Inhibition of hepatic HMG-CoA reductase by pravastatin results in an increased expression of hepatic LDL receptors, which explains the lowered plasma levels of LDL cholesterol.

We have recently demonstrated that cultured human alveolar macrophages efficiently convert cholesterol into excretable 27-oxygenated products. We show here that increasing the intracellular concentration of cholesterol by a factor of 10 leads to about a twofold increase in the excretion of 27-oxygenated products from cultured macrophages. Inhibition of the sterol 27-hydroxylase caused a significant intracellular accumulation of cholesterol. A direct comparison was made between flux of cholesterol and 27-oxygenated products from macrophages preloaded with [4-14C]cholesterol. Under the specific conditions employed with fetal calf serum in the culture medium, the flux of 27-oxygenated products was about 10% of that of cholesterol. Since the sterol 27-hydroxylase, which converts cholesterol to 27-oxygenated products, is present in many cell types, we suggest that 27-oxygenation is a general mechanism for removal of intracellular cholesterol. To evaluate this hypothesis, we measured the net uptake by the human liver of circulating 27-oxygenated products, which was found to be about 20 mg/24 h. This uptake corresponds to approximately 4% of the bile acid production, assuming quantitative conversion into bile acids. It is concluded that the 27-hydroxylase pathway is of significance for elimination of extrahepatic cholesterol.

Supersaturation of bile with cholesterol predisposes to the development of cholesterol gallstones. To identify the factors determining cholesterol saturation of bile, we analyzed the lipid composition of stimulated duodenal bile in 60 healthy subjects of various ages (31 men and 29 women) who were not obese and were free of gallstones. A positive correlation between age and cholesterol saturation of bile was found (P less than 0.001). To analyze the relation between age and cholesterol saturation, we studied the rates of hepatic secretion of biliary lipids and the kinetics of cholic acid and chenodeoxycholic acid in 22 and 18 of the subjects, respectively. Age was positively correlated with the cholesterol secretion rate (r = 0.48) and negatively correlated with bile acid synthesis (r = -0.60) and the size of the cholic acid pool (r = -0.54). We conclude that cholesterol saturation of bile increases with age as a consequence of enhanced hepatic secretion of cholesterol and decreased bile acid synthesis. These findings may explain why age is a risk factor for the development of cholesterol gallstones.

The plasma concentration of the atherogenic low density lipoproteins (LDL) increases with age. To clarify the mechanism of this change, we studied the kinetics of autologous '25I-LDL apolipoprotein B (apo B) in 41 normolipidemic, nonobese healthy males. For comparison, they were divided into three age groups: young, 21-39 yr (n = 18), middle-aged, 40-59 yr (n = 11), and old, 60-80 yr (n = 12). The levels of plasma LDL cholesterol and LDL apo B increased from respectively 3.4±0.1 (SEM) mmol/liter and 86±2 mg/dl in the young to 4.1±0.1 mmol/liter and 95±3 mg/dl in the old (P < 0.01), and this increase was linked to a progressively decreased (r = -0.38, P < 0.02) fractional catabolic rate of LDL apo B (0.348±0.010 pools per day in the young vs. 0.296±0.009 pools per day in the old, P < 0.01). The production rate of LDL apo B did not differ significantly between the groups. The reduced fractional catabolic rate of LDL apo B in the old was not associated with a decrease in binding affinity of the LDL particle to its receptor, as judged from its ability to compete for '"I-LDL fibroblast binding. When hepatic LDL receptor expression was stimulated by cholestyramine treatment in six old males, their LDL apo B fractional catabolic rate increased to the levels observed in the young subjects. We conclude that the increase in LDL which normally occurs with age is explained by a reduced capacity for its removal, and hypothesize that this is mediated via a reduced hepatic LDL receptor expression. (J. Clin. Invest. 1991. 87:591-596.).

Circulating levels of 7cz-hydroxy-4-cholesten-3-one have been compared with activities of the rate-limiting enzyme in bile acid synthesis. microsomal cholesterol 7l-hydroxylase, measured in liver biopsies obtained from patients undergoing surgery for gallstone disease. Some patients were treated with cholcstyraminc or bile acids prior to operation in order to alter the feed-back inhibition of the enzyme. The levels of the sterol were similar in untreated patients and in patients treated with ursodeoxycholic acid (median concentration 17 and 13 nglml. respectively), and so were the activities of the enzyme (median activity 7.0 and 5.5 pmol/min/mg protein, respectively). The sterol levels and enzyme activities were significantly increased in patients treated with cholestyramine (91 ng/ml and 45 pmol/min/mg protein) and decreased in patients treated with chenodeoxycholic acid (< 2.0 ng/ml and 0.7 pmol/min/mg protein). There was a strong positive correlation (r=0.90, P