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Regulation of the metabolism of lipoprotein-proteoglycan complexes in human monocyte-derived macrophages.

ABSTRACT: Studies were performed to evaluate the effect of several factors on the metabolism of lipoprotein-proteoglycan complexes in human monocyte-derived macrophages. In vivo apoB-lipoprotein-proteoglycan complex was isolated from human aorta fibrous-plaque lesions and low-density lipoprotein (LDL)-proteoglycan complex was formed in vitro. Degradation of LDL-proteoglycan complex and cholesteryl ester synthesis mediated by the in vivo and in vitro complexes were lowest in freshly isolated monocytes. With the maturation of monocytes into macrophages, there was a dramatic rise in both. The degradation of the complex and the resultant stimulation of cholesterol esterification increased significantly with increasing cell density. Preincubation of macrophages in medium containing lipoprotein cholesterol did not down-regulate the subsequent degradation of LDL-proteoglycan complex. Macrophage-conditioned medium had a profound stimulatory effect on the degradation of LDL-proteoglycan complex and cholesterol esterification by mature macrophages and freshly isolated monocytes. The conditioned medium lost its stimulatory activity after boiling, dialysis and trypsin digestion. Macrophage activation with phorbol ester and bacterial lipopolysaccharide resulted in a marked suppression of the binding and degradation of the complex, as well as the complex-mediated cholesteryl ester synthesis. These results demonstrate that several factors regulate the metabolism of lipoprotein-proteoglycan complexes in human monocyte-derived macrophages.

SUBMITTER: Vijayagopal P

PROVIDER: S-EPMC1137042 | biostudies-other | 1994 Aug

REPOSITORIES: biostudies-other

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Project description:We have shown recently that lipoprotein-proteoglycan complexes isolated from human atherosclerotic lesions stimulated cholesteryl ester synthesis in human monocyte-derived macrophages [Vijayagopal, Srinivasan, Radhakrishnamurthy and Berenson (1992) Arterioscler. Thromb. 12, 237-249]. The present study was conducted to determine the mechanism of cellular uptake of the complexes. A chondroitin sulphate-dermatan sulphate proteoglycan was isolated from normal human aorta and complexed to 125I-labelled human low-density lipoprotein (LDL). The binding and degradation of 125I-LDL-proteoglycan complex were then studied in human monocyte-derived macrophages. The specific binding and degradation of the complex showed saturability and concentration-dependency. The Kd for binding was 1.5 x 10(-8) M, which was greater than that reported for LDL in monocyte-derived macrophages. Binding of the complex was not subject to down-regulation. Chloroquine inhibited degradation of the complex and the resultant stimulation of cholesteryl ester synthesis. Limited treatment of macrophages with proteolytic enzymes abolished binding and degradation of the complex significantly. Macrophages bound 125I-methyl-LDL-proteoglycan complex to the same extent as 125I-LDL-proteoglycan complex. Excess LDL and proteoglycan did not compete against the binding of the complex; however, excess acetyl-LDL competed for 61% of the binding. Likewise, excess LDL-proteoglycan complex inhibited the binding of 125I-acetyl-LDL by 64%. Polyinosinic acid and cytochalasin D inhibited the binding of 125I-LDL-proteoglycan complex by 60% and 36% respectively. Compared with that of acetyl-LDL, the degradation of LDL-proteoglycan complex was retarded in human macrophages. The results indicate that the uptake of LDL-proteoglycan complex in human monocyte-derived macrophages is not mediated through binding to the LDL receptor; but occurs predominantly via the scavenger receptor, with phagocytosis playing a minor role in the process.

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Regulation of the metabolism of lipoprotein-proteoglycan complexes in human monocyte-derived macrophages.

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