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

Abstract

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 "SI-labeled LDL degradation and on the rates of cholesterol and phosphatidylcholine biosynthesis by freshly isolated cells. Rates of '25I-labeled LDL degradation were lower in mononuclear cells from patients with heterozygous familial hypercholesterolemia on no medication (3.1 ng per 4 X 106 cells per 5 hr) than in cells from normal control subjects (6.1 ng per 4 X 106 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 "2I-labeled LDL at nearnormal rates (5.0 ng per 4 x 106 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 '25I-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.Optimal treatment of patients with heterozygous familial hypercholesterolemia (FH) necessitates the use of diet and hypolipidemic medication, among which the bile acid-binding resins (colestipol and cholestyramine) and nicotinic acid are the most efficacious (1,2). Recent studies have clarified the mechanisms by which colestipol and cholestyramine decrease plasma concentrations of low-density lipoproteins (LDL) in both experimental animals and in humans (3, 4). Both drugs bind bile acids in the intestinal lumen, thereby interrupting the enterohepatic circulation and stimulating an increase in the hepatic conversion of cholesterol to bile acids. This in turn depletes the hepatic pool of cholesterol and results in two compensatory changes; an increase in the de novo biosynthesis of cholesterol (5) has been shown in humans and an increase in the number of specific high-affimity LDL receptors on hepatocyte membranes has been shown in rabbits and dogs (4, 6). The latter change also promotes an...

Determinants of Variable Response to Statin Treatment in Patients With Refractory Familial Hypercholesterolemia

“…An increase in LDL degradation in vitro, indicative of increased expression of LDL receptors, has previously been documented in mononuclear leukocytes obtained from FH heterozygotes treated with a BAS. 35 The apparent lack of response of mononuclear leukocyte HMG CoA reductase mRNA to inhibition (statin) and stimulation (BAS) in the present study could be ascribed to various causes. One difference between the present study and that of Powell and Kroon 34 is that we used FH patients, whereas they studied non-FH individuals.…”

Pravastatin inhibits cellular cholesterol synthesis and increases low density lipoprotein receptor activity in macrophages: in vitro and in vivo studies.

“…Foam cells in atherosclerotic lesions contain large amounts of cholesterol esters and there is considerable evidence that a substantial number of these foam cells originate from monocyte-derived macrophages [8]. Previous studies have indicated that human monocyte derived macrophages (HMDM) demonstrate a pattern of cholesterol homeostasis similar to cholesterol metabolism in the liver [9,10].…”

Cholesterol homeostasis in mononuclear leukocytes from patients with familial hypercholesterolemia treated with lovastatin.

“…16 - 18 For example, the rates of cholesterol synthesis and high affinity receptor-mediated degradation of I 12S -LDL in freshly isolated mononuctear leukocytes from patients with heterozygous familial hypercholesterolemia (FH) were both increased during therapy with the bile acid sequestrant colestipol. 15 Similarty, dietary cholesterol has been shown to depress cholesterol synthesis or HMG CoA reductase activity in freshly isolated mononuclear leukocytes. 1718 Both of these effects parallel those that are known to occur in the liver.…”