Probucol Inhibits ABCA1-Mediated Cellular Lipid Efflux
Elda Favari,Ilaria Zanotti,Francesca Zimetti,Nicoletta Ronda,Franco Bernini,George H. Rothblat +5 more
TLDR
Probucol is an effective inhibitor of ABCA1-mediated cholesterol efflux without influencing scavenger receptor class B type I–mediated efflux, which may in part explain the reported in vivo high-density lipoprotein–lowering action of probucol.Abstract:
Objective— ATP-binding cassette transporter A1 (ABCA1) mediates the efflux of lipids from cells to lipid-poor apolipoproteins. In this article, we characterize the effect of probucol on cellular ABCA1-mediated lipid efflux. Methods and Results— Probucol inhibited cholesterol efflux up to 80% in J774 macrophages expressing ABCA1. In Fu5AH hepatoma cells that contain scavenger receptor class B, type I, but not functional ABCA1, we observed no effect of probucol on cholesterol efflux. Probucol inhibited cholesterol efflux from normal human skin fibroblasts but not from fibroblasts from a Tangier patient. Fluorescent confocal microscopy and biotinylation assay demonstrated that in J774 cells probucol impaired the translocation of ABCA1 from intracellular compartments to the plasma membrane. Probucol also inhibited the formation of an ABCA1-linked cholesterol oxidase sensitive plasma membrane domain. Consistent with the inhibitory effect on ABCA1 translocation to the plasma membrane, probucol reduced cell surface–specific [ 125 I]-labeled apolipoprotein-AI binding. Conclusions— We conclude that probucol is an effective inhibitor of ABCA1-mediated cholesterol efflux without influencing scavenger receptor class B type I–mediated efflux. The inhibition of ABCA1 translocation to the plasma membrane may in part explain the reported in vivo high-density lipoprotein–lowering action of probucol.read more
Citations
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Macrophage ABCA1 and ABCG1, but not SR-BI, promote macrophage reverse cholesterol transport in vivo
Xun Wang,Heidi L. Collins,Mollie Ranalletta,Ilia V. Fuki,Jeffrey T. Billheimer,George H. Rothblat,Alan R. Tall,Daniel J. Rader +7 more
TL;DR: It is demonstrated that ABCA1 and ABCG1, but not SR-BI, promote macrophage RCT in vivo and are additive in their effects.
Journal ArticleDOI
The Ability to Promote Efflux Via ABCA1 Determines the Capacity of Serum Specimens With Similar High-Density Lipoprotein Cholesterol to Remove Cholesterol From Macrophages
Margarita de la Llera-Moya,Denise Drazul-Schrader,Bela F. Asztalos,Marina Cuchel,Daniel J. Rader,George H. Rothblat +5 more
TL;DR: It is found that independently of HDL-C, sera with higher efflux capacity had a significant increase in ABCA1-mediated efflux, which was significantly correlated to the concentration of pre&bgr;-1 HDL.
Cell Biology/Signaling The Ability to Promote Efflux Via ABCA1 Determines the Capacity of Serum Specimens With Similar High-Density Lipoprotein Cholesterol to Remove Cholesterol From Macrophages
Margarita de la Llera-Moya,Denise Drazul-Schrader,Bela F. Asztalos,Marina Cuchel,Daniel J. Rader,George H. Rothblat +5 more
TL;DR: In this article, the authors measured efflux from macrophages to apolipoprotein B-depleted serum from 263 specimens and found instances in which serum having similar high-density lipoprotein cholesterol (HDL-C) differed in their efflux capacity.
Journal ArticleDOI
The roles of different pathways in the release of cholesterol from macrophages.
Maria Pia Adorni,Francesca Zimetti,Jeffrey T. Billheimer,Nan Wang,Daniel J. Rader,Michael C. Phillips,George H. Rothblat +6 more
TL;DR: These studies demonstrate that the aqueous diffusion mechanism is one of the major contributors to efflux, particularly in cholesterol-normal cells.
Journal Article
Lipid metabolism and carcinogenesis, cancer development
TL;DR: The disorder of lipid metabolism is pathologically linked to hyperlipidemia, lipid storage disease, obesity and other related diseases, and elucidation of molecular mechanism between lipid metabolism and cancer is essential in developing novel diagnostic biomarkers and therapeutic targets of human cancers.
References
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Scavenger receptor BI promotes high density lipoprotein-mediated cellular cholesterol efflux.
Yong Ji,Bo Jian,Nan Wang,Yu Sun,Margarita de la Llera Moya,Michael C. Phillips,George H. Rothblat,J.B. Swaney,Alan R. Tall +8 more
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TL;DR: The relative importance of the SR-BI and ABCA1 efflux pathways in preventing the development of atherosclerotic plaque is not known but will depend on the expression levels of the two proteins and on the type of cholesterol acceptors available.
Journal ArticleDOI
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TL;DR: A complex intracellular trafficking pathway for human ABCA1 is established that may play important roles in modulatingABCA1 transporter activity and cellular cholesterol homeostasis.
Journal ArticleDOI
ABCA1-mediated transport of cellular cholesterol and phospholipids to HDL apolipoproteins.
John F. Oram,Ashley M. Vaughan +1 more
TL;DR: The ABCA1 pathway has become an important therapeutic target for mobilizing excess cholesterol from tissue macrophages and protecting against atherosclerosis.
Journal ArticleDOI
Regulation and Mechanisms of ATP-Binding Cassette Transporter A1-Mediated Cellular Cholesterol Efflux
Nan Wang,Alan R. Tall +1 more
TL;DR: This and other evidence suggest that ABCA1 promotes cholesterol and phospholipid efflux, probably by directly transporting both lipids as substrates, as well as distinctly regulated and affected by the activity of other gene products.