Cholesterol efflux from adipose cells is coupled to diacylglycerol production and protein kinase C activation

Théret, Nathalie; Delbart, Christiane; Aguie, Gustave; Fruchart, Jean‐Charles; Vassaux, Georges; Ailhaud, Gérard

doi:10.1016/s0006-291x(05)80938-6

Cited by 69 publications

(25 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…72,94 Activation of protein kinase C (PKC) enhances and inhibition of PKC suppresses apolipoprotein-mediated cholesterol efflux. 90,95,96 cAMP was also found to increase apolipoprotein-induced cholesterol efflux from macrophage cell lines. 45,[97][98][99] In RAW264 cells, this was associated with internalization and resecretion of apoA-I 45 as well as with secretion of apoE.…”

Section: Cellular Cholesterol Traffickingmentioning

confidence: 89%

“…DAG activates PKC, which has been shown to stimulate the translocation of newly synthesized cholesterol to the plasma membrane as well as cholesterol efflux. 95,96,104,108 By contrast, HDL-mediated breakdown of phosphatidylinositol biphosphate and the subsequent mobilization of intracellular calcium 106,109 does not stimulate cholesterol efflux but rather mediates the mitogenic effects of HDL. 110 In macrophages, HDL has been shown to increase the concentration of cAMP, resulting in the activation of protein kinase A, which may activate the hydrolysis of cytosolic cholesteryl esters by NCEH and the mobilization of cholesterol by ABC1.…”

Section: Cellular Cholesterol Traffickingmentioning

confidence: 99%

See 1 more Smart Citation

High Density Lipoproteins and Arteriosclerosis

Eckardstein

Nofer

Assmann

2001

ATVB

602

128

View full text Add to dashboard Cite

Abstract-High density lipoprotein (HDL) cholesterol is an important risk factor for coronary heart disease, and HDL exerts various potentially antiatherogenic properties, including the mediation of reverse transport of cholesterol from cells of the arterial wall to the liver and steroidogenic organs. Enhancement of cholesterol efflux and of reverse cholesterol transport (RCT) is considered an important target for antiatherosclerotic drug therapy. Levels and composition of HDL subclasses in plasma are regulated by many factors, including apolipoproteins, lipolytic enzymes, lipid transfer proteins, receptors, and cellular transporters. In vitro experiments as well as genetic family and population studies and investigation of transgenic animal models have revealed that HDL cholesterol plasma levels do not necessarily reflect the efficacy and antiatherogenicity of RCT. Instead, the concentration of HDL subclasses, the mobilization of cellular lipids for efflux, and the kinetics of HDL metabolism are important determinants of RCT and the risk of atherosclerosis. (Arterioscler Thromb Vasc Biol. 2001;21:13-27.)

show abstract

Section: Cellular Cholesterol Traffickingmentioning

confidence: 89%

Section: Cellular Cholesterol Traffickingmentioning

confidence: 99%

High Density Lipoproteins and Arteriosclerosis

Eckardstein

Nofer

Assmann

2001

ATVB

602

128

View full text Add to dashboard Cite

show abstract

“…Each value represents the mean of duplicate dishes (5.5% coefficient of variation). ,rum-free medium containing 0.5 jig/ml (0.11 M) "NI-labeled activate a cholesterol excretory pathway (3,4).…”

Section: Discussionmentioning

confidence: 99%

“…When cells are overloaded with sterol, however, cholesterol accumulates within an intracellular pool that is accessible to the enzyme acyl CoA/cholesterol acyltransferase (ACAT),' thus allowing cells to store excess cholesterol as ester-rich lipid droplets. Under this condition, excretion of excess ACAT-accessible cholesterol can be facilitated by an active process (3,4) that is stimulated by the interaction of HDL apolipoproteins with cell-surface binding sites or receptors (5).…”

Section: Introductionmentioning

confidence: 99%

Synthetic amphipathic helical peptides that mimic apolipoprotein A-I in clearing cellular cholesterol.

Mendez¹,

Anantharamaiah²,

Segrest³

et al. 1994

J. Clin. Invest.

178

149

View full text Add to dashboard Cite

Clearance of excess cholesterol from cells by HDL is facilitated by the interaction of HDL apolipoproteins with cellsurface binding sites or receptors, a process that may be important in preventing atherosclerosis. In this study, synthetic peptides containing 18-mer amphipathic helices of the class found in HDL apolipoproteins (class A) were tested for their abilities to remove cholesterol and phospholipid from cultured sterol-laden fibroblasts and macrophages and to interact with cell-surface HDL binding sites. Lipid-free peptides containing two identical tandem repeats of class A amphipathic helices promoted cholesterol and phospholipid efflux from cells and depleted cellular cholesterol accessible for esterification by acyl CoA/cholesterol acyltransferase, similar to what was observed for purified apolipoprotein A-I. Peptide-mediated removal of plasma membrane cholesterol and depletion of acyl CoA/cholesterol acyltransferaseaccessible cholesterol appeared to occur by separate mechanisms, as the latter process was less dependent on extracellular phospholipid. The dimeric amphipathic helical peptides also competed for high-affinity HDL binding sites on cholesterol-loaded fibroblasts and displayed saturable high-affinity binding to the cell surface. In contrast, peptides with a single helix had little or no ability to remove cellular cholesterol and phospholipid, or to interact with HDL binding sites, suggesting that cooperativity between two or more helical repeats is required for these activities. Thus, synthetic peptides comprising dimers of a structural motif common to exchangeable apolipoproteins can mimic apolipoprotein A-I in both binding to putative cell-surface receptors and clearing cholesterol from cells. (J. Clin. Invest. 1994.

show abstract

“…A good correlation for 1,2-diacylglycerol release was found between the [ 3 H]phosphatidylcholine method and the 1,2-diacylglycerol kinase assay. 23 - 24 1,2-Diacylglycerol release recorded in unstimulated platelets after a 5-minute incubation at 37°C ranged around 100 cpm, for a specific activity of 3500 cpm per 2.5xlO 8 cells.…”

Section: 2-diacylglycerol Releasementioning

confidence: 93%

Protein kinase C-dependent desensitization of HDL3-activated phospholipase C in human platelets.

Nazih

Nazih‐Sanderson

Magret

et al. 1994

Arterioscler Thromb

View full text Add to dashboard Cite

In isolated human platelets, exposure of subtraction 3 high-density lipoprotein (HDL,) binding sites to high concentrations of HDL, (1 mg/mL) causes rapid desensitization of HDL3 (50 jU,g/mL)-stimulated breakdown of phosphatidylcholine, as shown in approximately a 70% depression of the maximal 1,2-diacylglycerol release activity by phospholipase C. This desensitization is HDL, dose dependent (IC 50 , 150±20 ig/mL, n=6) and time dependent (t 1/2 , <30 seconds). It requires the binding of HDL,, as pretreatment of HDL, by tetranitromethane does not cause the desensitization of HDLj-induced phospholipase C activity. Permeabilization of human platelets with 10 /ig/mL digitonin, used to permit access of charged inhibitors to the cytosol, does not interfere with the pattern of HDLj (1 mg/mL) -induced desensitization of HDL, (50 /ig/mL)-stimulated phospholipase C. Inhibitors of protein kinase C (100 /umol/L H-7 and 10 /nmol/L staurosporine) markedly inhibit desensitization of HDL,-induced P revious studies have demonstrated that subtraction 3 high-density lipoprotein (HDL,) binding sites are present on platelet membranes. 13 Koller et al 3 have reported that the glycoprotein Ilb/IIIa complex, the inducible platelet fibrinogen receptor, is able to interact with lipoproteins. HDL3 was found to bind to either the 95-to 110-kD glycoprotein Ilia or to the 136-to 140-kD glycoprotein lib. Glycoprotein lib/ Ilia acts until now as a platelet HDL, binding site.Furthermore, HDL 3 binding sites are coupled to phospholipase C (PLC) through pertussis toxin-sensitive GTP binding proteins. 45 In human platelets, HDL 3 binding sites act via the PLC-mediated hydrolysis of phosphatidylcholine and the generation of 1,2-diacylglycerol, which activates the multifunctional enzyme protein kinase C (PKC). The HDL 3 -induced signaling pathway is recorded only when platelets are stimulated by low concentrations of HDL 3 (50 ixglmL). Higher HDL3 concentrations (1 mg/mL) are not able to trigger phosphatidylcholine hydrolysis, indicating a loss of responsiveness. 4 One major form of regulation of the activity of G protein-coupled receptors is desensitization, 6 -9 which is a general biological phenomenon whereby the response to a specific ligand wanes over time despite the continuous presence of the ligand. The impairment of receptor functions is linked to protein phosphorylation, which appears to be a key factor. Most often, homologous desensitization is accompanied by receptor phosphorylation, which triggers the process of functional uncoupling from G proteins. 1012 In addition, a rapid sequestration of the receptors away from the cell surface and a modulation of the expression of the receptor gene itself result in a net decrease in receptor number. 13 Whereas desensitization of the adrenergic system is rather well understood, less is known about receptors coupled to phosphatidylinositol or phosphatidylcholine turnover. 1417 Moreover, until now little has been known about HDL3 binding site regulation. Platelets therefore would seem to ...

show abstract

Cholesterol efflux from adipose cells is coupled to diacylglycerol production and protein kinase C activation

Cited by 69 publications

References 20 publications

High Density Lipoproteins and Arteriosclerosis

High Density Lipoproteins and Arteriosclerosis

Synthetic amphipathic helical peptides that mimic apolipoprotein A-I in clearing cellular cholesterol.

Protein kinase C-dependent desensitization of HDL3-activated phospholipase C in human platelets.

Contact Info

Product

Resources

About