Esterification of Low Density Lipoprotein Cholesterol in Human Fibroblasts and Its Absence in Homozygous Familial Hypercholesterolemia

Abstract

A new mechanism is described for the cellular esterification of cholesterol derived from extra-cellular lipoproteins. Incubation of monolayers of cultured fibroblasts from normal human subjects with low density lipoproteins led to a 30- to 40-fold increase in the rate of incorporation of either [(14)C]acetate or [(14)C]oleate into the fatty acid fraction of cholesteryl [(14)C]esters. This stimulation of cholesteryl ester formation by low density lipoproteins occurred despite the fact that endogenous synthesis of free cholesterol was completely suppressed by the lipoprotein. Thus, exogenous cholesterol contained in low density lipoproteins, rather than endogenously synthesized sterol, appeared to provide the cholesterol substrate for this cellular esterfication process. High density lipoproteins and the lipoprotein-deficient fraction of serum neither stimulated cholesteryl ester formation nor inhibited cholesterol synthesis. Both the low density lipoprotein-dependent increase in cholesterol esterification and decrease in free cholesterol synthesis required the interaction of the lipoprotein with its recently described cell surface receptor. Cells from homozygotes with familial hypercholesterolemia, which lack specific low density lipoprotein receptors, showed neither lipoprotein-dependent cholesterol esterification nor suppression of cholesterol synthesis. The reciprocal changes in free cholesterol synthesis and cholesteryl ester formation produced by low density lipoprotein-receptor interactions may play an important role in the regulation of the cholesterol content of mammalian cells.