Cholesteryl ester hydrolase activity in mononuclear cells from patients with type II hypercholesterolemia.

Cholesteryl ester hydrolase (CEH) activity was measured in freshly isolated mononuclear cells from patients with primary Type II hypercholesterolemia, heterozygous familial hypercholesterolemia (FH) and familial combined hyperlipidemia (CFH). CEH activity was significantly lower in mononuclear cells from Type II patients than in cells from matched normolipidemic individuals. Moreover, the reduced CEH activity in cells from the hypercholesterolemic patients was accompanied by significant accumulation of cholesteryl ester. This pattern of reduced CEH activity and cholesteryl ester accumulation was identical for cells from both the FH and CFH patients. Since low density lipoprotein (LDL) cholesterol concentrations were higher in the Type II patients, we incubated mononuclear cells from normolipidemic individuals with high concentrations of LDL-cholesterol (greater than 150 mg/dl). Under these conditions CEH activity was significantly decreased, cholesteryl ester content increased, and cholesterol linoleate, in particular, accumulated. These data suggest that the intracellular accumulation of cholesteryl esters is determined in part by the extracellular concentrations of LDL-cholesterol and by the activity of CEH within the cells.

Effects of hypolipidemic therapy on cholesterol homeostasis in freshly isolated mononuclear cells from patients with heterozygous familial hypercholesterolemia.

Freshly isolated mononuclear leukocytes have been reported to show changes in cholesterol synthesis and high-affinity degradation of low-density lipoproteins (LDL) that parallel those that occur in the liver. To examine whether hypolipidemic therapy in patients with heterozygous familial hypercholesterolemia influences cholesterol homeostasis in their mononuclear cells we assessed the effects of colestipol and nicotinic acid (alone and in combination) on the rates of high-affinity 125I-labeled LDL degradation and on the rates of cholesterol and phosphatidylcholine biosynthesis by freshly isolated cells. Rates of 125I-labeled LDL degradation were lower in mononuclear cells from patients with heterozygous familial hypercholesterolemia on no medication (3.1 ng per 4 X 10(6) cells per 5 hr) than in cells from normal control subjects (6.1 ng per 4 X 10(6) cells per 5 hr) and, in the former patients, the values were not significantly affected by therapy with nicotinic acid. In contrast, freshly isolated mononuclear cells from patients receiving colestipol degraded 125I-labeled LDL at near-normal rates (5.0 ng per 4 X 10(6) cells per 5 hr). The rates of cholesterol synthesis were also higher in mononuclear cells isolated from patients treated with colestipol than in cells from untreated patients or from those receiving nicotinic acid; in contrast the rate of synthesis of phosphatidylcholine did not show any consistent changes. Similar results were obtained in a smaller number of patients studied longitudinally, in which colestipol therapy significantly increased rates of cholesterol synthesis and high-affinity degradation of 125I-labeled LDL by freshly isolated mononuclear cells. We conclude that previously observed changes in cholesterol homeostasis in the liver of patients treated with bile acid sequestrants are paralleled by similar changes in freshly isolated mononuclear cells and that these cells offer an accessible model for further studies on how diet and pharmacologic agents influence cellular cholesterol homeostasis in humans.