Resistance of smooth muscle cells to assembly of high density lipoproteins with extracellular free apolipoproteins and to reduction of intracellularly accumulated cholesterol.

Komaba, Akira; Li, Qianqian; Hara, Hiroko; Yokoyama, Shinji

doi:10.1016/s0021-9258(19)37079-6

Cited by 38 publications

(33 citation statements)

References 40 publications

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“…The present investigation extends previous studies from this laboratory (Bielicki et al, 1991(Bielicki et al, ,1992 and by Yokoyama and colleagues (Hara & Yokoyama, 1991Komaba et al, 1992;Akira et al, 1993) on the flux of lipids from tissue culture cells exposed to lipid-free apoproteins. These studies have demonstrated that the kinetics and extent of cholesterol and phospholipid efflux are influenced by both acceptor and cell factors.…”

Section: Discussionsupporting

confidence: 90%

Efflux of cellular cholesterol and phospholipid to lipid-free apolipoproteins and class A amphipathic peptides

Yancey¹,

Bielicki²,

Johnson³

et al. 1995

Biochemistry

196

148

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The mechanism(s) by which lipid-free apolipoprotein (apo) AI is able to stimulate efflux of cholesterol and phospholipid from cells in cultures has (have) been examined. This process was found to be enhanced when macrophages were enriched with cholesterol. There were 12- and 4-fold increases in cholesterol and phospholipid efflux, respectively, from cholesterol-enriched mouse macrophages when compared to cells not loaded with cholesterol. This enhancement in cholesterol efflux to lipid-free apo AI from macrophages enriched with cholesterol was found to be controlled by the level of free cholesterol in the cells. When cholesterol-enriched mouse macrophages were exposed to lipid-free apo AI at 20 micrograms/mL (706 nM), there was significant efflux of [14C]cholesterol and [3H]phospholipid (20% +/- 0.5%/24 h and 6% +/- 0.3%/24 h, respectively). In comparison, HDL at equivalent protein concentrations only stimulated 11% and 4% efflux of cholesterol and phospholipid, respectively. Synthetic peptides containing amphipathic helical segments that mimic those present in apo AI were used to examine the structural features of the apoprotein which stimulate lipid efflux. Peptides containing only one (18A) or two (37pA) amphipathic helical segments stimulated as much cholesterol efflux from both mouse macrophages and L-cells as apo AI. The order of efficiency, as assessed by the mass concentration at which half-maximal efflux was reached (EC50), was apo AI > 37pA > 18A, indicating that acceptor efficiency was dependent on the number of amphipathic helical segments per molecule. When the helical content of 18A was increased by neutralizing the charges at the ends of the peptide (Ac-18A-NH2), there was a substantial increase in the efficiency for cholesterol efflux (EC50 18A = 17 micrograms/mL vs Ac-18A-NH2 = 6 micrograms/mL). In contrast, when the amphipathicity of the helix in 18A was decreased by scrambling the amino acid sequence, thereby reducing its lipid affinity, cholesterol and phospholipid efflux were not stimulated. The efficiency with which the peptides stimulated cholesterol efflux was in order of their lipid affinity (37pA > Ac-18A-NH2 > 18A), and this order was similar for phospholipid efflux. The time course of lipid release from mouse macrophages and L-cells indicated that phospholipid appeared in the extracellular medium before cholesterol. These results suggest that the apo AI or peptides first interacted with the cell to form protein/phospholipid complexes, that could then accept cholesterol.

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Section: Discussionsupporting

confidence: 90%

Efflux of cellular cholesterol and phospholipid to lipid-free apolipoproteins and class A amphipathic peptides

Yancey¹,

Bielicki²,

Johnson³

et al. 1995

Biochemistry

196

148

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“…Interaction between free apolipoprotein and cells is considered to be one mechanism for the formation of HDL ( 89) although not all cells participate in this process (90). In our laboratory, we have demonstrated that 14 Clabeled apoA-I is internalized by HepG2 cells (N. H. Fidge, unpublished observations) in a manner suggestive of a regulated rather than a passive process.…”

Section: Biochemical Events Affected By Hdl Receptorsmentioning

confidence: 81%

High density lipoprotein receptors, binding proteins, and ligands

Fidge

1999

Journal of Lipid Research

174

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Several HDL binding proteins, quite disparate in structure, have recently been cloned and their role in HDL metabolism is currently being assessed. High density lipoprotein binding protein, HBP (vigilin), which lacks a transmembrane domain is responsive to cell cholesterol levels, but its physiological significance remains unknown. On the other hand much is known about SR-B1, a member of the class B scavenger receptors. The level of SR-B1 expression correlates with both the selective transfer of cholesteryl ester into cells and cholesterol efflux from cells, the transfers probably mediated after docking of HDL at the cell surface. SR-B1 exhibits broad ligand specificity and, in animal models, appears to be regulated by the action of pituitary hormones that stimulate steroidogenesis, suggesting an important role for steroid hormone production in supplying precursor cholesterol. Another candidate HDL receptor, HB 2 , one of a pair of liver HDL binding proteins, shows high sequence homology with adhesion molecules, particularly activated leukocyte-cell adhesion molecule (ALCAM). When HB 2 is overexpressed in cells, HDL binding increases. After PMA-induced differentiation of monocytes into macrophages, HB 2 mRNA is strikingly elevated, which correlates with increased binding of HDL, but is down-regulated by cholesterol loading of macrophages. The ligand specificity of the HDL receptors, confounded by nonspecific lipid interactions, remains controversial. Their affinity for apoA-I versus apoA-I/A-II-rich HDL particles has clinical implications; both specific sequences in apoA-I and amphipathic ␣ -helices may determine binding events. Post-receptormediated signalling events may regulate cell functions which, although not primarily related to lipid transport, nevertheless protect against coronary artery disease. Growing evidence for the involvement of lipid-poor apoA-I as a mediator of such pathways is also discussed.-Fidge, N. H. High density lipoprotein receptors, binding proteins, and ligands.

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“…The extent to which a cell will release cholesterol or phospholipid to lipid-free apolipoproteins depends both on the cell type and on the metabolic status of the cell. Among the most responsive cells are macrophages (29,62) whereas smooth muscle cells are among the most resistant cells (63). Thus, exposure of macrophages, CHO cells, L-cells, and fibroblasts to apoA-I, apoA-II, apoE, or apoA-IV results in the release of both cellular cholesterol and cellular phospholipid (3,27,29,64).…”

Section: Observation 6: Lipid-free Apolipoproteins Can Stimulate the Efflux Of Cellular Cholesterol And Phospholipidmentioning

confidence: 99%

“…14, panel 2). The magnitude of the response varies among cells (63,71), and is also a function of the metabolic status of the cells. The two metabolic manipulations of cells that have been shown to enhance apolipoproteinmediated lipid efflux are cholesterol enrichment (Fig.…”

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

Journal of Lipid Research

443

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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.

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Resistance of smooth muscle cells to assembly of high density lipoproteins with extracellular free apolipoproteins and to reduction of intracellularly accumulated cholesterol.

Cited by 38 publications

References 40 publications

Efflux of cellular cholesterol and phospholipid to lipid-free apolipoproteins and class A amphipathic peptides

Efflux of cellular cholesterol and phospholipid to lipid-free apolipoproteins and class A amphipathic peptides

High density lipoprotein receptors, binding proteins, and ligands

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

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