Fatty acid transport across the cell membrane: Regulation by fatty acid transporters

Transport of long-chain fatty acids across the cell membrane has long been thought to occur by passive diffusion. However, in recent years there has been a fundamental shift in understanding, and it is now generally recognized that fatty acids cross the cell membrane via a protein-mediated mechanism. Membrane-associated fatty acid-binding proteins (‘fatty acid transporters’) not only facilitate but also regulate cellular fatty acid uptake, for instance through their inducible rapid (and reversible) translocation from intracellular storage pools to the cell membrane. A number of fatty acid transporters have been identified, including CD36, plasma membrane-associated fatty acid-binding protein (FABP_pm), and a family of fatty acid transport proteins (FATP1–6). Fatty acid transporters are also implicated in metabolic disease, such as insulin resistance and type-2 diabetes. In this report we briefly review current understanding of the mechanism of transmembrane fatty acid transport, and the function of fatty acid transporters in healthy cardiac and skeletal muscle, and in insulin resistance/type-2 diabetes. Fatty acid transporters hold promise as a future target to rectify lipid fluxes in the body and regain metabolic homeostasis.     

Metabolite transport across the peroxisomal membrane

In recent years, much progress has been made with respect to the unravelling of the functions of peroxisomes in metabolism, and it is now well established that peroxisomes are indispensable organelles, especially in higher eukaryotes. Peroxisomes catalyse a number of essential metabolic functions including fatty acid beta-oxidation, ether phospholipid biosynthesis, fatty acid alpha-oxidation and glyoxylate detoxification. The involvement of peroxisomes in these metabolic pathways necessitates the transport of metabolites in and out of peroxisomes. Recently, considerable progress has been made in the characterization of metabolite transport across the peroxisomal membrane. Peroxisomes posses several specialized transport systems to transport metabolites. This is exemplified by the identification of a specific transporter for adenine nucleotides and several half-ABC (ATP-binding cassette) transporters which may be present as hetero- and homo-dimers. The nature of the substrates handled by the different ABC transporters is less clear. In this review we will describe the current state of knowledge of the permeability properties of the peroxisomal membrane.     

肌肉脂肪酸转运膜蛋白及其相互关系

肌肉（骨骼肌）组织对脂肪酸的利用水平是影响机体能量稳态的关键因素.肌肉摄取的长链脂肪酸(long chain fatty acids,LCFAs)主要依赖细胞膜载体蛋白协助的跨膜转运过程.近年来,一系列与脂肪酸转运相关的膜蛋白被相继克隆鉴定,其中在肌肉中大量表达的有脂肪酸转运蛋白-1（fatty acid transport protein-1,FATP-1）、膜脂肪酸结合蛋白（plasma membrane fatty acid binding protein,FABPpm）、脂肪酸转位酶（fatty acid translocase,FAT/CD36）和小窝蛋白-1（caveolin-1）.研究上述肌肉脂肪酸转运膜蛋白的结构功能、调控机制及相互关系,可能为肥胖等脂类代谢紊乱疾病的诊治提供新的手段.     

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

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 m 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 are 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.     

Comparative biochemical studies of the murine fatty acid transport proteins (FATP) expressed in yeast

The fatty acid transport protein (FATP) family is a group of proteins that are predicted to be components of specific fatty acid trafficking pathways. In mammalian systems, six different isoforms have been identified, which function in the import of exogenous fatty acids or in the activation of very long-chain fatty acids. This has led to controversy as to whether these proteins function as membrane-bound fatty acid transporters or as acyl-CoA synthetases, which activate long-chain fatty acids concomitant with transport. The yeast FATP orthologue, Fat1p, is a dual functional protein and is required for both the import of long-chain fatty acids and the activation of very long-chain fatty acids; these activities intrinsic to Fat1p are separable functions. To more precisely define the roles of the different mammalian isoforms in fatty acid trafficking, the six murine proteins (mmFATP1-6) were expressed and characterized in a genetically defined yeast strain, which cannot transport long-chain fatty acids and has reduced long-chain acyl-CoA synthetase activity (fat1Delta faa1Delta). Each isoform was evaluated for fatty acid transport, fatty acid activation (using C18:1, C20:4, and C24:0 as substrates), and accumulation of very long-chain fatty acids. Murine FATP1, -2, and -4 complemented the defects in fatty acid transport and very long-chain fatty acid activation associated with a deletion of the yeast FAT1 gene; mmFATP3, -5, and -6 did not complement the transport function even though each was localized to the yeast plasma membrane. Both mmFATP3 and -6 activated C20:4 and C20:4, while the expression of mmFATP5 did not substantially increase acyl-CoA synthetases activities using the substrates tested. These data support the conclusion that the different mmFATP isoforms play unique roles in fatty acid trafficking, including the transport of exogenous long-chain fatty acids.     

Regulation of renal amino acid (AA) transport by hormones,drugs and xenobiotics – a review

Major advances have recently been made in our understanding of the mechanisms and functions of amino acid transport in mammalian cells: - from the whole organism to transporter molecular structure. In this article, we present a brief overview of current knowledge concerning amino acid transporters, followed by a detailed discussion of the relevance of this new information to our broader understanding of the physiological regulation of amino acid handling in the kidney. We focus especially on the influence of hormones and xenobiotics on renal amino acid transport systems. In a growing number of cases, it now seems possible to correlate the effects of hormones, drugs, and xenobiotics with the capacity of renal amino acid transporters. This topic is of clinical relevance for the treatment of many amino acid reabsorption disorders. For example, under suitable conditions glucocorticoids and thyroid hormones stimulate renal reabsorption of amino acids and might therefore be of benefit in the treatment of different kinds of aminoaciduria. Hormonal regulation also underlies the postnatal development of renal amino acid reabsorption capacity, which can be stimulated to mature earlier after exogenous administration of e.g. glucocorticoids. In contrast, many compounds (e.g. heavy metal complexes) selectively damage renal amino acid transporters resulting in urinary amino acid loss. These types of phenomena (stimulation or inhibition of amino acid transporters in the kidney) are reviewed from the perspectives of our new molecular understanding of transport processes and of clinical relevance.     

Enigma variations for peptides and their transporters in higher plants

BACKGROUND: Two families of proteins that transport small peptides, the oligopeptide transporters (OPTs) and the peptide transporters (PTRs), have been recognized in eukaryotes. Higher plants contain a far greater number of genes for these transporters than do other eukaryotes. This may be indicative of the relative importance of (oligo)peptides and their transport to plant growth and metabolism. RECENT PROGRESS: Recent studies are now allowing us to assign functions to these transporters and are starting to identify their in-planta substrates, revealing unexpected and important contributions of the transporters to plant growth and developmental processes. This Botanical Briefing appraises recent findings that PTRs and OPTs have key roles to play in the control of plant cell growth and development. Evidence is presented that some of these transporters have functions outside that of nitrogen nutrition and that these carriers can also surprise us with their totally unexpected choice of substrates.     

Greater Transport Efficiencies of the Membrane Fatty Acid Transporters FAT/CD36 and FATP4 Compared with FABPpm and FATP1 and Differential Effects on Fatty Acid Esterification and Oxidation in Rat Skeletal Muscle

In selected mammalian tissues, long chain fatty acid transporters (FABPpm, FAT/CD36, FATP1, and FATP4) are co-expressed. There is controversy as to whether they all function as membrane-bound transporters and whether they channel fatty acids to oxidation and/or esterification. Among skeletal muscles, the protein expression of FABPpm, FAT/CD36, and FATP4, but not FATP1, correlated highly with the capacities for oxidative metabolism (r ≥ 0.94), fatty acid oxidation (r ≥ 0.88), and triacylglycerol esterification (r ≥ 0.87). We overexpressed independently FABPpm, FAT/CD36, FATP1, and FATP4, within a normal physiologic range, in rat skeletal muscle, to determine the effects on fatty acid transport and metabolism. Independent overexpression of each fatty acid transporter occurred without altering either the expression or plasmalemmal content of other fatty acid transporters. All transporters increased fatty acid transport, but FAT/CD36 and FATP4 were 2.3- and 1.7-fold more effective than FABPpm and FATP1, respectively. Fatty acid transporters failed to alter the rates of fatty acid esterification into triacylglycerols. In contrast, all transporters increased the rates of long chain fatty acid oxidation, but the effects of FABPpm and FAT/CD36 were 3-fold greater than for FATP1 and FATP4. Thus, fatty acid transporters exhibit different capacities for fatty acid transport and metabolism. In vivo, FAT/CD36 and FATP4 are the most effective fatty acid transporters, whereas FABPpm and FAT/CD36 are key for stimulating fatty acid oxidation.Uptake of long chain fatty acids across the plasma membrane had long been considered to occur via passive diffusion. However, in recent years, there has been a fundamental shift in our understanding, and it is now widely recognized that long chain fatty acids cross the plasma membrane via a protein-mediated mechanism (for reviews, see Refs. 1–3). A number of fatty acid transporters have been identified, including fatty acid translocase/CD36 (FAT/CD36), plasma membrane-associated fatty acid binding proteins (FABPpm), and a family of fatty acid transport proteins (FATP1–6)⁵ (for reviews, see Refs. 1 and 4). Selected stimuli (muscle contraction, insulin, and AICAR) induce the translocation of selected fatty acid transporters (FABPpm, FAT/CD36, and FATP1) from an intracellular depot to the plasma membrane, in both heart and skeletal muscle, resulting in concurrently increased rates of fatty acid transport (for a review, see Ref. 1). Some fatty acid transporters have now also been implicated in the dysregulation of fatty acid metabolism in heart and skeletal muscle in models of insulin resistance and type 1 and 2 diabetes, including FAT/CD36 (5–9), FATP1 (10, 11), and possibly FATP4 (11, 12) but not FABPpm (5–7). Thus, in recent years, it has become widely accepted that (a) long chain fatty acids traverse the plasma membrane via a protein-mediated mechanism and (b) some of the fatty acid transporters are central to the dysregulation in skeletal muscle fatty acid metabolism in obesity and type 2 diabetes.In vivo, many of the fatty acid transporters are frequently co-expressed in different tissues. FAT/CD36 and FABPpm are ubiquitously expressed (1), whereas FATP1–6 exhibit a somewhat tissue-specific distribution pattern (13, 14). The reason for the co-expression of different fatty acid transporters within the same tissue remains unclear. It has been speculated that selected fatty acid transporters may need to interact with each other (15, 16). Alternatively, it is also possible that (a) different fatty acid transporters have discrepant transport capacities, and (b) selected transporters may channel fatty acids differentially to fatty acid oxidation and esterification into triacylglycerols in mammalian tissue.Recent evidence has shown that the transport capacities among FATPs can differ substantially, as revealed by overexpression (14, 17, 18) or knockdown studies (19), but there is little agreement as to which FATP is most effective. Extensive studies by DiRusso et al. (17) in yeast revealed that when FATP1–6 were overexpressed to similar levels (qualitative assessment), FATP4 exhibited 1.7- and 3-fold greater fatty acid transport effectiveness compared with FATP1 and FATP2, respectively, whereas no fatty acid transport capacities were attributable to FATP3, -5, and -6 (17). In contrast, in HEK293 cells, the FATP6 transport capacity was 3- and 6.5-fold greater than FATP1 and FATP4, respectively (14), whereas in 3T3-L1 adipocytes, a fatty acid transport role was evident only for FATP1 and not FATP4 (19). Others have also questioned the transport role of FATP4 (20). These discrepant findings with respect to the transport effectiveness of FATPs may reflect, in part, the use of diverse cell types with ill defined metabolic needs and/or machinery for fatty acid uptake and metabolism. Indeed, several recent reports indicate that fatty acid transport cannot be adequately examined in some cells, because these appear to lack accessory proteins that may be involved in fatty acid transport (21, 22). In addition, extrapolation of results from cultured cells to metabolically important tissue in vivo may also be problematic, since cells and mammalian tissues probably have different requirements for fatty acid utilization, and their regulation of fatty acid uptake may also differ. For example, the mechanisms regulating the acute contraction-induced up-regulation of fatty acid transport and oxidation, such as occurs in heart and skeletal muscle, is probably absent in selected cell cultures.Assessment of fatty acid transporter effectiveness, in vivo, cannot be determined in knock-out animals, since compensatory responses in some fatty acid transporters (FATP1 and -4) occur when another fatty acid transporter (FAT/CD36) has been ablated (23, 24). Thus, the relative effectiveness of selected fatty acid transporters on fatty acid transport in vivo remains unknown. In addition, whether fatty acid transporters channel fatty acids to a particular metabolic fate, as has been suggested based on studies in cultured cells (18, 19, 25), may depend on the cell type being examined.It is desirable to discern the effectiveness of selected fatty acid transporters in mammalian tissues that have a well known system for transporting and utilizing fatty acids and in which fatty acid transporters can be independently up-regulated without disturbing the expression of other fatty acid transporters. These criteria can be satisfied in rat skeletal muscle in which genes can be up-regulated under controlled conditions within a physiologically meaningful range (26–28). Therefore, in the present study, we have compared the independent transport effectiveness of fatty acid transporters (FABPpm, FAT/CD36, FATP1, and FATP4) in skeletal muscle, without disturbing the expression and plasmalemmal content of other fatty acid transporters. In addition, we also examined the contributions of these transporters to fatty acid oxidation and esterification into triacylglycerols. These are the first studies to reveal that in vivo (a) the fatty acid transport effectiveness of fatty acid transporters differs considerably, and (b) in skeletal muscle, these transporters serve to channel fatty acids to oxidation, not esterification into triacylglycerols.     

Amino acid transport in the renal proximal tubule

Summary. In the kidney the proximal tubule is responsible for the uptake of amino acids. This occurs via a variety of functionally and structurally different amino acid transporters located in the luminal and basolateral membrane. Some of these transporters show an ion-dependence (e.g. Na⁺, Cl⁻ and K⁺) or use an H⁺-gradient to drive transport. Only a few amino acid transporters have been cloned or functionally characterized in detail so far and their structure is known, while little is known about a majority of amino acid transporters. Only few attempts have been untertaken looking at the regulation of amino acid transport. We summarized more recent information on amino acid transport in the renal proximal tubule emphasizing functional and regulatory aspects. Received August 8, 1999; Accepted April 20, 2000     

Fatty acid transporters in skin development,function and disease

Fatty acids in the epidermis can be incorporated into complex lipids or exist in a free form, and they are crucial to proper functions of the epidermis and its appendages, such as sebaceous glands. Epidermal fatty acids can be synthesized de novo by keratinocytes or taken up from extracutaneous sources in a process that likely involves protein transporters. Several proteins that are expressed in the epidermis have been proposed to facilitate the uptake of long-chain fatty acids (LCFA) in mammalian cells, including fatty acid translocase/CD36, fatty acid binding protein, and fatty acid transport protein (FATP)/very long-chain acyl-CoA synthetase. In this review, we will discuss the mechanisms by which these candidate transporters facilitate the uptake of fatty acids. We will then discuss the clinical implications of defects in these transporters and relevant animal models, including the FATP4 animal models and ichthyosis prematurity syndrome, a congenital ichthyosis caused by FATP4 deficiency. This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis and their Role in the Formation and Maintenance of the Cutaneous Barrier. Guest Editors: Kenneth R. Feingold and Peter Elias.     

Carbon flux and fatty acid synthesis in plants.

The de novo synthesis of fatty acids in plants occurs in the plastids through the activity of fatty acid synthetase. The synthesis of the malonyl-coenzyme A that is required for acyl-chain elongation requires the import of metabolites from the cytosol and their subsequent metabolism. Early studies had implicated acetate as the carbon source for plastidial fatty acid synthesis but more recent experiments have provided data that argue against this. A range of cytosolic metabolites including glucose 6-phosphate, malate, phosphoenolpyruvate and pyruvate support high rates of fatty acid synthesis by isolated plastids, the relative utilisation of which depends upon the plant species and the organ from which the plastids are isolated. The import of these metabolites occurs via specific transporters on the plastid envelope and recent advances in the understanding of the role of these transporters are discussed. Chloroplasts are able to generate the reducing power and ATP required for fatty acid synthesis by capture of light energy in the reactions of photosynthetic electron transport. Regulation of chloroplast fatty acid synthesis is mediated by the response of acetyl-CoA carboxylase to the redox state of the plastid, which ensures that the carbon metabolism is linked to the energy status. The regulation of fatty acid synthesis in plastids of heterotrophic cells is much less well understood and is of particular interest in the tissues that accumulate large amounts of the storage oil, triacylglycerol. In these heterotrophic cells the plastids import ATP and oxidise imported carbon sources to produce the required reducing power. The sequencing of the genome of Arabidopsis thaliana has now enabled a number of aspects of plant fatty acid synthesis to be re-addressed, particularly those areas in which in vitro biochemical analysis had provided equivocal answers. Examples of such aspects and future opportunities for our understanding of plant fatty acid synthesis are presented and discussed.     

Unravelling the significance of cellular fatty acid-binding proteins

Cellular long-chain fatty acid (FA) transport and metabolism are believed to be regulated by membrane-associated and soluble proteins that bind and transport FAs. Several different classes of membrane proteins have been proposed as FA acceptors or transmembrane FA transporters. New evidence from in-vitro and whole-animal studies supports the existence of protein-mediated transmembrane transport of FAs, which is likely to coexist with passive diffusional uptake. The trafficking of FAs by intracellular fatty acid-binding proteins may involve their interaction with specific membrane or protein targets. Evidence is also emerging for concerted actions between the membrane and cytoplasmic fatty acid-binding proteins that allow for efficient regulation of FA transport and metabolism.     

Hypoxia-induced fatty acid transporter translocation increases fatty acid transport and contributes to lipid accumulation in the heart

Protein-mediated LCFA transport across plasma membranes is highly regulated by the fatty acid transporters FAT/CD36 and FABPpm. Physiologic stimuli (insulin stimulation, AMP kinase activation) induce the translocation of one or both transporters to the plasma membrane and increase the rate of LCFA transport. In the hypoxic/ischemic heart, intramyocardial lipid accumulation has been attributed to a reduced rate of fatty acid oxidation. However, since acute hypoxia (15 min) activates AMPK, we examined whether an increased accumulation of intramyocardial lipid during hypoxia was also attributable to an increased rate of LCFA uptake as a result AMPK-induced translocation of FAT/CD36 and FABPpm. In cardiac myocytes, hypoxia (15 min) induced the redistribution of FAT/CD36 from an intracellular pool (LDM) (-25%, P<0.05) to the plasma membranes (PM) (+54%, P<0.05). Hypoxia also induced an increase in FABPpm at the PM (+56%, P<0.05) and a concomitant FABPpm reduction in the LDM (-24%, P<0.05). Similarly, in intact, Langendorff perfused hearts, hypoxia induced the translocation of a both FAT/CD36 and FABPpm to the PM (+66% and +61%, respectively, P<0.05), with a concomitant decline in FAT/CD36 and FABPpm in the LDM (-24% and -23%, respectively, P<0.05). Importantly, the increased plasmalemmal content of these transporters was associated with increases in the initial rates of palmitate uptake into cardiac myocytes (+40%, P<0.05). Acute hypoxia also redirected palmitate into intracellular lipid pools, mainly to PL and TG (+48% and +28%, respectively, P<0.05), while fatty acid oxidation was reduced (-35%, P<0.05). Thus, our data indicate that the increased intracellular lipid accumulation in hypoxic hearts is attributable to both: (a) a reduced rate of fatty acid oxidation and (b) an increased rate of fatty acid transport into the heart, the latter being attributable to a hypoxia-induced translocation of fatty acid transporters.     

Evidence for concerted action of FAT/CD36 and FABPpm to increase fatty acid transport across the plasma membrane

There is substantial molecular, biochemical and physiologic evidence that long-chain fatty acid transport involves a protein-mediated process. A number of fatty acid transport proteins have been identified, and for unknown reasons, some of these are coexpressed in the same tissues. In muscle and heart FAT/CD36 and FABPpm appear to be key transporters. Both proteins are regulated acutely (within minutes) and chronically (hours to days) by selected physiologic stimuli (insulin, AMP kinase activation). Acute regulation involves the translocation of FAT/CD36 by insulin, muscle contraction and AMP kinase activation, while FABPpm is induced to translocate by muscle contraction and AMP kinase activation, but not by insulin. Protein expression ofFAT/CD36 and FABPpm is regulated by prolonged AMP kinase activation (heart) or increased muscle contraction. Prolonged insulin exposure increases the expression of FAT/CD36 but not FABPpm. Trafficking of fatty acid transporters between an intracellular compartment(s) and the plasma membrane is altered in insulin-resistant skeletal muscle, as some FAT/CD36 is permanently relocated to plasma membrane, thereby contributing to insulin resistance due to the increased influx of fatty acids into muscle cells. Studies in FAT/CD36 null mice have revealed that this transporter is key to regulating the increase in the rate of fatty acid metabolism in heart and skeletal muscle. It appears based on a number of experiments that FAT/CD36 and FABPpm may collaborate to increase the rates of fatty acid transport, as these proteins co-immunoprecipitate.     

The fatty acid transport function of fatty acid-binding proteins

The intracellular fatty acid-binding proteins (FABPs) comprise a family of 14-15 kDa proteins which bind long-chain fatty acids. A role for FABPs in fatty acid transport has been hypothesized for several decades, and the accumulated indirect and correlative evidence is largely supportive of this proposed function. In recent years, a number of experimental approaches which more directly examine the transport function of FABPs have been taken. These include molecular level in vitro modeling of fatty acid transfer mechanisms, whole cell studies of fatty acid uptake and intracellular transfer following genetic manipulation of FABP type and amount, and an examination of cells and tissues from animals engineered to lack expression of specific FABPs. Collectively, data from these studies have provided strong support for defining the FABPs as fatty acid transport proteins. Further studies are necessary to elucidate the fundamental mechanisms by which cellular fatty acid trafficking is modulated by the FABPs.     

New insight into the biochemical mechanisms regulating auxin transport in plants

The transport of the plant hormone auxin has been under intense investigation since its identification 80 years ago. Studies have gradually refined our understanding of the importance of auxin transport in many aspects of plant signalling and development, and the focus has intensified in recent years towards the identification of the proteins involved in auxin transport and their functional mechanism. Within the past 18 months, the field has progressed rapidly, with confirmation that several distinct classes of proteins, previously dubbed as 'putative auxin permeases' or 'auxin transport facilitators', are bona fide transporters of IAA (indol-3-ylacetic acid). In this review we will appraise the recent transport data and highlight likely future research directions, including the characterization of auxiliary proteins necessary for the regulation of auxin transporters.     

Regulation of membrane functions and fatty acid composition in Escherichia coli by cyclic AMP receptor protein.

Adenosine 3′,5′-cyclic monophosphate (cAMP) has been shown to be involved in regulating a number of membrane functions in Escherichia coli cells, including various respiratory and transport activities. In this report we show that this regulation is mediated by the cAMP receptor protein (CRP). In addition, data are presented which show that the cAMP-CRP system is involved in regulating the E. coli fatty acid composition.     

Peroxisomal ABC transporters: Structure, function and role in disease

ATP-binding cassette (ABC) transporters belong to one of the largest families of membrane proteins, and are present in almost all living organisms from eubacteria to mammals. They exist on plasma membranes and intracellular compartments such as the mitochondria, peroxisomes, endoplasmic reticulum, Golgi apparatus and lysosomes, and mediate the active transport of a wide variety of substrates in a variety of different cellular processes. These include the transport of amino acids, polysaccharides, peptides, lipids and xenobiotics, including drugs and toxins. Three ABC transporters belonging to subfamily D have been identified in mammalian peroxisomes. The ABC transporters are half-size and assemble mostly as a homodimer after posttranslational transport to peroxisomal membranes. ABCD1/ALDP and ABCD2/ALDRP are suggested to be involved in the transport of very long chain acyl-CoA with differences in substrate specificity, and ABCD3/PMP70 is involved in the transport of long and branched chain acyl-CoA. ABCD1 is known to be responsible for X-linked adrenoleukodystrophy (X-ALD), an inborn error of peroxisomal β-oxidation of very long chain fatty acids. Here, we summarize recent advances and important points in our advancing understanding of how these ABC transporters target and assemble to peroxisomal membranes and perform their functions in physiological and pathological processes, including the neurodegenerative disease, X-ALD. This article is part of a Special Issue entitled: Metabolic Functions and Biogenesis of Peroxisomes in Health and Disease.     

The complementary membranes forming the blood-brain barrier

Brain capillary endothelial cells form the blood-brain barrier. They are connected by extensive tight junctions, and are polarized into luminal (blood-facing) and abluminal (brain-facing) plasma membrane domains. The polar distribution of transport proteins allows for active regulation of brain extracellular fluid. Experiments on isolated membrane vesicles from capillary endothelial cells of bovine brain demonstrated the polar arrangement of amino acid and glucose transporters, and the utility of such arrangements have been proposed. For instance, passive carriers for glutamine and glutamate have been found only in the luminal membrane of blood-brain barrier cells, while Na-dependent secondary active transporters are at the abluminal membrane. This organization could promote the net removal of nitrogen-rich amino acids from brain, and account for the low level of glutamate penetration into the central nervous system. Furthermore, the presence of a gamma-glutamyl cycle at the luminal membrane and Na-dependent amino acid transporters at the abluminal membrane may serve to modulate movement of amino acids from blood-to-brain. Passive carriers facilitate amino acid transport into brain. However, activation of the gamma-glutamyl cycle by increased plasma amino acids is expected to generate oxoproline within the blood-brain barrier. Oxoproline stimulates secondary active amino acid transporters (Systems A and B(o)+) at the abluminal membrane, thereby reducing net influx of amino acids to brain. Finally, passive glucose transporters are present in both the luminal and abluminal membranes of the blood-brain barrier. Interestingly, a high affinity Na-dependent glucose carrier has been described only in the abluminal membrane. This raises the question whether glucose entry may be regulated to some extent. Immunoblotting studies suggest more than one type of passive glucose transporter exist in the blood-brain barrier, each with an asymmetrical distribution. In conclusion, it is now clear that the blood-brain barrier participates in the active regulation of brain extracellular fluid, and that the diverse functions of each plasma membrane domain contributes to these regulatory functions.