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The effect of statins on ABCA1 and ABCG1 expression in human macrophages is influenced by cellular cholesterol levels and extent of differentiation.

Abstract：

:The ATP-binding cassette transporters, ABCA1 and ABCG1, are LXR-target genes that participate in the removal of cholesterol from lipid-laden macrophages, a crucial anti-atherogenic mechanism. Statins are currently the most efficacious therapy for the treatment of hypercholesterolemia and cardiovascular disease. We and others have shown that statins decrease ABCA1 and ABCG1 expression as well as cholesterol efflux from human macrophages. However, other studies have reported that statins produce no change, or even a modest increase in these variables. In an attempt to reconcile these conflicting reports, we investigated how the effect of statins on transcription of ABCA1 and ABCG1 is modulated by cellular cholesterol status and the extent of macrophage differentiation. We showed that supplementing human macrophages with cholesterol reversed the statin-mediated down-regulation of ABC transporter expression whereas depletion of cellular cholesterol tended to accentuate the statin effect. Down-regulation of ABC transporter expression was more pronounced with increased macrophage differentiation status and already evident at statin concentrations equivalent to those present in plasma. Addition of LXR agonists, which are currently on trial as anti-atherogenic agents, reversed the effects on ABC transporter expression while PPAR alpha and PPAR gamma agonists did not. The significance of these results in light of current and future combination therapies is discussed.

journal_name

Atherosclerosis

journal_title

Atherosclerosis

authors

Wong J,Quinn CM,Gelissen IC,Jessup W,Brown AJ

doi

10.1016/j.atherosclerosis.2007.03.030

subject

Has Abstract

pub_date

2008-01-01 00:00:00

pages

180-189

issue

1

eissn

0021-9150

issn

1879-1484

pii

S0021-9150(07)00199-2

journal_volume

196

pub_type

杂志文章

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