Inhibition of LPL expression in human monocyte-derived macrophages is dependent on LDL oxidation state - A key role for lysophosphatidylcholine

被引：36

作者：

Stengel, D ^{[1
]}

Antonucci, M ^{[1
]}

Gaoua, W ^{[1
]}

Dachet, C ^{[1
]}

Lesnik, P ^{[1
]}

Hourton, D ^{[1
]}

Ninio, E ^{[1
]}

Chapman, MJ ^{[1
]}

Griglio, S ^{[1
]}

机构：

[1] Hop Pitie, INSERM, U321, F-75651 Paris 13, France

来源：

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY | 1998年 / 18卷 / 07期

关键词：

macrophage foam cells; lipid peroxidation; reverse transcription polymerase chain reaction; mRNA; lipoprotein lipase;

D O I：

10.1161/01.ATV.18.7.1172

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

The regulation of macrophage Lipoprotein lipase (LPL) secretion and mRNA expression by atherogenic lipoproteins is of critical relevance to foam cell formation. LPL is present in arterial lesions and constitutes a bridging ligand between lipoproteins, proteoglycans, and cell receptors, thus favoring macrophage lipoprotein uptake and lipid accumulation. We investigated the effects of native and of oxidized lipoproteins on the expression of LPL in an in vitro human monocyte-macrophage system. Exposure of mature macrophages (day 12) to highly copper-oxidized human low density lipoprotein (LDL) (100 mu g protein per milliliter) led to marked reduction in the expression of LPL activity (-62%, P<0.01) and mRNA level (-47%, P<0.05); native LDL, acetylated LDL, and LDL oxidized for <6 hours were without effect. The reduction in LPL activity became significant at a threshold of 6 hours of LDL oxidation (-31%, P<0.05). Among the biologically active sterols formed during LDL oxidation, only 7 beta-hydroxycholesterol (5 mu g/mL) induced a minor reduction in macrophage LPL activity, whereas 25-hydroxycholeslerol was without effect. By contrast, lysophosphatidylcholine, whose LDL content increased in parallel with the degree of oxidation, induced significant reductions in LPL activity and mRNA levels at concentrations of 2 to 20 mu mol/L (-34% to -53%, P<0.01), Our results demonstrate that highly oxidized LDL (>6-hour oxidation) exerts negative feedback on LPL secretion in human monocytes-macrophages via a reduction in mRNA levels. By contrast, native LDL and mildly oxidized LDL (<6-hour oxidation) did not exert a feedback effect on LPL expression. We speculate that the content of lysophosphatidylcholine and, to a lesser degree, of 7 beta-hydroxycholesterol in oxidized LDLs is responsible for the downregulation of LPL activity and mRNA abundance in human monocyte-derived macrophages and may therefore modulate LPL-mediated pathways of Lipoprotein uptake during conversion of macrophages to foam cells.

引用

页码：1172 / 1180

页数：9

共 61 条

[1] Oxidation of low density lipoproteins greatly enhances their association with lipoprotein lipase anchored to endothelial cell matrix [J].