Very low density lipoproteins promote triglyceride accumulation in macrophages.

Abstract

Incubation of mouse peritoneal macrophages with very low density lipoproteins (VLDL) from normal rats or rhesus monkeys markedly increased the levels of intracellular trlglycerldes by 10-to 56-fold and was accompanied by the production of oil red 0 positive vacuoles. The stimulation of triglyceride accumulation in macrophages was time-and concentration-dependent and was specific for VLDL. Three possible mechanisms for the VLDL-stlmulated triglyceride accumulation In macrophages were explored: receptor-mediated uptake, action of llpoprotein llpase, and phagocytosis. Macrophage uptake and degradation of 125 l-monkey and rat VLDL demonstrated saturable and nonsaturable components. Uptake of 125 I-VLDL could be inhibited by unlabeled normal VLDL, although hyperllpemlc VLDL was more effective. HDL did not compete to a significant extent. Heparln released llpoprotein lipase-llke activity from peritoneal macrophages. Addition of heparln with VLDL resulted in a greater, more rapid elevation in Intracellular triglycerides, which was partially Inhibited by albumin. Free fatty acid and Intrallpid also produced triglyceride accumulation In macrophages. The data showed that all three of the mechanisms examined could contribute to the metabolism of VLDL by macrophages and cause the production of trlglycerlderlch cells with a "foamy" appearance, although the evidence suggested that the action of llpoprotein llpase was probably the most important In this process.

Modification of very low density lipoproteins leads to macrophage scavenger receptor uptake and cholesteryl ester deposition.

“…21 " 23 Human VLDL represents a heterogeneous population of particles which can be separated using ultracentrifugation in a discontinuous NaCI gradient. 26 ' n The data shown in Figure 2B, that ALDL is a more effective competitor for AVLDL degradation than AVLDL itself, could potentially be explained by a greater scavenger-receptor affinity for ALDL.…”

“…Lipoprotein and cellular triglycerides were measured as described by Bates et al 23 Protein was measured with BSA as a standard by the method of Lowry et al 30 Statistical comparisons were performed by the two-tailed t test.…”

Effect of dietary fat saturation and cholesterol on LDL composition and metabolism. In vivo studies of receptor and nonreceptor-mediated catabolism of LDL in cebus monkeys.

“…10 Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) was performed according to the method of Weber and Osborne. 17 Liver and adipose tissue samples were obtained by biopsy in anes-thetized animals, and lipoprotein and tissue lipids were extracted by the method of Folch et al 18 Total and free cholesterol were measured by gas-liquid chromatography as described by Bates et al 19 Cholesterol ester was determined after the subtraction of free cholesterol from total cholesterol and was multiplied by 1.68 to correct for fatty acid content. Trigtycerides were quantitated by the thin-layer chromatography method of Kritchevsky et al 20 Methods employed for gas-liquid chromatography of esterified fatty acids have been detailed previously.…”

Triacylglycerol-rich lipoproteins alter the secretion, and the cholesterol-effluxing function, of apolipoprotein E-containing lipoprotein particles from human (THP-1) macrophages

“…The association between plasma triacylglycerol levels and atherosclerosis is particularly apparent in conditions associated with elevated levels of TGRLP, such as Type II (non-insulin dependent) diabetes (' NIDDM ') [4], Type III hyperlipoproteinaemia [5] and familial combined hyperlipidaemia [6]. Current research suggests that TGRLP might contribute directly to the atherosclerotic process [7] by triggering endothelial dysfunction [8], enhanced monocyte adhesion [9] and lipid accumulation within the artery wall [10]. Undegraded TGRLP and their remnants are present within human and experimental atherosclerotic lesions [11][12][13] ; Proctor and Mamo [13] provided visual evidence that chylomicron remnants directly transgress the endothelial cell layer and become trapped within the subendothelial space, leading to focal accumulation of these pro-atherogenic lipoproteins.…”

“…Exposure to TGRLP, particularly those isolated from patients with Type II diabetes [14], induces the intracellular accumulation of triacylglycerol and\or cholesteryl ester in human monocytederived [14,15] and murine [10,16] macrophages. Indeed, TGRLP are the only native, non-modified lipoproteins to cause macrophage ' foam cell ' formation in itro [10,[14][15][16][17].…”