Modulating Effects of Canine High Density Lipoproteins on Cholesteryl Ester Synthesis Induced by B‐Very Low Density Lipoproteins in Macrophages: Possible In Vitro Correlates with Atherosclerosis

We have previously observed that cholesterol-fed dogs with plasma cholesterol levels of 350 to 750 mg/dl failed to develop atherosclerosis (hyporesponders), whereas cholesterol-fed dogs with cholesterol levels greater than 750 mg/dl developed markedly accelerated atherosclerosis (hyperresponders). Two striking features of the hypercholesterolemia of the hyperresponders were the occurrence of cholesteryl ester-rich, β-mlgrating very low density llpoproteins (β-VLDL) In the d < 1.006 fraction and a decrease in plasma concentration of typical high density llpoproteins (HDL). Cholesterol-induced β-VLDL have been shown to cause massive accumulations of cholesteryl esters in mouse peritoneal macrophages in vitro, and HDL have been shown to remove cholesterol from these cells. In the present study, the mouse peritoneal macrophage system was used to explore the effects of high levels of cholesterol-Induced d < 1.006 llpoproteins and low levels of HDL In mediating cholesteryl ester synthesis and accumulation In these cells. It was found that the d < 1.006 lipoproteins from both the atherosclerotic hyperresponders and the nonatherosclerotlc hyporesponders stimulated cholesteryl [14 C]-oleate synthesis. The d < 1.006 llpoproteins from control chow-fed dogs were not capable of inducing cholesteryl ester formation. The ability of the d < 1.006 llpoproteins from the hypercholesterolemic dogs to stimulate cholesteryl ester synthesis in macrophages was best predicted by the enrichment of these llpoproteins with cholesterol and cholesteryl esters. The modulating effect of HDL was shown by the marked decrease In cholesteryl ester formation and accumulation when macrophages were incubated with both HDL and hypercholesterolemic d < 1.006 llpoproteins. The ratio of HDL cholesterol to d < 1.006 llpoproteln cholesterol added to the macrophages was predictive of the degree of cholesteryl ester formation and accumulation that occurred. HDL with apoproteln E (apo E) and HDL without apo E were capable of reversing the cholesteryl ester formation Induced by hypercholesterolemic d < 1.006 llpoproteins; however, the HDL without apo E were more effective. When the ratio of HDL cholesterol to d < 1.006 llpoproteln cholesterol added to the macrophages was > 0.5 to 1.0, there was a marked reduction in the ability of the hypercholesterolemic d < 1.006 llpoproteins to induce significant cholesteryl ester formation. When the ratios of HDL cholesterol to d < 1.006 cholesterol were less than 0.5, the amount of [14 C]oleate incorporated Into the cholesteryl esters of the macrophages was progressively Increased. It Is reasonable to speculate that an important determinant of whether cholesteryl esters accumulate In the macrophage model system, and possibly In the arterial wall, Is the ratio of those llpoproteins capable of delivering cholesterol to the cells (e.g., D-VLDL, cholesterol-enriched d < 1.006 lipoproteins) to those llpoproteins capable of removing cholesterol from the cells (e.g., HDL). More direct parallels between the In vivo and in vitro observations remain to be determined.