1. The effects of the cholesterol-lowering drug probucol on lipoprotein metabolism and on the key enzymes that regulate hepatic cholesterol metabolism in the rat were studied. 2. Probucol given for 2 weeks was accompanied by a significant reduction in plasma concentrations of low-density and high-density lipoproteins (LDL, HDL). The fractional catabolic rates of the apolipoproteins of HDL and LDL (apoHDL, apoLDL) were not affected by probucol, although the absolute rates of catabolism of both the apolipoproteins were significantly reduced. 3. The activities of 3-hydroxy-3-methyl-glutaryl-coenzyme A (CoA) reductase and cholesterol 7α-mono-oxygenase, as well as the rate of hepatic sterol synthesis, were unchanged during the first 2 weeks of probucol. More prolonged probucol led to inhibition of the activity of these enzymes and reduction in sterol synthesis, although the liver cellular content of cholesterol significantly increased. 4. It is postulated that a principal mode of action of the drug is to reduce the rate of lipoprotein synthesis.

1. The submicrosomal distribution of three enzymes concerned in cholesterol metabolism, and of free and esterified cholesterol, was determined in human liver by analytical isopycnic centrifugation on sucrose gradients. 2. The distribution profile and median density of acyl-CoA:cholesterol O -acyltransferase was similar to that of RNA, showing that this enzyme is confined largely to the ribosome-rich membranes of the endoplasmic reticulum. The distribution profiles and median densities of 3-hydroxy-3-methylglutaryl-CoA reductase and cholesterol 7α-mono-oxygenase showed that both enzymes are confined to the smooth, ribosome-poor, endoplasmic reticulum. 3. Most of the free cholesterol in the microsomal preparations was present in smooth membranes from the Golgi apparatus and in vesicles from plasma-membrane fragments. The distribution of esterified cholesterol was multimodal and extended throughout the whole gradient.

1. In the presence of CoA and ATP, human liver microsomes catalyse the incorporation of [ 14 C]oleate or [ 14 C]cholesterol into cholesteryl oleate, thus demonstrating the presence of acyl-coenzyme A-cholesterol acyltransferase (cholesterol acyltransferase) in human liver. 2. The enzyme has properties similar to those of rat liver enzyme and with both the concentration of endogenous cholesterol in the microsomal fraction is adequate to support a constant initial rate of esterification. However, unlike the rat liver enzyme, the human cholesterol acyltransferase does not efficiently utilize added cholesterol as substrate. 3. The activity of cholesterol acyltransferase in human liver was 25% of that measured in rat liver under similar conditions of assay.

1. The turnover of cholesteryl esters in plasma high-density (HDL) and low-density (LDL) lipoproteins was measured in patients with familial hyperbetalipoproteinaemia in the homozygous and heterozygous forms and in control subjects. 2. The fractional rates of turnover of HDL and LDL cholesteryl esters were significantly lower in the patients than in the control subjects, but there was no significant difference between the absolute rates of turnover (expressed in mg h −1 kg body wt. −1 ) in the patients and controls.