the concentration, affinity and diffusional mobility of the binding protein Different FABPs may have evolved to match the specific transport requirements of the cell type within which they are found (Mol Cell Biochem 239: 35–43, 2002)

Intracellular lipid binding proteins of the small intestine.

Abstract: The small intestine contains three distinct proteins belonging to the intracellular lipid binding protein family: the liver-type fatty acid binding protein (L-FABP), the intestinal fatty acid binding protein (I-FABP) and the ileal lipid binding protein (ilbp). The function of these proteins in the small intestine has remained enigmatic. Targeted gene disruption studies may shed insights into the physiological importance of these proteins. In the case of I-FABP, this approach has demonstrated that the complete elimination of this protein in murine intestine does not compromise dietary fat absorption in vivo but is associated with the development of insulin resistance.

Long-chain polyunsaturated fatty acid accretion in brain.

Abstract: Brain is highly enriched in long-chain polyunsaturated fatty acids (PUFAs), particularly arachidonic acid and docosahexaenoic acid, which play important roles in brain structural and biologic functions. Plasma transport, in the form of free fatty acids or esterified FAs in lysophosphatidylcholine and lipoproteins, and de-novo synthesis contribute to brain accretion of long-chain PUFAs. Transport of long-chain PUFAs from plasma may play important roles because of the limited ability of brain to synthesize long-chain PUFAs, in the face of high demand for them. Although several proteins involved in facilitated fatty acid transport (e.g. fatty acid transport protein, fatty acid binding protein and very-long-chain acyl-coenzyme A synthetase) have been found in brain, their roles in fatty acid accumulation in brain are poorly defined. The primary pathways that are involved in long-chain PUFA accumulation in brain may vary according to brain region and developmental stage.

Liver fatty acid-binding protein as a sensitive serum marker of acute hepatocellular damage in liver transplant recipients.

Abstract: Serum tests of acute hepatocellular injury are commonly used to investigate the presence and monitor the progress of liver disease (1)(2). The release of cytoplasmic proteins from damaged hepatocytes into the vascular system follows tissue necrosis caused by, e.g., acetaminophen intoxication, ischemia and reperfusion injury, or rejection after liver transplantation. Although the hepatocytes are in direct contact with the vasculature and no interstitial barrier is between the two, smaller proteins appear earlier in the circulation than do larger ones (1) and would therefore increase earlier in serum above their upper reference value after an acute hepatocellular injury. α-Glutathione S -transferase (α-GST; 26 kDa) is a more sensitive and specific marker of hepatocellular damage (3)(4) than either alanine transaminase (ALT; 96 kDa) or aspartate transaminase. α-GST is present in liver, kidney, and intestine; is released rapidly from damaged hepatocytes; and has a relatively short in vivo plasma half-life (3)(4). The use of α-GST for the detection of hepatocellular injury secondary to acute rejection after liver transplantation improved the biochemical monitoring of patients and decreased mortality and morbidity (3). In search of even smaller and more specific cytoplasmic proteins for the detection of liver injury, we have studied the liver-type fatty acid-binding protein (L-FABP). FABPs are a family of 15-kDa proteins that are involved in the intracellular transport of long-chain fatty acids (5). To date, nine different FABPs have been identified and named according to the tissues in which they were first identified (5). L-FABP occurs mainly in the liver but, in small quantities, also in kidney and small intestine. In the hepatic lobule, L-FABP is expressed in hepatocytes in a declining portal-to-central gradient (5)(6). Extensive studies …

Analysis on the phenotype of E-FABP-gene knockout mice.

Abstract: The fatty acids are shown to be critical in the maintenance of the water permeability barrier that is ascribed to the lipids in the intracellular milieu of the cornified cell layer in the epidermis. In view of this importance in the skin, we examined the phenotype of epidermal fatty acid binding protein (E-FABP)-deficient mice. In spite of total lack of E-FABP expression in the various tissues of E-FABP deficient mice, these animals appeared normal in gross and histological examination. In Northern blot analysis for other FABPs, the gene expression of heart (H-)-type FABP is specifically elevated in the liver of neonatal heterozygous and homozygous mice, suggesting the functional compensation of H-FABP for E-FABP deficiency during their development. In functional analyses of the skin, the basal transepidermal water loss (TEWL) of the adult homozygous mice showed lower levels compared with the wild-type mice, and the impairment of recovery in TEWL was observed in the homozygous mice when the lipid barrier of the skin was disrupted by acetone. These results demonstrate that E-FABP is responsible for the water permeability barrier of the skin, although the molecular mechanism remains to be further elucidated.