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Arend Bonen - One of the best experts on this subject based on the ideXlab platform.
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Fatty Acid Transport and Transporters in muscle are critically regulated by Akt2.
FEBS Letters, 2015Co-Authors: Swati S. Jain, Graham P. Holloway, Joost J. F. P. Luiken, Jan F. C. Glatz, Laelie A. Snook, Xiao-xia Han, Arend BonenAbstract:Muscle contains various Fatty Acid Transporters (CD36, FABPpm, FATP1, FATP4). Physiological stimuli (insulin, contraction) induce the translocation of all four Transporters to the sarcolemma to enhance Fatty Acid uptake similarly to glucose uptake stimulation via glucose Transporter-4 (GLUT4) translocation. Akt2 mediates insulin-induced, but not contraction-induced, GLUT4 translocation, but its role in muscle Fatty Acid Transporter translocation is unknown. In muscle from Akt2-knockout mice, we observed that Akt2 is critically involved in both insulin-induced and contraction-induced Fatty Acid Transport and translocation of Fatty Acid translocase/CD36 (CD36) and FATP1, but not of translocation of Fatty Acid-binding protein (FABPpm) and FATP4. Instead, Akt2 mediates intracellular retention of both latter Transporters. Collectively, our observations reveal novel complexities in signaling mechanisms regulating the translocation of Fatty Acid Transporters in muscle.
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Extremely rapid increase in Fatty Acid Transport and intramyocellular lipid accumulation but markedly delayed insulin resistance after high fat feeding in rats.
Diabetologia, 2015Co-Authors: Arend Bonen, Laelie A. Snook, Xiao-xia Han, Swati S. Jain, Yuko Yoshida, Kathryn H. Buddo, James S. V. Lally, Elizabeth D. Pask, Sabina Paglialunga, Marie-soleil BeaudoinAbstract:Aims/hypothesis The mechanisms for diet-induced intramyocellular lipid accumulation and its association with insulin resistance remain contentious. In a detailed time-course study in rats, we examined whether a high-fat diet increased intramyocellular lipid accumulation via alterations in Fatty Acid translocase (FAT/CD36)-mediated Fatty Acid Transport, selected enzymes and/or Fatty Acid oxidation, and whether intramyocellular lipid accretion coincided with the onset of insulin resistance.
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Acute endurance exercise increases plasma membrane Fatty Acid Transport proteins in rat and human skeletal muscle
American journal of physiology. Endocrinology and metabolism, 2011Co-Authors: Nicolette S. Bradley, Arend Bonen, Laelie A. Snook, George J. F. Heigenhauser, Swati S. Jain, Lawrence L. SprietAbstract:Fatty Acid Transport proteins are present on the plasma membrane and are involved in the uptake of long-chain Fatty Acids into skeletal muscle. The present study determined whether acute endurance ...
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Increasing skeletal muscle Fatty Acid Transport protein 1 (FATP1) targets Fatty Acids to oxidation and does not predispose mice to diet-induced insulin resistance.
Diabetologia, 2011Co-Authors: Graham P. Holloway, C. J. Chou, J. S. V. Lally, T. Stellingwerff, Amy C. Maher, Oksana Gavrilova, Martin Haluzik, Hakam Alkhateeb, Marc L. Reitman, Arend BonenAbstract:Aims/hypothesis We examined in skeletal muscle (1) whether Fatty Acid Transport protein (FATP) 1 channels long-chain Fatty Acid (LCFA) to specific metabolic fates in rats; and (2) whether FATP1-mediated increases in LCFA uptake exacerbate the development of diet-induced insulin resistance in mice. We also examined whether FATP1 is altered in insulin-resistant obese Zucker rats.
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Exercise training increases sarcolemmal and mitochondrial Fatty Acid Transport proteins in human skeletal muscle
American journal of physiology. Endocrinology and metabolism, 2010Co-Authors: Jason L. Talanian, Graham P. Holloway, Arend Bonen, Laelie A. Snook, George J. F. Heigenhauser, Lawrence L. SprietAbstract:Fatty Acid oxidation is highly regulated in skeletal muscle and involves several sites of regulation, including the Transport of Fatty Acids across both the plasma and mitochondrial membranes. Transport across these membranes is recognized to be primarily protein mediated, limited by the abundance of Fatty Acid Transport proteins on the respective membranes. In recent years, evidence has shown that Fatty Acid Transport proteins move in response to acute and chronic perturbations; however, in human skeletal muscle the localization of Fatty Acid Transport proteins in response to training has not been examined. Therefore, we determined whether high-intensity interval training (HIIT) increased total skeletal muscle, sarcolemmal, and mitochondrial membrane Fatty Acid Transport protein contents. Ten untrained females (22 +/- 1 yr, 65 +/- 2 kg; .VO(2peak): 2.8 +/- 0.1 l/min) completed 6 wk of HIIT, and biopsies from the vastus lateralis muscle were taken before training, and following 2 and 6 wk of HIIT. Training significantly increased maximal oxygen uptake at 2 and 6 wk (3.1 +/- 0.1, 3.3 +/- 0.1 l/min). Training for 6 wk increased FAT/CD36 at the whole muscle (10%) and mitochondrial levels (51%) without alterations in sarcolemmal content. Whole muscle plasma membrane Fatty Acid binding protein (FABPpm) also increased (48%) after 6 wk of training, but in contrast to FAT/CD36, sarcolemmal FABPpm increased (23%), whereas mitochondrial FABPpm was unaltered. The changes on sarcolemmal and mitochondrial membranes occurred rapidly, since differences (< or =2 wk) were not observed between 2 and 6 wk. This is the first study to demonstrate that exercise training increases Fatty Acid Transport protein content in whole muscle (FAT/CD36 and FABPpm) and sarcolemmal (FABPpm) and mitochondrial (FAT/CD36) membranes in human skeletal muscle of females. These results suggest that increases in skeletal muscle Fatty Acid oxidation following training are related in part to changes in Fatty Acid Transport protein content and localization.
Paul N. Black - One of the best experts on this subject based on the ideXlab platform.
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Fatty Acid Transport proteins: targeting FATP2 as a gatekeeper involved in the Transport of exogenous Fatty Acids
MedChemComm, 2016Co-Authors: Paul N. Black, Constance Ahowesso, David Montefusco, Nipun Saini, Concetta C. DirussoAbstract:The Fatty Acid Transport proteins (FATP) are classified as members of the Solute Carrier 27 (Slc27) family of proteins based on their ability to function in the Transport of exogenous Fatty Acids. These proteins, when localized to the plasma membrane or at intracellular membrane junctions with the endoplasmic reticulum, function as a gate in the regulated Transport of Fatty Acids and thus represent a therapeutic target to delimit the acquisition of Fatty Acids that contribute to disease as in the case of Fatty Acid overload. To date, FATP1, FATP2, and FATP4 have been used as targets in the selection of small molecule inhibitors with the goal of treating insulin resistance and attenuating dietary absorption of Fatty Acids. Several studies targeting FATP1 and FATP4 were based on the intrinsic acyl CoA synthetase activity of these proteins and not on Transport directly. While several classes of compounds were identified as potential inhibitors of Fatty Acid Transport, in vivo studies using a mouse model failed to provide evidence these compounds were effective in blocking or attenuating Fatty Acid Transport. Studies targeting FATP2 employed a naturally occurring splice variant, FATP2b, which lacks intrinsic acyl CoA synthetase due to the deletion of exon 3, yet is fully functional in Fatty Acid Transport. These studies identified two compounds, 5'-bromo-5-phenyl-spiro[3H-1,3,4-thiadiazole-2,3'-indoline]-2'-one), now referred to as Lipofermata, and 2-benzyl-3-(4-chlorophenyl)-5-(4-nitrophenyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one, now called Grassofermata, that are effective Fatty Acid Transport inhibitors both in vitro using a series of model cell lines and in vivo using a mouse model.
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Overexpression of Human Fatty Acid Transport Protein 2/Very Long Chain Acyl-CoA Synthetase 1 (FATP2/Acsvl1) Reveals Distinct Patterns of Trafficking of Exogenous Fatty Acids
Biochemical and biophysical research communications, 2013Co-Authors: Elaina M. Melton, Concetta C. Dirusso, Ronald L. Cerny, Paul N. BlackAbstract:Abstract In mammals, the Fatty Acid Transport proteins (FATP1 through FATP6) are members of a highly conserved family of proteins, which function in Fatty Acid Transport proceeding through vectorial acylation and in the activation of very long chain Fatty Acids, branched chain Fatty Acids and secondary bile Acids. FATP1, 2 and 4, for example directly function in Fatty Acid Transport and very long chain Fatty Acids activation while FATP5 does not function in Fatty Acid Transport but activates secondary bile Acids. In the present work, we have used stable isotopically labeled Fatty Acids differing in carbon length and saturation in cells expressing FATP2 to gain further insights into how this protein functions in Fatty Acid Transport and intracellular Fatty Acid trafficking. Our previous studies showed the expression of FATP2 modestly increased C16:0-CoA and C20:4-CoA and significantly increased C18:3-CoA and C22:6-CoA after 4 h. The increases in C16:0-CoA and C18:3-CoA suggest FATP2 must necessarily partner with a long chain acyl CoA synthetase (Acsl) to generate C16:0-CoA and C18:3-CoA through vectorial acylation. The very long chain acyl CoA synthetase activity of FATP2 is consistent in the generation of C20:4-CoA and C22:6-CoA coincident with Transport from their respective exogenous Fatty Acids. The trafficking of exogenous Fatty Acids into phosphatidic Acid (PA) and into the major classes of phospholipids (phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), and phosphatidyserine (PS)) resulted in distinctive profiles, which changed with the expression of FATP2. The trafficking of exogenous C16:0 and C22:6 into PA was significant where there was 6.9- and 5.3-fold increased incorporation, respectively, over the control; C18:3 and C20:4 also trended to increase in the PA pool while there were no changes for C18:1 and C18:2. The trafficking of C18:3 into PC and PI trended higher and approached significance. In the case of C20:4, expression of FATP2 resulted in increases in all four classes of phospholipid, indicating little selectivity. In the case of C22:6, there were significant increases of this exogenous Fatty Acids being trafficking into PC and PI. Collectively, these data support the conclusion that FATP2 has a dual function in the pathways linking the Transport and activation of exogenous Fatty Acids. We discuss the differential roles of FATP2 and its role in both Fatty Acid Transport and Fatty Acid activation in the context of lipid homeostasis.
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human Fatty Acid Transport protein 2a very long chain acyl coa synthetase 1 fatp2a acsvl1 has a preference in mediating the channeling of exogenous n 3 Fatty Acids into phosphatidylinositol
Journal of Biological Chemistry, 2011Co-Authors: Paul A. Watkins, Concetta C. Dirusso, Elaina M. Melton, Ronald L. Cerny, Paul N. BlackAbstract:The trafficking of Fatty Acids across the membrane and into downstream metabolic pathways requires their activation to CoA thioesters. Members of the Fatty Acid Transport protein/very long chain acyl-CoA synthetase (FATP/Acsvl) family are emerging as key players in the trafficking of exogenous Fatty Acids into the cell and in intracellular Fatty Acid homeostasis. We have expressed two naturally occurring splice variants of human FATP2 (Acsvl1) in yeast and 293T-REx cells and addressed their roles in Fatty Acid Transport, activation, and intracellular trafficking. Although both forms (FATP2a (Mr 70,000) and FATP2b (Mr 65,000 and lacking exon3, which encodes part of the ATP binding site)) were functional in Fatty Acid import, only FATP2a had acyl-CoA synthetase activity, with an apparent preference toward very long chain Fatty Acids. To further address the roles of FATP2a or FATP2b in Fatty Acid uptake and activation, LC-MS/MS was used to separate and quantify different acyl-CoA species (C14–C24) and to monitor the trafficking of different classes of exogenous Fatty Acids into intracellular acyl-CoA pools in 293T-REx cells expressing either isoform. The use of stable isotopically labeled Fatty Acids demonstrated FATP2a is involved in the uptake and activation of exogenous Fatty Acids, with a preference toward n-3 Fatty Acids (C18:3 and C22:6). Using the same cells expressing FATP2a or FATP2b, electrospray ionization/MS was used to follow the trafficking of stable isotopically labeled n-3 Fatty Acids into phosphatidylcholine and phosphatidylinositol. The expression of FATP2a resulted in the trafficking of C18:3-CoA and C22:6-CoA into both phosphatidylcholine and phosphatidylinositol but with a distinct preference for phosphatidylinositol. Collectively these data demonstrate FATP2a functions in Fatty Acid Transport and activation and provides specificity toward n-3 Fatty Acids in which the corresponding n-3 acyl-CoAs are preferentially trafficked into acyl-CoA pools destined for phosphatidylinositol incorporation.
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Methods to monitor Fatty Acid Transport proceeding through vectorial acylation.
Methods in molecular biology (Clifton N.J.), 2009Co-Authors: Elsa Arias-barrau, Concetta C. Dirusso, Paul N. BlackAbstract:The process of Fatty Acid Transport across the plasma membrane occurs by several mechanisms that involve distinct membrane-bound and membrane-associated proteins and enzymes. Among these are the Fatty Acid Transport proteins (FATP) and long-chain acyl CoA synthetases (Acsl). Previous studies in yeast and adipocytes have shown FATP and Acsl form a physical complex at the plasma membrane and are required for Fatty Acid Transport, which proceeds through a coupled process-linking Transport with metabolic activation termed vectorial acylation. At present, six isoforms of FATP and five isoforms of ACSL have been identified in mice and man. In addition, there are a number of splice variants of different FATP and Acsl isoforms. The different FATP and Acsl isoforms have distinct tissue expression profiles and different cellular locations suggesting they function in the channeling of Fatty Acids into discrete metabolic pools. The concerted activity of these proteins is proposed to allow cells to discriminate different classes of Fatty Acids and provides the mechanistic basis underpinning the selectivity and specificity of the Fatty Acid Transport process.
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Targeting the Fatty Acid Transport proteins (FATP) to understand the mechanisms linking Fatty Acid Transport to metabolism
Immunology endocrine & metabolic agents in medicinal chemistry, 2009Co-Authors: Paul N. Black, Elsa Arias-barrau, Angel Sandoval, Concetta C. DirussoAbstract:One principal process driving Fatty Acid Transport is vectorial acylation, where Fatty Acids traverse the membrane concomitant with activation to CoA thioesters. Current evidence is consistent with the proposal that specific Fatty Acid Transport (FATP) isoforms alone or in concert with specific long chain acyl CoA synthetase (Acsl) isoforms function to drive this energy-dependent process. Understanding the details of vectorial acylation is of particular importance as disturbances in lipid metabolism many times leads to elevated levels of circulating free Fatty Acids, which in turn increases Fatty Acid internalization and ectopic accumulation of triglycerides. This is associated with changes in Fatty Acid oxidation rates, accumulation of reactive oxygen species, the synthesis of ceramide and ER stress. The correlation between chronically elevated plasma free Fatty Acids and triglycerides with the development of obesity, insulin resistance and cardiovascular disease has led to the hypothesis that decreases in pancreatic insulin production, cardiac failure, arrhythmias, and hypertrophy are due to aberrant accumulation of lipids in these tissues. To this end, a detailed understanding of how Fatty Acids traverse the plasma membrane, become activated and trafficked into downstream metabolic pools and the precise roles provided by the different FATP and Acsl isoforms are especially important questions. We review our current understanding of vectorial acylation and the contributions by specific FATP and Acsl isoforms and the identification of small molecule inhibitors from high throughput screens that inhibit this process and thus provide new insights into the underlying mechanistic basis of this process.
Joost J. F. P. Luiken - One of the best experts on this subject based on the ideXlab platform.
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Fatty Acid Transport and Transporters in muscle are critically regulated by Akt2.
FEBS Letters, 2015Co-Authors: Swati S. Jain, Graham P. Holloway, Joost J. F. P. Luiken, Jan F. C. Glatz, Laelie A. Snook, Xiao-xia Han, Arend BonenAbstract:Muscle contains various Fatty Acid Transporters (CD36, FABPpm, FATP1, FATP4). Physiological stimuli (insulin, contraction) induce the translocation of all four Transporters to the sarcolemma to enhance Fatty Acid uptake similarly to glucose uptake stimulation via glucose Transporter-4 (GLUT4) translocation. Akt2 mediates insulin-induced, but not contraction-induced, GLUT4 translocation, but its role in muscle Fatty Acid Transporter translocation is unknown. In muscle from Akt2-knockout mice, we observed that Akt2 is critically involved in both insulin-induced and contraction-induced Fatty Acid Transport and translocation of Fatty Acid translocase/CD36 (CD36) and FATP1, but not of translocation of Fatty Acid-binding protein (FABPpm) and FATP4. Instead, Akt2 mediates intracellular retention of both latter Transporters. Collectively, our observations reveal novel complexities in signaling mechanisms regulating the translocation of Fatty Acid Transporters in muscle.
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Fatty Acid Transport across the cell membrane: Regulation by Fatty Acid Transporters
Prostaglandins Leukotrienes and Essential Fatty Acids, 2010Co-Authors: Robert W. Schwenk, Graham P. Holloway, Joost J. F. P. Luiken, Arend Bonen, Jan F. C. GlatzAbstract:Abstract 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.
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Fatty Acid Transport in skeletal muscle: role in energy provision and insulin resistance
Clinical Lipidology, 2010Co-Authors: Graham P. Holloway, Robert W. Schwenk, Joost J. F. P. Luiken, Jan F. C. Glatz, Arend BonenAbstract:Long-chain Fatty Acid uptake has now been shown to occur via a highly regulated, protein-mediated mechanism involving plasma membrane Fatty Acid Transporters. This process is especially important in skeletal muscle, a tissue with a highly variable metabolic rate that constitutes approximately 40% of body mass. We review the evidence that skeletal muscle Fatty Acid Transport is acutely and chronically regulated by muscle contraction and insulin, largely by the Fatty Acid Transporter CD36. We also examine recent data suggesting that CD36 may contribute to regulating Fatty Acid oxidation by mitochondria. In addition, we review evidence showing that skeletal muscle insulin resistance is associated with the dysregulation of CD36-mediated Fatty Acid Transport, and that the insulin-sensitizing effects of proliferator-activated receptor-γ coactivator-1α may depend on limiting CD36 upregulation. Taken altogether, it is apparent that skeletal muscle Fatty Acid Transport is central to the regulation of whole-body li...
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Cardiac and skeletal muscle Fatty Acid Transport and Transporters and triacylglycerol and Fatty Acid oxidation in lean and Zucker diabetic Fatty rats.
American journal of physiology. Regulatory integrative and comparative physiology, 2009Co-Authors: Arend Bonen, Graham P. Holloway, Jan F. C. Glatz, Narendra N. Tandon, Xiao-xia Han, Jay T. Mcfarlan, Joost J. F. P. LuikenAbstract:We examined Fatty Acid Transporters, Transport, and metabolism in hearts and red and white muscles of lean and insulin-resistant (week 6) and type 2 diabetic (week 24) Zucker diabetic Fatty (ZDF) rats. Cardiac Fatty Acid Transport was similar in lean and ZDF hearts at week 6 but was reduced at week 24 (-40%) in lean but not ZDF hearts. Red muscle of ZDF rats exhibited an early susceptibility to upregulation (+66%) of Fatty Acid Transport at week 6 that was increased by 50% in lean and ZDF rats at week 24 but remained 44% greater in red muscle of ZDF rats. In white muscle, no differences were observed in Fatty Acid Transport between groups or from week 6 to week 24. In all tissues (heart and red and white muscle), FAT/CD36 protein and plasmalemmal content paralleled the changes in Fatty Acid Transport. Triacylglycerol content in red and white muscles, but not heart, in lean and ZDF rats correlated with Fatty Acid Transport (r = 0.91) and sarcolemmal FAT/CD36 (r = 0.98). Red and white muscle Fatty Acid oxidation by isolated mitochondria was not impaired in ZDF rats but was reduced by 18-24% in red muscle of lean rats at week 24. Thus, in red, but not white, muscle of insulin-resistant and type 2 diabetic animals, a marked upregulation in Fatty Acid Transport and intramuscular triacylglycerol was associated with increased levels of FAT/CD36 expression and plasmalemmal content. In heart, greater rates of Fatty Acid Transport and FAT/CD36 in ZDF rats (week 24) were attributable to the inhibition of age-related reductions in these parameters. However, intramuscular triacylglycerol did not accumulate in hearts of ZDF rats. Thus insulin resistance and type 2 diabetes are accompanied by tissue-specific differences in FAT/CD36 and Fatty Acid Transport and metabolism. Upregulation of Fatty Acid Transport increased red muscle, but not cardiac, triacylglycerol accumulation. White muscle lipid metabolism dysregulation was not observed.
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additive effects of insulin and muscle contraction on Fatty Acid Transport and Fatty Acid Transporters fat cd36 fabppm fatp1 4 and 6
FEBS Letters, 2009Co-Authors: Swati S. Jain, Robert W. Schwenk, Joost J. F. P. Luiken, Jan F. C. Glatz, Laelie A. Snook, Adrian Chabowski, Arend BonenAbstract:Insulin and muscle contraction increase Fatty Acid Transport into muscle by inducing the translocation of FAT/CD36. We examined (a) whether these effects are additive, and (b) whether other Fatty Acid Transporters (FABPpm, FATP1, FATP4, and FATP6) are also induced to translocate. Insulin and muscle contraction increased glucose Transport and plasmalemmal GLUT4 independently and additively (positive control). Palmitate Transport was also stimulated independently and additively by insulin and by muscle contraction. Insulin and muscle contraction increased plasmalemmal FAT/CD36, FABPpm, FATP1, and FATP4, but not FATP6. Only FAT/CD36 and FATP1 were stimulated in an additive manner by insulin and by muscle contraction.
Concetta C. Dirusso - One of the best experts on this subject based on the ideXlab platform.
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Fatty Acid Transport proteins: targeting FATP2 as a gatekeeper involved in the Transport of exogenous Fatty Acids
MedChemComm, 2016Co-Authors: Paul N. Black, Constance Ahowesso, David Montefusco, Nipun Saini, Concetta C. DirussoAbstract:The Fatty Acid Transport proteins (FATP) are classified as members of the Solute Carrier 27 (Slc27) family of proteins based on their ability to function in the Transport of exogenous Fatty Acids. These proteins, when localized to the plasma membrane or at intracellular membrane junctions with the endoplasmic reticulum, function as a gate in the regulated Transport of Fatty Acids and thus represent a therapeutic target to delimit the acquisition of Fatty Acids that contribute to disease as in the case of Fatty Acid overload. To date, FATP1, FATP2, and FATP4 have been used as targets in the selection of small molecule inhibitors with the goal of treating insulin resistance and attenuating dietary absorption of Fatty Acids. Several studies targeting FATP1 and FATP4 were based on the intrinsic acyl CoA synthetase activity of these proteins and not on Transport directly. While several classes of compounds were identified as potential inhibitors of Fatty Acid Transport, in vivo studies using a mouse model failed to provide evidence these compounds were effective in blocking or attenuating Fatty Acid Transport. Studies targeting FATP2 employed a naturally occurring splice variant, FATP2b, which lacks intrinsic acyl CoA synthetase due to the deletion of exon 3, yet is fully functional in Fatty Acid Transport. These studies identified two compounds, 5'-bromo-5-phenyl-spiro[3H-1,3,4-thiadiazole-2,3'-indoline]-2'-one), now referred to as Lipofermata, and 2-benzyl-3-(4-chlorophenyl)-5-(4-nitrophenyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one, now called Grassofermata, that are effective Fatty Acid Transport inhibitors both in vitro using a series of model cell lines and in vivo using a mouse model.
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Overexpression of Human Fatty Acid Transport Protein 2/Very Long Chain Acyl-CoA Synthetase 1 (FATP2/Acsvl1) Reveals Distinct Patterns of Trafficking of Exogenous Fatty Acids
Biochemical and biophysical research communications, 2013Co-Authors: Elaina M. Melton, Concetta C. Dirusso, Ronald L. Cerny, Paul N. BlackAbstract:Abstract In mammals, the Fatty Acid Transport proteins (FATP1 through FATP6) are members of a highly conserved family of proteins, which function in Fatty Acid Transport proceeding through vectorial acylation and in the activation of very long chain Fatty Acids, branched chain Fatty Acids and secondary bile Acids. FATP1, 2 and 4, for example directly function in Fatty Acid Transport and very long chain Fatty Acids activation while FATP5 does not function in Fatty Acid Transport but activates secondary bile Acids. In the present work, we have used stable isotopically labeled Fatty Acids differing in carbon length and saturation in cells expressing FATP2 to gain further insights into how this protein functions in Fatty Acid Transport and intracellular Fatty Acid trafficking. Our previous studies showed the expression of FATP2 modestly increased C16:0-CoA and C20:4-CoA and significantly increased C18:3-CoA and C22:6-CoA after 4 h. The increases in C16:0-CoA and C18:3-CoA suggest FATP2 must necessarily partner with a long chain acyl CoA synthetase (Acsl) to generate C16:0-CoA and C18:3-CoA through vectorial acylation. The very long chain acyl CoA synthetase activity of FATP2 is consistent in the generation of C20:4-CoA and C22:6-CoA coincident with Transport from their respective exogenous Fatty Acids. The trafficking of exogenous Fatty Acids into phosphatidic Acid (PA) and into the major classes of phospholipids (phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), and phosphatidyserine (PS)) resulted in distinctive profiles, which changed with the expression of FATP2. The trafficking of exogenous C16:0 and C22:6 into PA was significant where there was 6.9- and 5.3-fold increased incorporation, respectively, over the control; C18:3 and C20:4 also trended to increase in the PA pool while there were no changes for C18:1 and C18:2. The trafficking of C18:3 into PC and PI trended higher and approached significance. In the case of C20:4, expression of FATP2 resulted in increases in all four classes of phospholipid, indicating little selectivity. In the case of C22:6, there were significant increases of this exogenous Fatty Acids being trafficking into PC and PI. Collectively, these data support the conclusion that FATP2 has a dual function in the pathways linking the Transport and activation of exogenous Fatty Acids. We discuss the differential roles of FATP2 and its role in both Fatty Acid Transport and Fatty Acid activation in the context of lipid homeostasis.
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human Fatty Acid Transport protein 2a very long chain acyl coa synthetase 1 fatp2a acsvl1 has a preference in mediating the channeling of exogenous n 3 Fatty Acids into phosphatidylinositol
Journal of Biological Chemistry, 2011Co-Authors: Paul A. Watkins, Concetta C. Dirusso, Elaina M. Melton, Ronald L. Cerny, Paul N. BlackAbstract:The trafficking of Fatty Acids across the membrane and into downstream metabolic pathways requires their activation to CoA thioesters. Members of the Fatty Acid Transport protein/very long chain acyl-CoA synthetase (FATP/Acsvl) family are emerging as key players in the trafficking of exogenous Fatty Acids into the cell and in intracellular Fatty Acid homeostasis. We have expressed two naturally occurring splice variants of human FATP2 (Acsvl1) in yeast and 293T-REx cells and addressed their roles in Fatty Acid Transport, activation, and intracellular trafficking. Although both forms (FATP2a (Mr 70,000) and FATP2b (Mr 65,000 and lacking exon3, which encodes part of the ATP binding site)) were functional in Fatty Acid import, only FATP2a had acyl-CoA synthetase activity, with an apparent preference toward very long chain Fatty Acids. To further address the roles of FATP2a or FATP2b in Fatty Acid uptake and activation, LC-MS/MS was used to separate and quantify different acyl-CoA species (C14–C24) and to monitor the trafficking of different classes of exogenous Fatty Acids into intracellular acyl-CoA pools in 293T-REx cells expressing either isoform. The use of stable isotopically labeled Fatty Acids demonstrated FATP2a is involved in the uptake and activation of exogenous Fatty Acids, with a preference toward n-3 Fatty Acids (C18:3 and C22:6). Using the same cells expressing FATP2a or FATP2b, electrospray ionization/MS was used to follow the trafficking of stable isotopically labeled n-3 Fatty Acids into phosphatidylcholine and phosphatidylinositol. The expression of FATP2a resulted in the trafficking of C18:3-CoA and C22:6-CoA into both phosphatidylcholine and phosphatidylinositol but with a distinct preference for phosphatidylinositol. Collectively these data demonstrate FATP2a functions in Fatty Acid Transport and activation and provides specificity toward n-3 Fatty Acids in which the corresponding n-3 acyl-CoAs are preferentially trafficked into acyl-CoA pools destined for phosphatidylinositol incorporation.
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Methods to monitor Fatty Acid Transport proceeding through vectorial acylation.
Methods in molecular biology (Clifton N.J.), 2009Co-Authors: Elsa Arias-barrau, Concetta C. Dirusso, Paul N. BlackAbstract:The process of Fatty Acid Transport across the plasma membrane occurs by several mechanisms that involve distinct membrane-bound and membrane-associated proteins and enzymes. Among these are the Fatty Acid Transport proteins (FATP) and long-chain acyl CoA synthetases (Acsl). Previous studies in yeast and adipocytes have shown FATP and Acsl form a physical complex at the plasma membrane and are required for Fatty Acid Transport, which proceeds through a coupled process-linking Transport with metabolic activation termed vectorial acylation. At present, six isoforms of FATP and five isoforms of ACSL have been identified in mice and man. In addition, there are a number of splice variants of different FATP and Acsl isoforms. The different FATP and Acsl isoforms have distinct tissue expression profiles and different cellular locations suggesting they function in the channeling of Fatty Acids into discrete metabolic pools. The concerted activity of these proteins is proposed to allow cells to discriminate different classes of Fatty Acids and provides the mechanistic basis underpinning the selectivity and specificity of the Fatty Acid Transport process.
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Targeting the Fatty Acid Transport proteins (FATP) to understand the mechanisms linking Fatty Acid Transport to metabolism
Immunology endocrine & metabolic agents in medicinal chemistry, 2009Co-Authors: Paul N. Black, Elsa Arias-barrau, Angel Sandoval, Concetta C. DirussoAbstract:One principal process driving Fatty Acid Transport is vectorial acylation, where Fatty Acids traverse the membrane concomitant with activation to CoA thioesters. Current evidence is consistent with the proposal that specific Fatty Acid Transport (FATP) isoforms alone or in concert with specific long chain acyl CoA synthetase (Acsl) isoforms function to drive this energy-dependent process. Understanding the details of vectorial acylation is of particular importance as disturbances in lipid metabolism many times leads to elevated levels of circulating free Fatty Acids, which in turn increases Fatty Acid internalization and ectopic accumulation of triglycerides. This is associated with changes in Fatty Acid oxidation rates, accumulation of reactive oxygen species, the synthesis of ceramide and ER stress. The correlation between chronically elevated plasma free Fatty Acids and triglycerides with the development of obesity, insulin resistance and cardiovascular disease has led to the hypothesis that decreases in pancreatic insulin production, cardiac failure, arrhythmias, and hypertrophy are due to aberrant accumulation of lipids in these tissues. To this end, a detailed understanding of how Fatty Acids traverse the plasma membrane, become activated and trafficked into downstream metabolic pools and the precise roles provided by the different FATP and Acsl isoforms are especially important questions. We review our current understanding of vectorial acylation and the contributions by specific FATP and Acsl isoforms and the identification of small molecule inhibitors from high throughput screens that inhibit this process and thus provide new insights into the underlying mechanistic basis of this process.
Jan F. C. Glatz - One of the best experts on this subject based on the ideXlab platform.
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Fatty Acid Transport and Transporters in muscle are critically regulated by Akt2.
FEBS Letters, 2015Co-Authors: Swati S. Jain, Graham P. Holloway, Joost J. F. P. Luiken, Jan F. C. Glatz, Laelie A. Snook, Xiao-xia Han, Arend BonenAbstract:Muscle contains various Fatty Acid Transporters (CD36, FABPpm, FATP1, FATP4). Physiological stimuli (insulin, contraction) induce the translocation of all four Transporters to the sarcolemma to enhance Fatty Acid uptake similarly to glucose uptake stimulation via glucose Transporter-4 (GLUT4) translocation. Akt2 mediates insulin-induced, but not contraction-induced, GLUT4 translocation, but its role in muscle Fatty Acid Transporter translocation is unknown. In muscle from Akt2-knockout mice, we observed that Akt2 is critically involved in both insulin-induced and contraction-induced Fatty Acid Transport and translocation of Fatty Acid translocase/CD36 (CD36) and FATP1, but not of translocation of Fatty Acid-binding protein (FABPpm) and FATP4. Instead, Akt2 mediates intracellular retention of both latter Transporters. Collectively, our observations reveal novel complexities in signaling mechanisms regulating the translocation of Fatty Acid Transporters in muscle.
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Fatty Acid Transport across the cell membrane: Regulation by Fatty Acid Transporters
Prostaglandins Leukotrienes and Essential Fatty Acids, 2010Co-Authors: Robert W. Schwenk, Graham P. Holloway, Joost J. F. P. Luiken, Arend Bonen, Jan F. C. GlatzAbstract:Abstract 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.
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Fatty Acid Transport in skeletal muscle: role in energy provision and insulin resistance
Clinical Lipidology, 2010Co-Authors: Graham P. Holloway, Robert W. Schwenk, Joost J. F. P. Luiken, Jan F. C. Glatz, Arend BonenAbstract:Long-chain Fatty Acid uptake has now been shown to occur via a highly regulated, protein-mediated mechanism involving plasma membrane Fatty Acid Transporters. This process is especially important in skeletal muscle, a tissue with a highly variable metabolic rate that constitutes approximately 40% of body mass. We review the evidence that skeletal muscle Fatty Acid Transport is acutely and chronically regulated by muscle contraction and insulin, largely by the Fatty Acid Transporter CD36. We also examine recent data suggesting that CD36 may contribute to regulating Fatty Acid oxidation by mitochondria. In addition, we review evidence showing that skeletal muscle insulin resistance is associated with the dysregulation of CD36-mediated Fatty Acid Transport, and that the insulin-sensitizing effects of proliferator-activated receptor-γ coactivator-1α may depend on limiting CD36 upregulation. Taken altogether, it is apparent that skeletal muscle Fatty Acid Transport is central to the regulation of whole-body li...
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Cardiac and skeletal muscle Fatty Acid Transport and Transporters and triacylglycerol and Fatty Acid oxidation in lean and Zucker diabetic Fatty rats.
American journal of physiology. Regulatory integrative and comparative physiology, 2009Co-Authors: Arend Bonen, Graham P. Holloway, Jan F. C. Glatz, Narendra N. Tandon, Xiao-xia Han, Jay T. Mcfarlan, Joost J. F. P. LuikenAbstract:We examined Fatty Acid Transporters, Transport, and metabolism in hearts and red and white muscles of lean and insulin-resistant (week 6) and type 2 diabetic (week 24) Zucker diabetic Fatty (ZDF) rats. Cardiac Fatty Acid Transport was similar in lean and ZDF hearts at week 6 but was reduced at week 24 (-40%) in lean but not ZDF hearts. Red muscle of ZDF rats exhibited an early susceptibility to upregulation (+66%) of Fatty Acid Transport at week 6 that was increased by 50% in lean and ZDF rats at week 24 but remained 44% greater in red muscle of ZDF rats. In white muscle, no differences were observed in Fatty Acid Transport between groups or from week 6 to week 24. In all tissues (heart and red and white muscle), FAT/CD36 protein and plasmalemmal content paralleled the changes in Fatty Acid Transport. Triacylglycerol content in red and white muscles, but not heart, in lean and ZDF rats correlated with Fatty Acid Transport (r = 0.91) and sarcolemmal FAT/CD36 (r = 0.98). Red and white muscle Fatty Acid oxidation by isolated mitochondria was not impaired in ZDF rats but was reduced by 18-24% in red muscle of lean rats at week 24. Thus, in red, but not white, muscle of insulin-resistant and type 2 diabetic animals, a marked upregulation in Fatty Acid Transport and intramuscular triacylglycerol was associated with increased levels of FAT/CD36 expression and plasmalemmal content. In heart, greater rates of Fatty Acid Transport and FAT/CD36 in ZDF rats (week 24) were attributable to the inhibition of age-related reductions in these parameters. However, intramuscular triacylglycerol did not accumulate in hearts of ZDF rats. Thus insulin resistance and type 2 diabetes are accompanied by tissue-specific differences in FAT/CD36 and Fatty Acid Transport and metabolism. Upregulation of Fatty Acid Transport increased red muscle, but not cardiac, triacylglycerol accumulation. White muscle lipid metabolism dysregulation was not observed.
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additive effects of insulin and muscle contraction on Fatty Acid Transport and Fatty Acid Transporters fat cd36 fabppm fatp1 4 and 6
FEBS Letters, 2009Co-Authors: Swati S. Jain, Robert W. Schwenk, Joost J. F. P. Luiken, Jan F. C. Glatz, Laelie A. Snook, Adrian Chabowski, Arend BonenAbstract:Insulin and muscle contraction increase Fatty Acid Transport into muscle by inducing the translocation of FAT/CD36. We examined (a) whether these effects are additive, and (b) whether other Fatty Acid Transporters (FABPpm, FATP1, FATP4, and FATP6) are also induced to translocate. Insulin and muscle contraction increased glucose Transport and plasmalemmal GLUT4 independently and additively (positive control). Palmitate Transport was also stimulated independently and additively by insulin and by muscle contraction. Insulin and muscle contraction increased plasmalemmal FAT/CD36, FABPpm, FATP1, and FATP4, but not FATP6. Only FAT/CD36 and FATP1 were stimulated in an additive manner by insulin and by muscle contraction.
