Role of the macrophage very-low-density lipoprotein receptor in atherosclerotic lesion development.
ABSTRACT The very-low-density lipoprotein receptor (VLDLr) is highly expressed in macrophage-rich areas of atherosclerotic lesions. The exact role of the macrophage VLDLr in atherosclerotic lesion development, however, is presently unclear.
To assess the role of the macrophage VLDLr in atherosclerotic lesion development in vivo, we used the technique of bone marrow transplantation to selectively disrupt or reconstitute the VLDLr in macrophages in VLDLr+/+ and VLDLr-/- mice, respectively. After 10 weeks high-cholesterol diet feeding, the lesion area in control transplanted wild-type mice was 17+/-4 x 10(3)+/-microm(2). Disruption of the macrophage VLDLr by transplanting bone marrow from VLDLr-/- mice to wild-type VLDLr+/+ littermates resulted in a tendency to a slight reduction in lesion size to 12+/-3 x 10 microm. The mean atherosclerotic lesion area, measured in control transplanted VLDLr-/- mice, lacking the VLDLr in all tissues was 12+/-3 x 10(3)microm(2). Interestingly, reconstitution of the macrophage VLDLr in VLDLr-deficient recipients resulted in a 2.7-fold increase (P<0.05) in the mean atherosclerotic lesion area to 32+/-3 x 10(3)microm(2).
The macrophage VLDLr facilitates atherosclerotic lesion development, probably by mediating the accumulation of atherogenic lipoproteins.
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ABSTRACT: therosclerosis, along with the resultant coronary artery disease (CAD), is a leading cause of mortality in industrialized countries. Significant attention has focused on the role of low-density lipoprotein (LDL) in the pathogenesis of CAD. A dyslipidemia characterized by a combination of abnormalities in the plasma levels of triglycerides and high- density lipoprotein (HDL) cholesterol, with or without ele- vated LDL cholesterol levels, affects many persons with premature CAD, however. In particular, both qualitative and quantitative abnormalities in circulating triglyceride-rich li- poproteins (TRLPs) may be a key factor in the development of CAD.1 A number of advances have led to an increased apprecia- tion of TRLP concentrations as independent predictors of risk for CAD. First, the meta-analysis by Hokanson and Austin2 demonstrated that increases in plasma triglyceride levels were associated with increased risk for CAD events, even after adjusting for numerous other predictive factors. The meta- analysis was supported by a more recent prospective study by Jeppesen et al,3 which demonstrated that triglyceride levels were independent predictors of ischemic heart disease in men. Second, a number of studies have demonstrated that TRLPs, whether assembled in and secreted from the intestine or the liver, can penetrate the artery wall and initiate or aggravate atherogenesis. Third, during the last decade, we have gained a much more detailed understanding of the metabolic rela- tionship between high levels of TRLPs, low levels of high- density lipoprotein (HDL) cholesterol, and an abnormally small, cholesterol-depleted, dense LDL.4 This review will attempt to bring together information from recent cellular, biochemical, physiological, and molecular studies to provide an update of our understanding of both normal and abnormal TRLP metabolism and of the atherogenicity of TRLPs.Circulation 11/2002; 106(16):2137-42. · 15.20 Impact Factor
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ABSTRACT: The transfer of normal human fibroblasts from medium containing whole serum to medium devoid of lipoproteins produced a 90 percent decrease in the cellular content of cholesteryl esters and a 30 percent decrease in the free cholesterol content. When these lipoprotein-deprived cells were subsequently incubated with human low density lipoprotein (LDL), there was a 7-fold increase in the cellular content of esterified cholesterol and a 1.6-fold increase in the cellular content of free cholesterol. The concentration at which LDL produced its half-maximal effect in elevating cellular sterol content (30 mug/ml of LDL-cholesterol) was similar to the half-maximal concentration previously reported for high affinity binding of LDL to its cell surface receptor. High density lipoprotein (HDL) and whole serum from a patient with abetalipoproteinemia (neither of which contains a component that binds to the LDL receptor) did not produce a significant increase in the content of either cholesterol or cholesteryl esters in normal cells. Furthermore, in fibroblasts from patients with the homozygous form of familial hypercholesterolemia, which lack functional LDL receptors, LDL had no effect in raising the cellular content of either free or esterified cholesterol even when present in the medium at concentrations as high as 450 mug sterol/ml. It is concluded that LDL-receptor interactions constitute an important biochemical mechanism for the regulation of the cholesterol content of normal human fibroblasts. Moreover, when considered in light of current concepts of LDL metabolism in intact mammals, the present data suggest that a major function of plasma LDL may be to transport cholesterol from its site of synthesis in liver and intestine to its site of uptake in peripheral tissues.Journal of Clinical Investigation 05/1975; 55(4):783-93. · 12.81 Impact Factor
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ABSTRACT: Background—Expression of the VLDL receptor, primarily in macrophages, has been confirmed in human and rabbit atherosclerotic lesions. The high binding affinity of the VLDL receptor for remnant particles implicates the VLDL receptor pathway in the foam cell formation mechanism in macrophages. This study investigates the effect of interferon (IFN)-g on VLDL receptor expression in phorbol-12-myristate-13-acetate (PMA)-treated THP-1, HL-60 macrophages, and human monocyte-derived macrophages. Methods and Results—THP-1 cells were induced to differentiate into macrophages by PMA treatment. IFN- g was added to the medium, and expression of the VLDL receptor was determined. 125I-b-VLDL degradation study and oil red O staining were examined. In THP-1 macrophages, VLDL receptor protein expression decreased at 2 days after PMA treatment but increased at 3 days and increased up to 5 days. Scavenger receptor proteins, which were not originally present, appeared at 3 days after PMA treatment. IFN-g inhibited VLDL receptor expression in a dose-and time-dependent manner in macrophages. However, no inhibitory effect was observed in monocytes. Moreover, IFN-g receptor mRNA increased during differentiation to macrophages. 125I-b-VLDL degradation study and oil red O staining showed that IFN-g significantly inhibited foam cell formation after the uptake of b-VLDL. LDL receptor-related protein (LRP) and LDL receptor mRNAs were not expressed in macrophages. In PMA-treated HL-60 macrophages and human monocyte-derived macrophages, IFN-g also inhibited VLDL receptor expression and foam cell formation by b-VLDL. Conclusions—VLDL receptor expression is upregulated during monocyte-macrophage differentiation. IFN- g inhibits VLDL receptor expression and foam cell formation only in macrophages. Remnant particles induce macrophage foam cell formation through the VLDL receptor pathway. (Circulation. 2001;103:1142-1147.)