The Experts below are selected from a list of 297 Experts worldwide ranked by ideXlab platform
H B Brewer - One of the best experts on this subject based on the ideXlab platform.
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decreased reverse cholesterol transport from tangier disease fibroblasts acceptor specificity and effect of brefeldin on lipid efflux
Arteriosclerosis Thrombosis and Vascular Biology, 1997Co-Authors: Alan T Remaley, Uwe K Schumacher, John A Stonik, B D Farsi, H Nazih, H B BrewerAbstract:Abstract Tangier disease is characterized by HDL hypercatabolism and increased deposition of cholesterol in tissues. Tangier disease skin fibroblasts have decreased apoA-I-mediated cholesterol and phospholipid efflux, which may lead to the excess accumulation of cellular cholesterol. The mechanism of Apolipoprotein-mediated cholesterol efflux and the Apolipoprotein acceptor specificity for cholesterol efflux from normal and Tangier disease fibroblasts was investigated. Normal cells readily effluxed cholesterol and phospholipid to apoA-I and to all of the other Apolipoproteins tested (apoA-II, AIV, C-I, C-II, C-III). In contrast, Tangier cells were almost completely defective in cholesterol efflux to apoA-I and to all of the other Apolipoproteins tested. HDL was also less effective, by approximately 50%, in stimulating cholesterol efflux from Tangier cells compared with normal cells. In addition, Tangier cells also showed significantly reduced phospholipid efflux to both Apolipoproteins and HDL. A similar rate of cholesterol efflux, however, was observed from normal and Tangier cells when phospholipid vesicles or cyclodextrin were used as acceptors. In contrast to normal cells, only phospholipid vesicles and cyclodextrin and not apoA-I or HDL depleted intracellular cholesteryl esters from Tangier cells. Brefeldin, an inhibitor of intracellular vesicular trafficking, decreased HDL-mediated cholesterol efflux by approximately 40% but almost completely blocked both cholesterol and phospholipid efflux to apoA-I from normal cells. Brefeldin also inhibited cholesteryl ester depletion by apoA-I and HDL from normal cells. Brefeldin, however, had no significant effect on cholesterol efflux from Tangier cells to HDL. In summary, Tangier cells were found to be defective in both cholesterol and phospholipid efflux to HDL and apoA-I. The defect in Apolipoprotein-mediated lipid efflux was not specific for apoA-I but also occurred for other Apolipoproteins, and brefeldin blocked HDL-mediated lipid efflux from normal but not Tangier disease cells. On the basis of these results, a model is proposed whereby decreased cholesterol efflux by Apolipoproteins in Tangier cells is the result of a defect in a brefeldin-sensitive pathway of lipid efflux. ( Arterioscler Thromb Vasc Biol . 1997;17:1813-1821.)
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decreased reverse cholesterol transport from tangier disease fibroblasts acceptor specificity and effect of brefeldin on lipid efflux
Arteriosclerosis Thrombosis and Vascular Biology, 1997Co-Authors: Alan T Remaley, Uwe K Schumacher, John A Stonik, B D Farsi, H Nazih, H B BrewerAbstract:Tangier disease is characterized by HDL hypercatabolism and increased deposition of cholesterol in tissues. Tangier disease skin fibroblasts have decreased apoA-I-mediated cholesterol and phospholipid efflux, which may lead to the excess accumulation of cellular cholesterol. The mechanism of Apolipoprotein-mediated cholesterol efflux and the Apolipoprotein acceptor specificity for cholesterol efflux from normal and Tangier disease fibroblasts was investigated. Normal cells readily effluxed cholesterol and phospholipid to apoA-I and to all of the other Apolipoproteins tested (apoA-II, AIV, C-I, C-II, C-III). In contrast, Tangier cells were almost completely defective in cholesterol efflux to apoA-I and to all of the other Apolipoproteins tested. HDL was also less effective, by approximately 50%, in stimulating cholesterol efflux from Tangier cells compared with normal cells. In addition, Tangier cells also showed significantly reduced phospholipid efflux to both Apolipoproteins and HDL. A similar rate of cholesterol efflux, however, was observed from normal and Tangier cells when phospholipid vesicles or cyclodextrin were used as acceptors. In contrast to normal cells, only phospholipid vesicles and cyclodextrin and not apoA-I or HDL depleted intracellular cholesteryl esters from Tangier cells. Brefeldin, an inhibitor of intracellular vesicular trafficking, decreased HDL-mediated cholesterol efflux by approximately 40% but almost completely blocked both cholesterol and phospholipid efflux to apoA-I from normal cells. Brefeldin also inhibited cholesteryl ester depletion by apoA-I and HDL from normal cells. Brefeldin, however, had no significant effect on cholesterol efflux from Tangier cells to HDL. In summary, Tangier cells were found to be defective in both cholesterol and phospholipid efflux to HDL and apoA-I. The defect in Apolipoprotein-mediated lipid efflux was not specific for apoA-I but also occurred for other Apolipoproteins, and brefeldin blocked HDL-mediated lipid efflux from normal but not Tangier disease cells. On the basis of these results, a model is proposed whereby decreased cholesterol efflux by Apolipoproteins in Tangier cells is the result of a defect in a brefeldin-sensitive pathway of lipid efflux.
John F. Oram - One of the best experts on this subject based on the ideXlab platform.
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abca1 mutants reveal an interdependency between lipid export function apoa i binding activity and janus kinase 2 activation
Journal of Lipid Research, 2009Co-Authors: Ashley M. Vaughan, Chongren Tang, John F. OramAbstract:ABCA1 exports cholesterol and phospholipids from cells by a multistep pathway that involves forming cell surface lipid domains, solubilizing these lipids by Apolipoproteins, binding of Apolipoproteins to ABCA1, and activating signaling processes. Here we used a mutational analysis approach to evaluate the relationship between these events. We prepared seven naturally occurring mutants and one artificial missense mutant of ABCA1 with varying degrees of impaired function, expressed them to similar levels as wild-type ABCA1 on the cell surface of BHK cells, and measured ABCA1-dependent lipid export, Apolipoprotein A-I (apoA-I) binding, and signaling activities. Linear regression analyses showed that cholesterol and phospholipid efflux and cellular apoA-I binding correlated significantly with the ability of ABCA1 to form cell surface lipid domains. Lipid export and cellular apoA-I binding activities and formation of lipid domains also correlated with the amount of apoA-I that could be cross-linked to ABCA1. Moreover, each of these lipid export and apoA-I binding activities correlated with apoA-I-induced Janus kinase 2 (JAK2) activation. Thus, these missense mutations in ABCA1 impair lipid export, apoA-I binding, and apoA-I-stimulated JAK2 activities to similar extents, indicating that these processes are highly interactive components of a pathway that functions to export lipids from cells.
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abca1 redistributes membrane cholesterol independent of Apolipoprotein interactions
Journal of Lipid Research, 2003Co-Authors: Ashley M. Vaughan, John F. OramAbstract:ATP binding cassette transporter A1 (ABCA1) mediates the transport of phospholipids and cholesterol from cells to lipid-poor HDL Apolipoproteins. Cholesterol loading of cells induces ABCA1, implicating cholesterol as its major physiologic substrate. It is believed, however, that ABCA1 is primarily a phospholipid transporter and that cholesterol efflux occurs by diffusion to ABCA1-generated phospholipid-rich Apolipoproteins. Here we show that over- expression of ABCA1 in baby hamster kidney cells in the ab- sence of Apolipoproteins redistributed membrane choles- terol to cell-surface domains accessible to treatment with the enzyme cholesterol oxidase. The cholesterol removed by Apolipoprotein A-I (apoA-I), but not by HDL phospholip- ids, was derived exclusively from these domains. ABCA1 overexpression also increased cholesterol esterification, which was prevented by addition of apoA-I, suggesting that some of the cell-surface cholesterol not removed by apolipo- proteins is transported to the intracellular esterifying enzyme acyl-CoA:cholesterol acyltransferase. ABCA1 expression was essential for cholesterol efflux even when apolipopro- teins had already acquired phospholipids during prior ex- posure to ABCA1-expressing cells. These studies show that ABCA1 redistributes cholesterol to cell-surface do- mains, where it becomes accessible for removal by apolipo- proteins, consistent with a direct role of ABCA1 in choles- terol transport. —Vaughan, A. M., and J. F. Oram. ABCA1 redistributes membrane cholesterol independent of apoli- poprotein interactions. J. Lipid Res. 2003. 44: 1373-1380.
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hdl Apolipoproteins and abca1 partners in the removal of excess cellular cholesterol
Arteriosclerosis Thrombosis and Vascular Biology, 2003Co-Authors: John F. OramAbstract:It is widely believed that HDL protects against atherosclerosis by removing excess cholesterol from arterial cells. Lipid-poor HDL Apolipoproteins promote efflux of cholesterol, phospholipids, and other lipophilic molecules from cells by an active process mediated by a cell-membrane transporter called the ATP binding cassette transporter A-1 (ABCA1). ABCA1 either directly or indirectly translocates phospholipids and cholesterol to the cell surface, where they appear to form lipid domains that interact with amphipathic α-helixes in Apolipoproteins. This interaction solubilizes these lipids and generates nascent HDL particles that dissociate from the cell. Binding of Apolipoproteins to ABCA1 may also enhance the activity of this lipid-transport pathway. Thus, the Apolipoprotein/ABCA1 pathway efficiently clears cells of excess cholesterol that would otherwise accumulate as intracellular lipid droplets. ABCA1 expression is highly induced by cholesterol loading of cells and is also modulated by sterol-independent mechanisms at both the transcriptional and posttranslational level. Studies of human disease and animal models have shown that both an increased availability of Apolipoproteins and an enhanced macrophage ABCA1 activity are atheroprotective. These findings implicate the Apolipoprotein/ABCA1 pathway as an important therapeutic target for treating cardiovascular disease.
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abca1 is the camp inducible Apolipoprotein receptor that mediates cholesterol secretion from macrophages
Journal of Biological Chemistry, 2000Co-Authors: John F. Oram, Richard M Lawn, Michael R Garvin, David WadeAbstract:Abstract Lipid-poor high density lipoprotein Apolipoproteins remove cholesterol and phospholipids from cells by an active secretory pathway controlled by an ABC transporter called ABCA1. This pathway is induced by cholesterol and cAMP analogs in a cell-specific manner. Here we provide evidence that increased plasma membrane ABCA1 accounts for the enhanced Apolipoprotein-mediated lipid secretion from macrophages induced by cAMP analogs. Treatment of RAW264 macrophages with 8-bromo-cAMP caused parallel increases in apoA-I-mediated cholesterol efflux, ABCA1 mRNA and protein levels, incorporation of ABCA1 into the plasma membrane, and binding of apoA-I to cell-surface ABCA1. All of these parameters declined to near base-line values within 6 h after removal of 8-bromo-cAMP, indicating that ABCA1 is highly unstable and is degraded rapidly in the absence of inducer. Thus, ABCA1 is likely to be the cAMP-inducible Apolipoprotein receptor that promotes removal of cholesterol and phospholipids from macrophages.
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limited proteolysis of high density lipoprotein abolishes its interaction with cell surface binding sites that promote cholesterol efflux
Biochimica et Biophysica Acta, 1997Co-Authors: Armando J Mendez, John F. OramAbstract:High-density lipoprotein (HDL) components remove cholesterol from cells by two independent mechanisms. Whereas HDL phospholipids pick up cholesterol that desorbs from the plasma membranes, HDL Apolipoproteins appear to interact with cell-surface binding sites that target for removal pools of cellular cholesterol that feed into the cholesteryl ester cycle. Here we show that mild trypsin treatment of HDL almost completely abolishes this Apolipoprotein-mediated cholesterol removal process. When HDL was treated with trypsin for various periods of time and then incubated with cholesterol-loaded fibroblasts, treatment for only 5 min reduced the ability of HDL to remove excess cholesterol from cellular pools that were accessible to esterification by the enzyme acyl CoA:cholesterol acyltransferase. This mild treatment digested less than 20% of HDL Apolipoproteins and did not alter the lipid composition, size distribution, or electrophoretic mobility of the particles. Trypsin treatment of HDL for up to 1 h caused no further reduction in its ability to remove cellular cholesterol despite a greater than 2-fold increase in Apolipoprotein digestion. Trypsin treatment of HDL also reduced its ability to deplete the cholesteryl ester content of sterol-laden macrophages. Promotion of cholesterol efflux from the plasma membrane by HDL phospholipids was unaffected by even extensive proteolysis. In parallel to the loss of cholesterol transport-stimulating activity, trypsin treatment of HDL for only 5 min nearly abolished its interaction with high-affinity binding sites on cholesterol-loaded fibroblasts. Reconstitution of trypsin-modified HDL with isolated apo A-I or apo A-II restored the cholesterol transport-stimulating activity of the particles. Thus a minor trypsin-labile fraction of HDL Apolipoproteins is almost exclusively responsible for the Apolipoprotein-dependent component of cholesterol efflux mediated by HDL particles.
Alan T Remaley - One of the best experts on this subject based on the ideXlab platform.
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binding and internalization of lipopolysaccharide by cla 1 a human orthologue of rodent scavenger receptor b1
Journal of Biological Chemistry, 2003Co-Authors: Tatyana G Vishnyakova, Alan T Remaley, Alexander V Bocharov, Irina N Baranova, Zhigang Chen, Gyorgy Csako, Thomas L Eggerman, Amy P PattersonAbstract:Abstract Scavenger receptor, class B, type I (SR-BI) mediates selective uptake of high density lipoprotein (HDL) cholesteryl ester. SR-BI recognizes HDL, low density lipoprotein (LDL), exchangeable Apolipoproteins, and protein-free lipid vesicles containing negatively charged phospholipids. Lipopolysaccharides (LPS) are highly glycosylated anionic phospholipids contributing to septic shock. Despite significant structural similarities between anionic phospholipids and LPS, the role of SR-BI in LPS uptake is unknown. Cla-1, the human SR-BI orthologue, was determined to be a LPS-binding protein and endocytic receptor mediating the binding and internalization of lipoprotein-free, monomerized LPS. LPS strongly competed with HDL, lipidfree apoA-I and apoA-II for HDL binding to the mouse RAW cells. Stably transfected HeLa cells expressing Cla-1-bound LPS with a Kd of about 16 μg/ml, and had a 3–4-fold increase in binding capacity and LPS uptake. Bodipy-labeled LPS uptake was found to initially accumulate in the plasma membrane and subsequently in a perinuclear region identified predominantly as the Golgi complex. Bodipy-LPS and Alexa-apoA-I had staining that colocalized on the cell surface and intracellularly indicating similar transport mechanisms. When associated with HDL, LPS uptake was increased in Cla-1 overexpressing HeLa cells by 5–10-fold. Cla-1-associated 3H-LPS uptake exceeded 125I-Apolipoprotein uptake by 5-fold indicating a selective LPS uptake. Upon interacting with Cla-1 overexpressing HeLa cells, the complex (Bodipy-LPS/Alexa 488 Apolipoprotein-labeled HDL) bound and was internalized as a holoparticle. Intracellularly, LPS and Apolipoproteins were sorted to different intracellular compartments. With LPS-associated HDL, intracellular LPS co-localized predominantly with transferrin, indicating delivery to an endocytic recycling compartment. Our study reveals a close similarity between Cla-1-mediated selective LPS uptake and the recently described selective lipid sorting by rodent SR-BI. In summary, Cla-1 was found to bind and internalize monomerized and HDL-associated LPS, indicating that Cla-1 may play important role in septic shock by affecting LPS cellular uptake and clearance.
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decreased reverse cholesterol transport from tangier disease fibroblasts acceptor specificity and effect of brefeldin on lipid efflux
Arteriosclerosis Thrombosis and Vascular Biology, 1997Co-Authors: Alan T Remaley, Uwe K Schumacher, John A Stonik, B D Farsi, H Nazih, H B BrewerAbstract:Abstract Tangier disease is characterized by HDL hypercatabolism and increased deposition of cholesterol in tissues. Tangier disease skin fibroblasts have decreased apoA-I-mediated cholesterol and phospholipid efflux, which may lead to the excess accumulation of cellular cholesterol. The mechanism of Apolipoprotein-mediated cholesterol efflux and the Apolipoprotein acceptor specificity for cholesterol efflux from normal and Tangier disease fibroblasts was investigated. Normal cells readily effluxed cholesterol and phospholipid to apoA-I and to all of the other Apolipoproteins tested (apoA-II, AIV, C-I, C-II, C-III). In contrast, Tangier cells were almost completely defective in cholesterol efflux to apoA-I and to all of the other Apolipoproteins tested. HDL was also less effective, by approximately 50%, in stimulating cholesterol efflux from Tangier cells compared with normal cells. In addition, Tangier cells also showed significantly reduced phospholipid efflux to both Apolipoproteins and HDL. A similar rate of cholesterol efflux, however, was observed from normal and Tangier cells when phospholipid vesicles or cyclodextrin were used as acceptors. In contrast to normal cells, only phospholipid vesicles and cyclodextrin and not apoA-I or HDL depleted intracellular cholesteryl esters from Tangier cells. Brefeldin, an inhibitor of intracellular vesicular trafficking, decreased HDL-mediated cholesterol efflux by approximately 40% but almost completely blocked both cholesterol and phospholipid efflux to apoA-I from normal cells. Brefeldin also inhibited cholesteryl ester depletion by apoA-I and HDL from normal cells. Brefeldin, however, had no significant effect on cholesterol efflux from Tangier cells to HDL. In summary, Tangier cells were found to be defective in both cholesterol and phospholipid efflux to HDL and apoA-I. The defect in Apolipoprotein-mediated lipid efflux was not specific for apoA-I but also occurred for other Apolipoproteins, and brefeldin blocked HDL-mediated lipid efflux from normal but not Tangier disease cells. On the basis of these results, a model is proposed whereby decreased cholesterol efflux by Apolipoproteins in Tangier cells is the result of a defect in a brefeldin-sensitive pathway of lipid efflux. ( Arterioscler Thromb Vasc Biol . 1997;17:1813-1821.)
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decreased reverse cholesterol transport from tangier disease fibroblasts acceptor specificity and effect of brefeldin on lipid efflux
Arteriosclerosis Thrombosis and Vascular Biology, 1997Co-Authors: Alan T Remaley, Uwe K Schumacher, John A Stonik, B D Farsi, H Nazih, H B BrewerAbstract:Tangier disease is characterized by HDL hypercatabolism and increased deposition of cholesterol in tissues. Tangier disease skin fibroblasts have decreased apoA-I-mediated cholesterol and phospholipid efflux, which may lead to the excess accumulation of cellular cholesterol. The mechanism of Apolipoprotein-mediated cholesterol efflux and the Apolipoprotein acceptor specificity for cholesterol efflux from normal and Tangier disease fibroblasts was investigated. Normal cells readily effluxed cholesterol and phospholipid to apoA-I and to all of the other Apolipoproteins tested (apoA-II, AIV, C-I, C-II, C-III). In contrast, Tangier cells were almost completely defective in cholesterol efflux to apoA-I and to all of the other Apolipoproteins tested. HDL was also less effective, by approximately 50%, in stimulating cholesterol efflux from Tangier cells compared with normal cells. In addition, Tangier cells also showed significantly reduced phospholipid efflux to both Apolipoproteins and HDL. A similar rate of cholesterol efflux, however, was observed from normal and Tangier cells when phospholipid vesicles or cyclodextrin were used as acceptors. In contrast to normal cells, only phospholipid vesicles and cyclodextrin and not apoA-I or HDL depleted intracellular cholesteryl esters from Tangier cells. Brefeldin, an inhibitor of intracellular vesicular trafficking, decreased HDL-mediated cholesterol efflux by approximately 40% but almost completely blocked both cholesterol and phospholipid efflux to apoA-I from normal cells. Brefeldin also inhibited cholesteryl ester depletion by apoA-I and HDL from normal cells. Brefeldin, however, had no significant effect on cholesterol efflux from Tangier cells to HDL. In summary, Tangier cells were found to be defective in both cholesterol and phospholipid efflux to HDL and apoA-I. The defect in Apolipoprotein-mediated lipid efflux was not specific for apoA-I but also occurred for other Apolipoproteins, and brefeldin blocked HDL-mediated lipid efflux from normal but not Tangier disease cells. On the basis of these results, a model is proposed whereby decreased cholesterol efflux by Apolipoproteins in Tangier cells is the result of a defect in a brefeldin-sensitive pathway of lipid efflux.
Hugo Jozef Bellen - One of the best experts on this subject based on the ideXlab platform.
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the glia neuron lactate shuttle and elevated ros promote lipid synthesis in neurons and lipid droplet accumulation in glia via apoe d
Cell Metabolism, 2017Co-Authors: Kevin R. Mackenzie, Mirjana Maleticsavatic, Nagireddy Putluri, Hugo Jozef BellenAbstract:Summary Elevated reactive oxygen species (ROS) induce the formation of lipids in neurons that are transferred to glia, where they form lipid droplets (LDs). We show that glial and neuronal monocarboxylate transporters (MCTs), fatty acid transport proteins (FATPs), and Apolipoproteins are critical for glial LD formation. MCTs enable glia to secrete and neurons to absorb lactate, which is converted to pyruvate and acetyl-CoA in neurons. Lactate metabolites provide a substrate for synthesis of fatty acids, which are processed and transferred to glia by FATP and Apolipoproteins. In the presence of high ROS, inhibiting lactate transfer or lowering FATP or Apolipoprotein levels decreases glial LD accumulation in flies and in primary mouse glial-neuronal cultures. We show that human APOE can substitute for a fly glial Apolipoprotein and that APOE4, an Alzheimer's disease susceptibility allele, is impaired in lipid transport and promotes neurodegeneration, providing insights into disease mechanisms.
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the glia neuron lactate shuttle and elevated ros promote lipid synthesis in neurons and lipid droplet accumulation in glia via apoe d
Cell Metabolism, 2017Co-Authors: Kevin R. Mackenzie, Mirjana Maleticsavatic, Nagireddy Putluri, Hugo Jozef BellenAbstract:Summary Elevated reactive oxygen species (ROS) induce the formation of lipids in neurons that are transferred to glia, where they form lipid droplets (LDs). We show that glial and neuronal monocarboxylate transporters (MCTs), fatty acid transport proteins (FATPs), and Apolipoproteins are critical for glial LD formation. MCTs enable glia to secrete and neurons to absorb lactate, which is converted to pyruvate and acetyl-CoA in neurons. Lactate metabolites provide a substrate for synthesis of fatty acids, which are processed and transferred to glia by FATP and Apolipoproteins. In the presence of high ROS, inhibiting lactate transfer or lowering FATP or Apolipoprotein levels decreases glial LD accumulation in flies and in primary mouse glial-neuronal cultures. We show that human APOE can substitute for a fly glial Apolipoprotein and that APOE4, an Alzheimer's disease susceptibility allele, is impaired in lipid transport and promotes neurodegeneration, providing insights into disease mechanisms.
Mirjana Maleticsavatic - One of the best experts on this subject based on the ideXlab platform.
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the glia neuron lactate shuttle and elevated ros promote lipid synthesis in neurons and lipid droplet accumulation in glia via apoe d
Cell Metabolism, 2017Co-Authors: Kevin R. Mackenzie, Mirjana Maleticsavatic, Nagireddy Putluri, Hugo Jozef BellenAbstract:Summary Elevated reactive oxygen species (ROS) induce the formation of lipids in neurons that are transferred to glia, where they form lipid droplets (LDs). We show that glial and neuronal monocarboxylate transporters (MCTs), fatty acid transport proteins (FATPs), and Apolipoproteins are critical for glial LD formation. MCTs enable glia to secrete and neurons to absorb lactate, which is converted to pyruvate and acetyl-CoA in neurons. Lactate metabolites provide a substrate for synthesis of fatty acids, which are processed and transferred to glia by FATP and Apolipoproteins. In the presence of high ROS, inhibiting lactate transfer or lowering FATP or Apolipoprotein levels decreases glial LD accumulation in flies and in primary mouse glial-neuronal cultures. We show that human APOE can substitute for a fly glial Apolipoprotein and that APOE4, an Alzheimer's disease susceptibility allele, is impaired in lipid transport and promotes neurodegeneration, providing insights into disease mechanisms.
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the glia neuron lactate shuttle and elevated ros promote lipid synthesis in neurons and lipid droplet accumulation in glia via apoe d
Cell Metabolism, 2017Co-Authors: Kevin R. Mackenzie, Mirjana Maleticsavatic, Nagireddy Putluri, Hugo Jozef BellenAbstract:Summary Elevated reactive oxygen species (ROS) induce the formation of lipids in neurons that are transferred to glia, where they form lipid droplets (LDs). We show that glial and neuronal monocarboxylate transporters (MCTs), fatty acid transport proteins (FATPs), and Apolipoproteins are critical for glial LD formation. MCTs enable glia to secrete and neurons to absorb lactate, which is converted to pyruvate and acetyl-CoA in neurons. Lactate metabolites provide a substrate for synthesis of fatty acids, which are processed and transferred to glia by FATP and Apolipoproteins. In the presence of high ROS, inhibiting lactate transfer or lowering FATP or Apolipoprotein levels decreases glial LD accumulation in flies and in primary mouse glial-neuronal cultures. We show that human APOE can substitute for a fly glial Apolipoprotein and that APOE4, an Alzheimer's disease susceptibility allele, is impaired in lipid transport and promotes neurodegeneration, providing insights into disease mechanisms.