Uptake of cholesterol-rich remnant lipoproteins by human monocyte-derived macrophages is mediated by low density lipoprotein receptors.

Koo, Catherine H.; Wernette-Hammond, M E; Garcia, Z; Malloy, Mary J.; Uauy, Ricardo; East, Cara; Bilheimer, D. W.; Mahley, Robert W.; Innerarity, Thomas L.

doi:10.1172/jci113460

Cited by 118 publications

(80 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…0-VLDL from cholesterol-fed animals has been considered to be the only naturally occurring lipoprotein with the capacity to induce foam cell formation in vitro by interacting with a specific receptor, originally thought to be a distinct /3-VLDL receptor. 25 - 27 Recent evidence shows that uptake and degradation of 0-VLDL by mouse J774, P388D, and peritoneal macrophages 28 - 29 and by human monocyte-derived macrophages 30 is probably mediated by the LDL receptor and not by a unique /3-VLDL receptor. Interest in the interactions of human VLDL with macrophages has been stimulated by the possibility that triglyceride-rich lipoproteins and their remnants may be atherogenic.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Cholesterol accumulation in J774 macrophages induced by triglyceride-rich lipoproteins. Comparison of very low density lipoprotein from subjects with type III, IV, and V hyperlipoproteinemias.

Huff

Evans

Sawyez

et al. 1991

Arterioscler Thromb

View full text Add to dashboard Cite

Tbe capacity of human triglyceride-rich lipoproteins to induce cholesterol accumulation in the murine J774 macrophage cell line was investigated with large very low density lipoprotein (VLDL, S, 60-400) obtained from subjects with type III, IV, and V hyperlipoproteinemias. After incubation for 24 hours, VLDLs from type IV and type V subjects were similar in their ability to raise cellular cholesterol deposition threefold to fourfold and cellular triglyceride 16-fold. 1 Within VLDL, there is metabolic heterogeneity with respect to density and apoprotein (apo) content.2 -5 After secretion, large

show abstract

mentioning

confidence: 99%

“…Although not conclusive, these findings suggest that both types of lipoproteins share the same uptake mechanism. Ellsworth et al, 28 using J774 cells, and Koo et al, 29 -30 using mouse peritoneal and human monocyte-derived macrophages, demonstrated that /3-VLDL (from cholesterol-fed animals) are taken up by the LDL receptor.…”

mentioning

confidence: 99%

Cholesterol accumulation in J774 macrophages induced by triglyceride-rich lipoproteins. Comparison of very low density lipoprotein from subjects with type III, IV, and V hyperlipoproteinemias.

Huff

Evans

Sawyez

et al. 1991

Arterioscler Thromb

View full text Add to dashboard Cite

show abstract

“…Macrophage LDLr metabolizes LDL and VLDL/chylomicron remnants (1,15,32,33), and uptake of LDL by macrophages through the LDLr can induce foam cell formation in culture (32,34). Thus, previous studies have shown that WT mice that received BM cells with WT LDLr develop larger diet-induced plaques compared with the WT mice that received cells lacking LDLr (18,34).…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein E4 in Macrophages Enhances Atherogenesis in a Low Density Lipoprotein Receptor-dependent Manner

Altenburg¹,

Johnson

Wilder

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

Apolipoprotein E (apoE) and the low density lipoprotein receptor (LDLr) are well recognized determinants of atherosclerosis. In addition to hepatocytes, where both are highly expressed and contribute to plasma lipoprotein clearance, they are expressed in vascular cells and macrophages. In this study, we examined the effects of human apoE isoforms and LDLr levels in atherogenic pathways in primary macrophages ex vivo and atherosclerosis development after bone marrow transfer in vivo using mice expressing human apoE isoforms and different levels of LDLr expression. Increases in LDLr expression significantly increased cholesterol delivery into macrophages in culture, and the effects were more prominent with lipoproteins containing apoE4 than those containing apoE3. Conversely, increased LDLr expression reduced cholesterol efflux in macrophages expressing apoE4 but not in macrophages expressing apoE3. Furthermore, apoE3 protected VLDL from oxidation in vitro more than did apoE4. In LDLr-deficient mice expressing the human apoE4 isoform, Apoe 4/4 Ldlr ؊/؊ , the replacement of bone marrow cells with those expressing LDLr increased atherosclerotic lesions in a dose-dependent manner compared with mice transplanted with cells having no LDLr. In contrast, atherosclerosis in Apoe 3/3 Ldlr ؊/؊ mice, expressing the human apoE3 isoform, did not differ by the levels of macrophage LDLr expression. Our results demonstrate that apoE4, but not apoE3, in macrophages enhances atherosclerotic plaque development in mice in an LDLr-dependent manner and suggests that this interaction may contribute to the association of apoE4 with an increased cardiovascular risk in humans.

show abstract

“…Similarly, because of its low affinity for the LDL receptor on mouse macrophages, LDL does not compete effectively with 125 I-/3-VLDL or apo E-containing lipoproteins for receptor binding. 36 Because the LDL receptor could be fully downregulated after the uptake of ox-LDL by the scavenger receptor, the importance of the uptake of ox-LDL by the LDL receptor is not clear. It was reported recently 37 -38 that on SDS-PAGE, Western blot analysis, and enzyme-linked immunosorbent assay, ox-LDL revealed a positive interaction with Mab MB47 (which was shown to bind to the LDL receptor-binding domains).…”

Section: Discussionmentioning

confidence: 99%

“…LDL binds to MPMs with a 10-fold lower affinity than it does to cultured human fibroblasts. 36 Koo et al 36 reported recently that the LDL receptor on MPMs differs from the same receptors on HMDMs and fibroblasts with regard to its molecular size, binding affinity to LDL, and relative insensitivity to downregulation. Using specific antibodies against the rat liver LDL receptor, Ellsworth et al 39 have shown that MPMs, J774 macrophages, and a mouse fibroblast cell line (3T3) all possess LDL receptors with a molecular weight about 5,000 d less than that of the rat liver LDL receptor.…”

Section: Discussionmentioning

confidence: 99%

Involvement of the macrophage low density lipoprotein receptor-binding domains in the uptake of oxidized low density lipoprotein.

Keidar

Brook

Fuhrman

et al. 1992

Arterioscler Thromb

View full text Add to dashboard Cite

Macrophages, unlike most other cells, possess both low density lipoprotein (LDL) and scavenger receptors. The scavenger receptor has been shown to mediate the uptake of oxidized LDL (ox-LDL), which ultimately leads to cholesterol loading of the macrophages. The present study was undertaken to define epitopes on ox-LDL that are important for lipoprotein binding to macrophages and to ascertain whether ox-LDL can bind to the LDL receptor. Monoclonal antibodies (Mabs) directed against several epitopes along the apolipoprotein B-100 (apo B-100) molecule were used. LDL (300 /tg/ml) was oxidized by incubation with 10 jtM CuSO, for 24 hours. Ox-LDL, as opposed to acetylated LDL (ac-LDL), reacted with Mabs directed against the LDL receptor-binding domains (Mabs B1B6 and B1B3). Similarly, uptake of ox-LDL but not ac-LDL by a murine J774 macrophage-like cell line was inhibited by as much as 40% after using Mab B1B6. The anti-LDL receptor antibody IgG-C7 also inhibited '"I-ox-LDL uptake by macrophages by 60%. Chromatography on heparin-Sepharose columns of LDL that was partially oxidized for only 3 hours resulted in two fractions: an unbound traction with characteristics similar to those of ox-LDL and a bound fraction similar to native LDL. Macrophage degradation of the unbound fraction was inhibited by Mab IgG-C7 and Mab B1B6, whkh are directed toward the LDL receptor and the LDL receptor-binding domains on apo B-100, respectively. When incubated with three types of macrophages, J774 macrophage cells, mouse peritoneal macrophages, and human monocyte-derived macrophages, excess amounts of unlabeled ox-LDL, like native LDL but unlike ac-LDL, substantially suppressed the uptake and degradation of l25 l-labekd LDL. Similar studies with fibroblasts, however, revealed that unlabeled LDL but not unlabeled ox-LDL or ac-LDL competed with ""I-LDL for cellular uptake and degradation. Mab directed against epitopes on the amino terminus domain of apo B-100 (C14) demonstrates a similar immunoreactivity with ox-LDL and native LDL but a much lower reactivity with ac-LDL. Mab C14 inhibited macrophage degradation of ox-LDL by 34% but had no inhibitory effect on the uptake of native LDL or ac-LDL. Thus, the ac-LDL and LDL receptor-binding domains as well as a unique epitope on the ammo terminus of apo B-100 may be involved in macrophage binding of ox-LDL. We conclude that 1) ox-LDL contains epitopes that are also present in native LDL, although considerable changes in these epitopes are suggested and 2) these epitopes are involved in the uptake of ox-LDL by macrophages. {Arteriosclerosis and Thrombosis 1992;12:484-493) KEY WORDS • oxidized low density lipoproteins • monoclonal antibodies • macrophages M acrophages, like those resident in the atherosclerotic lesion, poorly take up native low density lipoprotein (LDL), whereas several modified forms of LDL are taken up avidly by the macrophage scavenger receptor.

show abstract

Uptake of cholesterol-rich remnant lipoproteins by human monocyte-derived macrophages is mediated by low density lipoprotein receptors.

Cited by 118 publications

References 37 publications

Cholesterol accumulation in J774 macrophages induced by triglyceride-rich lipoproteins. Comparison of very low density lipoprotein from subjects with type III, IV, and V hyperlipoproteinemias.

Cholesterol accumulation in J774 macrophages induced by triglyceride-rich lipoproteins. Comparison of very low density lipoprotein from subjects with type III, IV, and V hyperlipoproteinemias.

Apolipoprotein E4 in Macrophages Enhances Atherogenesis in a Low Density Lipoprotein Receptor-dependent Manner

Involvement of the macrophage low density lipoprotein receptor-binding domains in the uptake of oxidized low density lipoprotein.

Contact Info

Product

Resources

About