Scavenger receptor BI (SR-BI) mediates free cholesterol flux independently of HDL tethering to the cell surface

Self Cite

443

Numerous studies using a variety of cell/acceptor combinations have demonstrated differences in cholesterol efflux among cells. These studies also show that different acceptors, ranging from simple molecules like cyclodextrins to serum, stimulate efflux through a variety of mechanisms. By combining early observations with data derived from recent studies, it is now possible to formulate a model for cell cholesterol efflux which proposes that an array of different mechanisms, including aqueous diffusion, lipid-free apolipoprotein membrane microsolubilization, and SR-BI-mediated cholesterol exchange contribute to cholesterol flux. In this model the relative importance of each mechanism would be determined both by the cell type and the nature of the extracellular cholesterol acceptor. -Rothblat, G.

Section: Observation 7: the Rate Of Cell Cholesterol Release And The Extent Of Stimulation By Phospholipid Supplementation Of Serum Corrementioning

confidence: 99%

Section: Mechanism 1: Desorption Of Cholesterol Molecules Out Of the Plasma Membrane And Diffusion Through The Aqueous Phase To Phospholimentioning

confidence: 99%

Cell cholesterol efflux: integration of old and new observations provides new insights

Rothblat

Llera-Moya

Atger

et al. 1999

Self Cite

443

“…However, the contribution of SR-BI in peritoneal macrophages may be limited, as message levels for CD36 are far more abundant (12). Although its efficiency is 7-fold less than SR-BI, CD36 can also facilitate the selective uptake of HDL cholesterol (31), suggesting that the down-Fig. 6.…”

Section: Discussionmentioning

confidence: 99%

TGF-β increases cholesterol efflux and ABC-1 expression in macrophage-derived foam cells: opposing the effects of IFN-γ

Panousis

Evans

Zuckerman

2001

The regulation of ATP-binding cassette transporter 1 (ABC-1) expression by cytokines present within the microenvironment of the atheroma may play an important role in determining the impact of reverse cholesterol transport on the atherosclerotic lesion. We recently reported that the macrophage-activating cytokine interferon (IFN)-␥ inhibited both cholesterol efflux and ABC-1 expression. In the present study, we investigated the effects of transforming growth factor (TGF)-␤ , a cytokine also apparent within the atheroma, on cholesterol efflux, ABC-1 expression, and its ability to antagonize the inhibitory effects of IFN-␥ . TGF-␤ significantly increased cholesterol efflux in macrophage-derived foam cells from apolipoprotein E (apoE) knockout mice, with maximal effects apparent at 300 pg/ml. The increases in efflux occurred without any effect on the passive diffusion component of efflux mediated by ␤ -cyclodextrin. Furthermore, the increase in cholesterol efflux occurred without any changes in free or esterified cholesterol pools and was consistent with an increase in both ABC-1 message and protein. Finally, TGF-␤ was also demonstrated to inhibit the IFN-␥ -mediated down-regulation of ABC-1. These results further demonstrate the importance of cytokine crosstalk to impact the process of reverse cholesterol transport through a multitude of processes including the regulation of ABC-1.-Panousis, C. G., G. Evans, and S. H. Zuckerman. TGF-␤ increases cholesterol efflux and ABC-1 expression in macrophage-derived foam cells: opposing the effects of IFN-␥ .

“…They showed that although HDL binding to CD36 is greater than its binding to SR-BI, only the latter promoted significant cholesterol efflux. Moreover, there was more cholesterol efflux to phospholipid vesicles (which do not bind to surface receptors) in SR-BI-expressing cells than in CD36-expressing cells (27). These results led to the conclusion that SR-BI promotes cholesterol efflux through a process not dependent on the tethering of HDL to its receptor (27).…”

Section: Sr-bimentioning

confidence: 97%

“…There is some controversy surrounding the question of whether HDL must physically bind to SR-BI in order to mediate cholesterol efflux. Rothblat and co-workers (27) compared HDL binding to SR-BI and to another scavenger receptor, CD36. They showed that although HDL binding to CD36 is greater than its binding to SR-BI, only the latter promoted significant cholesterol efflux.…”

Section: Sr-bimentioning

confidence: 99%

Pivotal role of ABCA1 in reverse cholesterol transport influencing HDL levels and susceptibility to atherosclerosis

Attie

Kastelein

Hayden

2001

250

The identification of mutations in ABCA1 in patients with Tangier disease and familial HDL deficiency demonstrated that inadequate transport of phospholipid and cholesterol to the extracellular space results in the hypercatabolism of lipid-poor nascent HDL particles. However, the relationship between changes in ABCA1 activity and HDL levels is not clear. To address this question directly in vivo, we have used bacterial artificial chromosome transgenic approaches, which allow for appropriate developmental and cellular localization of human ABCA1 in mouse tissues. Increased expression of ABCA1 is directly associated with an increase in HDL levels, and the relationship between the increase in efflux and HDL is completely linear ( r 2 ‫؍‬ 0.87). Preliminary data have suggested that coronary artery disease (CAD) is increased in heterozygotes for ABCA1 deficiency. These results may have been biased by clinical sampling, and CAD end points are insensitive markers. We have now used surrogate end points of intimamedia complex thickness (IMT) and have shown that mean IMT in ABCA1 heterozygotes is indeed increased. A strong correlation between adjusted IMT and HDL cholesterol values and apolipoprotein A-I-driven efflux has been established. These studies suggest that compromised ABCA1 activity leads to accelerated and early atherogenesis and provides a link between the cholesterol deposition in macrophages within the arterial wall and cholesterol efflux in humans. -Attie, A