Suppression of synthesis and esterification of cholesterol and stimulation of low density lipoprotein receptor activity by polyoxyethylated cholesterol in cultured human fibroblasts.

In cultured skin fibroblasts from normal and homozygous familial hypercholesterolemic subjects, a water-soluble polyoxyethylated derivative of cholesterol suppresses the incorporation of [2-14C]acetate into cholesterol and decreases the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme of cholesterol synthesis. The effect of this compound on low density lipoprotein (LDL) receptor-mediated activities (binding, internalization, and degradation of LDL) and on cholesterol ester formation was compared to that of LDL and 25-hydroxycholesterol. In normal fibroblasts preincubated in lipoprotein-deficient serum, LDL or 25-hydroxycholesterol decreased cholesterol synthesis and LDL receptor activity and increased cholesterol ester formation. In contrast, polyoxyethylated cholesterol stimulated LDL receptor activity, inhibited cholesterol ester formation mediated by LDL and 25-hydroxycholesterol, and inhibited the activity of acyl-CoA:cholesterol acyltransferase in cell extracts. Polyoxyethylated cholesterol had no effect on the low level of LDL receptor activity of homozygous hypercholesterolemic fibroblasts but stimulated the half-normal activity of heterozygous cells.