Receptor-mediated uptake and ‘retroendocytosis’ of high-density lipoproteins by cholesterol-loaded human monocyte-derived macrophages: possible role in enhancing reverse cholesterol transport

Macrophages play a pivotal role in the development of atherosclerosis. During the initial stages of the disease, monocytes migrate into the subendothelial space of blood vessels and differentiate into macrophages. The uptake of excessive amounts of lipoprotein-derived lipids leads to their conversion into foam cells (1). The availability of oxidized lipids in the subendothelial space and the macrophage-specific expression of scavenger receptors, which lack feedback regulation (2, 3), mediate the high degree of lipid enrichment. Under physiological conditions, the net accumulation of lipids in the subendothelial space of blood vessels is a result of a complex set of events, including the overall local redox balance and the rate of cholesterol accumulation/uptake and its removal via the reverse cholesterol transport pathway (4, 5).Caveolins and caveolin-1 specifically, have been implicated in the regulation of cellular cholesterol metabolism and lipid uptake, as well as efflux (6). The majority of the available information about caveolins comes primarily from studies on fibroblasts and endothelial cells, which are relatively rich in caveolae and express high amounts of caveolin-1 and caveolin-2. The evidence for caveolin expression in macrophages has been conflicting, at least in part due to the use of different macrophage-like cell lines in the various inquiries. Our laboratory has recently investigated caveolin expression in mouse primary macrophages as well as J774 cells in detail.The potential role of caveolins in the intracellular transport of cholesterol and its physical association with the cholesterol-rich rafts makes it tempting to speculate that these proteins play an important role in cholesterol metabolism of macrophages. Macrophage cholesterol metabolism may be, in turn, a central determinant in maintaining cholesterol homeostasis in the arterial wall. CAVEOLINS AND CAVEOLAELipid rafts are tightly-packed, liquid-ordered plasma membrane microdomains enriched in cholesterol, sphingomyelin, and glycolipids. They are characterized by their insolubility in non-ionic detergents at 4 Њ C and their light density on sucrose gradients. Their unique lipid composition may act to compartmentalize specific membrane proteins, including caveolins. Caveolae represent a subset of lipid rafts, characterized by high caveolin content and formation of 50-100 nm flask-shaped membrane invaginations (7).Caveolin-1, a member of the caveolin family, was first identified as a tyrosine-phosphorylated protein in Rous sarcoma virus-transformed chick embryo fibroblasts (8, 9). To-date, three mammalian caveolin genes have been identified (10). Of the three isoforms, caveolin-1 and -2 are expressed ubiq-

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“…Retroendocytosis of HDL by macrophages has been previously documented (101)(102)(103)(104). Our own data, using gold- Fig.…”

Section: Cholesterol Effluxmentioning

confidence: 65%

Caveolins and macrophage lipid metabolism

Gargalovic

Dory

2003

Journal of Lipid Research

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“…Schmitz et al 32 have suggested such a function for retroendocytosed HDL in cholesteryl ester-laden macrophages based on the association of gold-labeled HDL with cholesterol ester storage vesicles in these cells. Also, Alam et al 34 have recently reported that HDL 3 is converted to a larger apo E-containing particle (of HDL 2 size and density) during retroendocytosis through cholesterol-laden macrophages, an observation that is consistent with an enrichment of HDL3 with cholesterol.…”

Section: Discussionmentioning

confidence: 82%

“…Using HDL conjugated to colloidal gold, they presented electron microscopic evidence suggesting that the conjugates were bound, internalized into endosomes, and subsequently resecreted from the cells. Oram et al 33 were unable to find evidence of internalization and resecretion by these mouse cells using 125 I-HDL, but Alam et al 34 found that iodinated HDL appeared to be retroendocytosed by human monocyte-derived macrophages and that the process was up-regulated by cholesterol loading. Recently, Takahashi et al 35 have also found evidence for internalization and resecretion of 12S I-HDL by rat peritoneal macrophages.…”

Section: Discussionmentioning

confidence: 97%

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Retroendocytosis of high density lipoproteins by the human hepatoma cell line, HepG2.

et al. 1990

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“…Monocyte-derived macrophages have been shown to possess a variety of receptors for the uptake of lipoprotein and other substances [18][19][20][21]. They are also capable of synthesizing and processing lipids [19,22,23].…”

Section: Discussionmentioning

confidence: 99%

Dietary Cholesterol-Induced Hyperlipidemia Modulates Lipid Synthesis in Rabbit Monocytes.

Gupta

Thomson

Kappagoda³

et al. 1993

J. Clin. Biochem. Nutr.

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SummaryLipid synthesis in monocytes isolated from rabbits fed a high-cholesterol diet and subsequently a low-cholesterol one was examined. Rabbits were fed diet containing 2.5% (w/w) cholesterol for 3 weeks and then transferred to a normal diet for another 6 weeks. The total and free cholesterol levels in the blood increased up to 3 weeks and then steadily decreased. Esterified cholesterol increased only during the first week on the high-cholesterol diet and then decreased throughout the remainder of the experimental period. Lipid synthesis, as assessed by [1-1 4C]acetate incorporation , was significantly reduced in monocytes isolated from animals on the high-cholesterol diet. This reduction in lipid synthetic activity continued another 3 weeks even after cessation of the high-cholesterol diet and then lipid synthesis was rather increased significantly. Specifically an increase in cholesterol and fatty acid synthesis was observed when animals were fed a high-cholesterol diet for 3 weeks and then allowed to recover for another 6 weeks.

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Receptor-mediated uptake and ‘retroendocytosis’ of high-density lipoproteins by cholesterol-loaded human monocyte-derived macrophages: possible role in enhancing reverse cholesterol transport

Cited by 48 publications

References 34 publications

Caveolins and macrophage lipid metabolism

Caveolins and macrophage lipid metabolism

Retroendocytosis of high density lipoproteins by the human hepatoma cell line, HepG2.

Dietary Cholesterol-Induced Hyperlipidemia Modulates Lipid Synthesis in Rabbit Monocytes.

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