Lipoprotein lipase stimulates the binding and uptake of moderately oxidized low-density lipoprotein by J774 macrophages

Hendriks, W.L.; Boom, H. van der; Vark, L.C. van; Havekes, Louis M.

doi:10.1042/bj3140563

Cited by 55 publications

(46 citation statements)

References 37 publications

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“…31 From this observation and from our own findings, we speculate that LPL is particularly efficient in promoting macrophage uptake of mildly oxLDL because LPL expression is not downregulated by the latter. In vivo, LDLs isolated from plaques and fatty streaks are moderately oxidized.…”

Section: Time Course Of Evolution Of Oxidation Parameters and Phosphomentioning

confidence: 70%

“…In contrast, mildly oxLDL did not downregulate LPL expression; therefore, their binding and uptake by macrophages are markedly increased given the high affinity of LPL for such LDL. 31 These investigations demonstrate that the degree of oxidation of LDL is intimately related to the mechanism of their binding and uptake by macrophages and in turn, to the role of LPL in this process. Clearly, LPL play a key role in the cellular and molecular mechanisms that regulate foam cell formation.…”

Section: Time Course Of Evolution Of Oxidation Parameters and Phosphomentioning

confidence: 99%

“…29 LPL preanchored to endothelial cells binds mildly oxLDL with high affinity. 30 Moreover, addition of LPL to J774 macrophages markedly increased the binding (50-to 100-fold) and uptake (20-fold) of mildly oxLDL 31 but did not enhance the uptake of highly oxLDL. 31 In contrast with extensive data on the interactions between LPL and lipoproteins, cell receptors, and proteoglycans, there is a paucity of information on the regulation of LPL secretion and mRNA expression in human macrophages by native and modified LDL.…”

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confidence: 99%

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Inhibition of LPL Expression in Human Monocyte–Derived Macrophages Is Dependent on LDL Oxidation State

Stengel

Antonucci

Gaoua

et al. 1998

ATVB

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Abstract-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 g protein per milliliter) led to marked reduction in the expression of LPL activity (Ϫ62%, PϽ0.01) and mRNA level (Ϫ47%, PϽ0.05); native LDL, acetylated LDL, and LDL oxidized for Ͻ6 hours were without effect. The reduction in LPL activity became significant at a threshold of 6 hours of LDL oxidation (Ϫ31%, PϽ0.05). Among the biologically active sterols formed during LDL oxidation, only 7␤-hydroxycholesterol (5 g/mL) induced a minor reduction in macrophage LPL activity, whereas 25-hydroxycholesterol 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 mol/L (Ϫ34% to Ϫ53%, PϽ0.01).Our results demonstrate that highly oxidized LDL (Ͼ6-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 (Ͻ6-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␤-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. 2-5The mechanism of the conversion of macrophages to foam cells containing large amounts of cholesterol, cholesteryl esters, and TGs is presently the subject of extensive investigation. 6 The uptake of lipoproteins by such cells involves several receptors of distinct specificity, including scavenger receptors, 7 CD36, 8 and Fc receptors 9 for oxLDL; the LDL receptor; the LDL receptor-related protein receptor 10,11 ; the VLDL receptor for TG-rich lipoproteins 12 ; and last, membrane-binding proteins for uptake of certain TG-rich lipoproteins. 13 These cellular uptake mechanisms are rendered complex by the contribution of additional factors such as heparan sulfate proteoglycans of the matrix and cell plasma membranes and equally by LPL, 14 which may serve to "anchor" lipoproteins to the cell surface.LPL is a key enzyme of lipoprotein metabolism that hydrolyzes the TG component of chylomicrons and VLDL. 15 Moreover, LPL can act as a ligand to create a "bridge" between TG-rich lipoproteins and several receptors of the LDL family.16 LPL may al...

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Section: Time Course Of Evolution Of Oxidation Parameters and Phosphomentioning

confidence: 70%

Section: Time Course Of Evolution Of Oxidation Parameters and Phosphomentioning

confidence: 99%

mentioning

confidence: 99%

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Inhibition of LPL Expression in Human Monocyte–Derived Macrophages Is Dependent on LDL Oxidation State

Stengel

Antonucci

Gaoua

et al. 1998

ATVB

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“…LPL within the vessel wall increases lipoprotein retention within the subendothelial cell matrix (9,10) and in the aortic segment (11,12). LPL can also enhance monocyte adhesion to endothelial cells (13,14).…”

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confidence: 99%

Endothelial Lipase Modulates Monocyte Adhesion to the Vessel Wall

Kojma

Hirata

Ishida

et al. 2004

Journal of Biological Chemistry

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Endothelial lipase (EL), a new member of the lipoprotein lipase gene family, plays a central role in high density lipoprotein metabolism. Previous studies indicated that EL is expressed in endothelial cells, macrophages, and smooth muscle cells in atherosclerotic lesions in human coronary arteries. However, the functional role of EL in the local vessel wall remains obscure. In this study, we evaluated the ability of EL to modulate monocyte adhesion to the endothelial cell surface. EL mRNA and protein levels were markedly increased in tissues of the mouse model of inflammation induced by lipopolysaccharide injection. Adhesion assays in vitro revealed that overexpression of EL in COS7 or Pro5 cells enhanced monocyte bindings to the EL-expression cells. Heparin or heparinase treatment inhibited EL-mediated increases of monocyte adhesion in a dose-dependent manner. Moreover, ex vivo adhesion assays revealed that the number of adherent monocytes on aortic strips was significantly increased in EL transgenic mice and decreased in EL knock-out mice as compared with wildtype mice. These results suggest that EL on the endothelial cell surface can promote monocyte adhesion to the vascular endothelium through the interaction with heparan sulfate proteoglycans. Thus, the up-regulation of EL by inflammatory stimuli may be involved in the progression of inflammation.The lipoprotein lipase gene family plays a crucial role in the lipid metabolism for the regulation of circulating lipoprotein levels and affects the process of atherosclerotic vascular diseases (1-4). The lipoprotein lipase gene family includes lipoprotein lipase (LPL) 1 and hepatic lipase (HL), both of which are synthesized and secreted by non-endothelial cells. We and other groups have reported a new member of the lipase gene family, endothelial lipase (EL). EL is mainly synthesized and secreted by vascular endothelial cells (5, 6). Previous studies have demonstrated that EL showed preferential substrate specificity for high density lipoprotein (HDL) (7). EL knock-out mice (LIPGϪ/Ϫ) showed an elevated plasma HDL-cholesterol (HDL-C) level. In contrast, human EL transgenic mice (hLIPGTg) or overexpression of human EL in mice by adenovirus vectors showed decreased plasma HDL-C and apoA-I levels (6,8). These data suggest that EL is a determinant of HDL levels in mice. In addition to their functional role in lipoprotein metabolism at the endothelial cell surface, lipases possess non-enzymatic functions in the vascular wall. LPL within the vessel wall increases lipoprotein retention within the subendothelial cell matrix (9, 10) and in the aortic segment (11, 12). LPL can also enhance monocyte adhesion to endothelial cells (13,14). The local expression of LPL in the vascular wall has been implicated in the accumulation of lipoproteins and the acceleration of atherosclerosis progression through this bridging function (15). Macrophage-derived LPL in the vessel wall is known to act as a proatherogenic molecule, determining susceptibility to atherosclerotic lesion formation...

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“…In search of a potential binding partner and uptake mechanism for gLDL, we investigated the ability of LPL to facilitate this process. LPL appeared to be an attractive candidate because, first, it is expressed in or located on the surface of cells that exhibit the most pronounced biological response to gLDL (macrophages and endothelial cells) and, second, LPL has been shown to interact with native and modified LDL mediating their cellular uptake (40,41). Several basic mechanisms have been shown to contribute to LPL-mediated lipoprotein uptake.…”

Section: Discussionmentioning

confidence: 99%

Lipoprotein Lipase Mediates the Uptake of Glycated LDL in Fibroblasts, Endothelial Cells, and Macrophages

Zimmermann

Panzenboeck²,

Wintersperger³

et al. 2001

Diabetes

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The nonenzymatic glycation of LDL is a naturally occurring chemical modification of apolipoprotein (apo)-B lysine residues by glucose. Once glycated, LDL is only poorly recognized by lipoprotein receptors including the LDL receptor (LDL-R), the LDL-R-related protein (LRP), and scavenger receptors. Glycated LDL (gLDL) is a preferred target for oxidative modifications. Additionally, its presence initiates different processes that can be considered "proatherogenic." Thus, LDL glycation might contribute to the increased atherosclerotic risk of patients with diabetes and familial hypercholesterolemia. Here we investigate whether lipoprotein lipase (LPL) can mediate the cellular uptake of gLDL. The addition of exogenous LPL to the culture medium of human skin fibroblasts, porcine aortic endothelial cells, and mouse peritoneal macrophages enhanced the binding, uptake, and degradation of gLDL markedly, and the relative effect of LPL on lipoprotein uptake increased with the degree of apoB glycation. The efficient uptake of gLDL by LDL-R-deficient fibroblasts and LRP-deficient Chinese hamster ovary cells in the presence of LPL suggested a mechanism that was independent of the LDL-R and LRP. In macrophages, the uptake of gLDL was also correlated with their ability to produce LPL endogenously. Mouse peritoneal macrophages from genetically modified mice, which lacked LPL, exhibited a 75% reduction of gLDL uptake compared with normal macrophages. The LPL-mediated effect required the association of the enzyme with cell surface glycosaminoglycans but was independent of its enzymatic activity. The uptake of gLDL in different cell types by an LPLmediated process might have important implications for the cellular response after gLDL exposure as well as the removal of gLDL from the circulation.

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Lipoprotein lipase stimulates the binding and uptake of moderately oxidized low-density lipoprotein by J774 macrophages

Cited by 55 publications

References 37 publications

Inhibition of LPL Expression in Human Monocyte–Derived Macrophages Is Dependent on LDL Oxidation State

Inhibition of LPL Expression in Human Monocyte–Derived Macrophages Is Dependent on LDL Oxidation State

Endothelial Lipase Modulates Monocyte Adhesion to the Vessel Wall

Lipoprotein Lipase Mediates the Uptake of Glycated LDL in Fibroblasts, Endothelial Cells, and Macrophages

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