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Daniel J. Rader - One of the best experts on this subject based on the ideXlab platform.
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lymphatics as a new active player in reverse Cholesterol Transport
Cell Metabolism, 2013Co-Authors: Mark L Kahn, Daniel J. RaderAbstract:Reverse Cholesterol Transport (RCT), a key function of high-density lipoproteins (HDL), prevents excess Cholesterol in tissues. A study in this issue (Lim et al., 2013) suggests that lymphatic vessels are critical for normal RCT and mediate the active trans-endothelial Transport of HDL via the HDL receptor SR-BI.
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tissue specific liver x receptor activation promotes macrophage reverse Cholesterol Transport in vivo
Arteriosclerosis Thrombosis and Vascular Biology, 2010Co-Authors: Tomoyuki Yasuda, Didier Grillot, Jeffery T Billheimer, Francois Briand, Philippe Delerive, Stephane Huet, Daniel J. RaderAbstract:Objective— We previously reported that a systemic liver X receptor (LXR) agonist promoted macrophage reverse-Cholesterol Transport (mRCT) in vivo. Because LXR are expressed in multiple tissues invo...
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Macrophage Reverse Cholesterol Transport in Mice Expressing ApoA-I Milano
Arteriosclerosis thrombosis and vascular biology, 2009Co-Authors: Eric T. Alexander, George H Rothblat, Michael C. Phillips, Ginny L. Weibel, Michelle R. Joshi, Charulatha Vedhachalam, Margarita De La Llera-moya, Daniel J. RaderAbstract:Objective— To compare the abilities of human wild-type apoA-I (WT apoA-I) and human apoA-IMilano (apoA-IM) to promote macrophage reverse Cholesterol Transport (RCT) in apoA-I–null mice infected wit...
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molecular regulation of macrophage reverse Cholesterol Transport
Current Opinion in Cardiology, 2007Co-Authors: Xun Wang, Daniel J. RaderAbstract:Purpose of reviewMacrophage reverse Cholesterol Transport is one of the key mechanisms mediating the protective effects of high-density lipoproteins on atherosclerosis. This review focuses on the recent developments in our understanding of molecular mechanisms of macrophage reverse Transport and reg
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regulation of reverse Cholesterol Transport and clinical implications
American Journal of Cardiology, 2003Co-Authors: Daniel J. RaderAbstract:Plasma levels of high-density lipoprotein (HDL) Cholesterol and its major protein, apolipoprotein A-I, are inversely correlated with the incidence of atherosclerotic cardiovascular disease. Low HDL Cholesterol and apolipoprotein A-I levels often are found in association with other cardiovascular risk factors, including the metabolic syndrome, insulin resistance, and type 2 diabetes mellitus. However, overexpression of apolipoprotein A-I in animals has been shown to reduce progression and even induce regression of atherosclerosis, indicating that apolipoprotein A-I is directly protective against atherosclerosis. A major mechanism by which apolipoprotein A-I inhibits atherosclerosis may be by promoting Cholesterol efflux from macrophages and returning it to the liver for excretion, a process termed reverse Cholesterol Transport. This article focuses on new developments in the regulation of reverse Cholesterol Transport and the clinical implications of those developments.
Laura Liscum - One of the best experts on this subject based on the ideXlab platform.
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deficiency in ethanolamine plasmalogen leads to altered Cholesterol Transport
Journal of Lipid Research, 2003Co-Authors: Natalie J Munn, Emily Arnio, Raphael A Zoeller, Laura LiscumAbstract:Plasmalogens are a major sub-class of ethanolamine and choline phospholipids in which the sn -1 position has a long chain fatty alcohol attached through a vinyl ether bond. These phospholipids are proposed to play a role in membrane fusion-mediated events. In this study, we investi- gated the role of the ethanolamine plasmalogen plasmenyl- ethanolamine (PlsEtn) in intracellular Cholesterol Transport in Chinese hamster ovary cell mutants NRel-4 and NZel-1, which have single gene defects in PlsEtn biosynthesis. We found that PlsEtn was essential for specific Cholesterol Transport path- ways, those from the cell surface or endocytic compart- ments to acyl-CoA/Cholesterol acyltransferase in the endo- plasmic reticulum. The movement of Cholesterol from the endoplasmic reticulum or endocytic compartments to the cell surface was normal in PlsEtn-deficient cells. Also, vesicle trafficking was normal in PlsEtn-deficient cells, as measured by fluid phase endocytosis and exocytosis, as was the move- ment of newly-synthesized proteins to the cell surface. The mutant Cholesterol Transport phenotype was due to the lack of PlsEtn, since it was corrected when NRel-4 cells were transfected with a cDNA encoding the missing enzyme or supplied with a metabolic intermediate that enters the PlsEtn biosynthetic pathway downstream of the defect. Fu- ture work must determine the precise role that plasmalogens have on Cholesterol Transport to the endoplasmic reticulum.— Munn, N. J., E. Arnio, D. Liu, R. A. Zoeller, and L. Liscum. Deficiency in ethanolamine plasmalogen leads to altered Cholesterol Transport. J. Lipid Res. 2003. 44: 182-192.
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Deficiency in ethanolamine plasmalogen leads to altered Cholesterol Transport
Journal of lipid research, 2003Co-Authors: Natalie J Munn, Emily Arnio, Raphael A Zoeller, Dailan Liu, Laura LiscumAbstract:Plasmalogens are a major sub-class of ethanolamine and choline phospholipids in which the sn-1 position has a long chain fatty alcohol attached through a vinyl ether bond. These phospholipids are proposed to play a role in membrane fusion-mediated events. In this study, we investigated the role of the ethanolamine plasmalogen plasmenylethanolamine (PlsE11167) in intracellular Cholesterol Transport in Chinese hamster ovary cell mutants NRel-4 and NZel-1, which have single gene defects in PlsEtn biosynthesis. We found that PlsEtn was essential for specific Cholesterol Transport pathways, those from the cell surface or endocytic compartments to acyl-CoA/Cholesterol acyltransferase in the endoplasmic reticulum. The movement of Cholesterol from the endoplasmic reticulum or endocytic compartments to the cell surface was normal in PlsEtn-deficient cells. Also, vesicle trafficking was normal in PlsEtn-deficient cells, as measured by fluid phase endocytosis and exocytosis, as was the movement of newly-synthesized proteins to the cell surface. The mutant Cholesterol Transport phenotype was due to the lack of PlsEtn, since it was corrected when NRel-4 cells were transfected with a cDNA encoding the missing enzyme or supplied with a metabolic intermediate that enters the PlsEtn biosynthetic pathway downstream of the defect. Future work must determine the precise role that plasmalogens have on Cholesterol Transport to the endoplasmic reticulum.
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INTRACELLULAR Cholesterol Transport
Biochimica et biophysica acta, 1999Co-Authors: Laura Liscum, Natalie J MunnAbstract:The intracellular movement of Cholesterol in mam- malian cells may involve complex pathways by which the sterol moves to various cellular sites and mediates transcriptional regu- lation, enzyme activation, and protein degradation. Current evidence indicates that there are three distinct pathways modulating intracellular Cholesterol trafficking. The movement of endogenously synthesized Cholesterol from the endoplasmic reticulum appears to be distinct from movement of exogenous, low density lipoprotein (LDL)-derived Cholesterol to the plasma membrane. In addition, steroidogenic cells possess a third mechanism by which Cholesterol is Transported to the mitochon- dria to initiate steroid hormone synthesis. In this review, we have outlined the current knowledge of Cholesterol Transport mecha- nisms and pathways and have described approaches that may help define Cholesterol trafficking mechanisms in molecular de- tail. The use of genetic and molecular biologic techniques can potentially reveal gene products that are involved in intracellular Cholesterol Transport and regulation as well as those that may secondarily affect this process.-Liscum, L., and N. K. Dahl. Intracellular Cholesterol Transport. J. Lipid Res. 1992. 33: 1239-1254.
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Analysis of Somatic Cell Mutants That Express Defective Intracellular Cholesterol Transport
Intracellular Cholesterol Trafficking, 1998Co-Authors: Laura LiscumAbstract:The distribution of Cholesterol in mammalian cells is tightly controlled. However, the factors involved in shuttling Cholesterol among cellular membranes have not been well defined. Our experimental approach employs somatic cell mutants and pharmacological agents to investigate the routes and mechanisms of intracellular Cholesterol Transport. Two complementation groups of Chinese hamster ovary cell mutants have been isolated, with gene defects that impair separate Cholesterol Transport pathways. Identification of genes that correct the Cholesterol Transport defects is in progress. Pharmacological inhibitor studies have revealed a pathway that lipoprotein-derived Cholesterol takes to reach the endoplasmic reticulum. The mechanism of that Transport pathway is under investigation. In coming years, our studies should turn from biochemical description of Transport pathways to molecular analysis of candidate Transport proteins.
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Quantitative analysis of hydrophobic amine inhibition of intracellular Cholesterol Transport
Journal of lipid research, 1996Co-Authors: Kathryn W. Underwood, Biree Andemariam, G L Mcwilliams, Laura LiscumAbstract:U 18666A and imipramine are hydrophobic amines that inhibit intracellular Cholesterol Transport path- ways. In this study, we conducted dose-response curves for each of the Cholesterol Transport pathways. Our analyses indi- cate that hydrophobic amine inhibition of LDL-stimulated Cholesterol esterification is much more sensitive to inhibition than either the combined bulk movement of Cholesterol from lysosomes to the plasma membrane and from the plasma membrane to the endoplasmic reticulum. Hydrophobic amines must inhibit a previously uncharacterized pathway from lysosomes to the endoplasmic reticulum or a signaling event that activates acyl CoA:Cholesterol acyltransferase. Pos- sible mechanisms for U18666A action were evaluated. The function of p-glycoprotein, which has been implicated in cho- lesterol Transport, was unaffected by U18666A. MWe have evidence for a specific membrane U18666A binding site, which we hypothesize is involved in the plasma membrane to endoplasmic reticulum Cholesterol Transport pathway. Identi- fication of the binding site and mechanism of hydrophobic amine action may provide information essential for under- standing intracellular Cholesterol Transport.-Underwood, K. W., B. Andemariam, G. L. McWdliams, and L. Liscum. Quantitative analysis of hydrophobic amine inhibition of in- tracellular Cholesterol Transport. J. Lipid Res. 1996. 37: 1556- 1568.
Peter P Toth - One of the best experts on this subject based on the ideXlab platform.
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Reverse Cholesterol Transport: high-density lipoprotein's magnificent mile.
Current Atherosclerosis Reports, 2003Co-Authors: Peter P TothAbstract:High-density lipoproteins (HDLs) are among the most structurally complex and functionally versatile forms of circulating serum lipoproteins. HDLs undergo extensive enzymatic remodeling during their maturation in serum, interact with highly specific receptors in peripheral tissues and the liver, and are able to exert a variety of antiatherogenic effects (eg, inhibit inflammation, oxidation, and apoptosis). Considerable epidemiologic, clinical, and basic scientific investigation supports the conclusion that HDLs as a molecular class are atheroprotective. One of the most important antiatherogenic functions of HDL is its capacity to drive reverse Cholesterol Transport, the process by which excess Cholesterol in peripheral tissues is extracted and delivered to the liver for disposal. Despite the rapid expansion in our understanding of how HDL antagonizes many of mechanisms etiologic for atherosclerosis and the observation that a low serum level of HDL is the most frequent lipid abnormality in patients with premature coronary artery disease, many physicians still focus inadequate attention on recognizing and treating hypoalphalipoproteinemia. Our current understanding of reverse Cholesterol Transport reinforces the clinical importance of including HDL screening when evaluating any given patient’s risk for cardiovascular disease.
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Reverse Cholesterol Transport: High-density lipoprotein’s magnificent mile
Current Atherosclerosis Reports, 2003Co-Authors: Peter P TothAbstract:High-density lipoproteins (HDLs) are among the most structurally complex and functionally versatile forms of circulating serum lipoproteins. HDLs undergo extensive enzymatic remodeling during their maturation in serum, interact with highly specific receptors in peripheral tissues and the liver, and are able to exert a variety of antiatherogenic effects ( eg , inhibit inflammation, oxidation, and apoptosis). Considerable epidemiologic, clinical, and basic scientific investigation supports the conclusion that HDLs as a molecular class are atheroprotective. One of the most important antiatherogenic functions of HDL is its capacity to drive reverse Cholesterol Transport, the process by which excess Cholesterol in peripheral tissues is extracted and delivered to the liver for disposal. Despite the rapid expansion in our understanding of how HDL antagonizes many of mechanisms etiologic for atherosclerosis and the observation that a low serum level of HDL is the most frequent lipid abnormality in patients with premature coronary artery disease, many physicians still focus inadequate attention on recognizing and treating hypoalphalipoproteinemia. Our current understanding of reverse Cholesterol Transport reinforces the clinical importance of including HDL screening when evaluating any given patient’s risk for cardiovascular disease.
Michael C. Phillips - One of the best experts on this subject based on the ideXlab platform.
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high density lipoprotein heterogeneity and function in reverse Cholesterol Transport
Current Opinion in Lipidology, 2010Co-Authors: George H Rothblat, Michael C. PhillipsAbstract:Purpose of reviewHDL is a cardioprotective lipoprotein, at least in part, because of its ability to mediate reverse Cholesterol Transport (RCT). It is becoming increasingly clear that the antiatherogenic effects of HDL are not only dependent on its concentration in circulating blood but also on its
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high density lipoprotein structure function and role in reverse Cholesterol Transport
Sub-cellular biochemistry, 2010Co-Authors: Sissel Lundkatz, Michael C. PhillipsAbstract:High density lipoprotein (HDL) possesses important anti-atherogenic properties and this review addresses the molecular mechanisms underlying these functions. The structures and Cholesterol Transport abilities of HDL particles are determined by the properties of their exchangeable apolipoprotein (apo) components. ApoA-I and apoE, which are the best characterized in structural terms, contain a series of amphipathic α-helical repeats. The helices located in the amino-terminal two-thirds of the molecule adopt a helix bundle structure while the carboxy-terminal segment forms a separately folded, relatively disorganized, domain. The latter domain initiates lipid binding and this interaction induces changes in conformation; the α-helix content increases and the amino-terminal helix bundle can open subsequently. These conformational changes alter the abilities of apoA-I and apoE to function as ligands for their receptors. The apoA-I and apoE molecules possess detergent-like properties and they can solubilize vesicular phospholipid to create discoidal HDL particles with hydrodynamic diameters of ~10 nm. In the case of apoA-I, such a particle is stabilized by two protein molecules arranged in an anti-parallel, double-belt, conformation around the edge of the disc. The abilities of apoA-I and apoE to solubilize phospholipid and stabilize HDL particles enable these proteins to be partners with ABCA1 in mediating efflux of cellular phospholipid and Cholesterol, and the biogenesis of HDL particles. ApoA-I-containing nascent HDL particles play a critical role in Cholesterol Transport in the circulation whereas apoE-containing HDL particles mediate Cholesterol Transport in the brain. The mechanisms by which HDL particles are remodeled by lipases and lipid transfer proteins, and interact with SR-BI to deliver Cholesterol to cells, are reviewed.
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Macrophage Reverse Cholesterol Transport in Mice Expressing ApoA-I Milano
Arteriosclerosis thrombosis and vascular biology, 2009Co-Authors: Eric T. Alexander, George H Rothblat, Michael C. Phillips, Ginny L. Weibel, Michelle R. Joshi, Charulatha Vedhachalam, Margarita De La Llera-moya, Daniel J. RaderAbstract:Objective— To compare the abilities of human wild-type apoA-I (WT apoA-I) and human apoA-IMilano (apoA-IM) to promote macrophage reverse Cholesterol Transport (RCT) in apoA-I–null mice infected wit...
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Reverse Cholesterol Transport.
Methods in Enzymology, 2004Co-Authors: George H Rothblat, Menachem Bamberger, Michael C. PhillipsAbstract:Publisher Summary This chapter focuses on the process of reverse Cholesterol Transport. As peripheral cells do not degrade Cholesterol, the only mechanism for removal is by efflux of intact free (unesterified) Cholesterol molecules. Such molecules enter the “reverse Cholesterol Transport” pathway whereby they are delivered to the liver, converted to bile acids, and then excreted from the body. On the basis of an inverse correlation between serum high-density lipoprotein (HDL) levels and the incidence of atherosclerosis in the population, the purported lipoprotein vehicle for this Transport is HDL. Cellular Cholesterol pools can be labeled using exogenous Cholesterol or by supplying labeled precursors. In either case, sufficient incubation times are needed to ensure the equilibration of the label among all subcellular pools. When using the exogenous labeling approach all radiolabeled Cholesterol should be repurified prior to use. Repurification is necessary to remove oxidized compounds that, because of their increased polarity, exchange more rapidly than Cholesterol.
Christopher J. Fielding - One of the best experts on this subject based on the ideXlab platform.
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intracellular Cholesterol Transport
Journal of Lipid Research, 1997Co-Authors: Christopher J. Fielding, Phoebe E FieldingAbstract:Recent data on the roles of vesicle- and 'raft'-medi- ated pathways in intracellular free Cholesterol (FC) Transport are reviewed. Cholesterol internalized from .plasma lipopro- teins is transferred via endocytic vesicles to the trum-Golgi net- work (TGN), consistent with prior data indicating a key role for this organelle in protein and lipid sorting and Transport. Newly synthesized and lipoproteinderived FC are returned to the cell surface by a common raftdependent pathway. Intra- cellular FC Transport promotes the delivery of GPI-anchored proteins to the cell surface; it is also an additional mechanism to regulate cell FC content. Many peripheral cells express ca- veolin, an FGbinding protein localized to plasma membrane caveolae. FC delivery to cell surface caveolae is accelerated by caveolin. Caveolar FC becomes targeted to small, lipid-poor (prebeta-) high density lipoprotein particles. Caveolin may protect quiescent cells, regulating FC efflux more efficiently in response to changing medium lipoprotein concentrations. Overall, these recent findings suggest that cell FC content can be regulated at the levels of both influx and efflux, and indi- cate key roles for the TGN and in cells expressing caveolin, cell-surface caveolae.-Fielding, C. J., and P. E. Fielding. In- tracellular Cholesterol Transport. J. Lipid Res. 1997. 38 1503- 1521.
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molecular physiology of reverse Cholesterol Transport
Journal of Lipid Research, 1995Co-Authors: Christopher J. Fielding, P E FieldingAbstract:: Reverse Cholesterol Transport (RCT) is the pathway by which peripheral cell Cholesterol can be returned to the liver for catabolism. Evidence of specific functions for molecular structures within individual plasma lipoprotein species has rapidly accumulated from recent studies using molecular and cellular physiology techniques. The removal of Cholesterol from cells, like its delivery, appears to be specific and well regulated. Although further research will be needed, RCT can now be understood in molecular terms.
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Reverse Cholesterol Transport
Current Opinion in Lipidology, 1991Co-Authors: Christopher J. FieldingAbstract:New research firmly establishes the reverse Cholesterol Transport pathway, which carries Cholesterol through the high-density lipoprotein, as significant in normal Cholesterol homeostasis. Modulation of this pathway by transgenic and pharmacological techniques indicates potential therapeutic functions for increased high-density lipoprotein levels in atherosclerosis.