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Cholesterol homeostasis in mononuclear leukocytes from patients with familial hypercholesterolemia treated with
F C Hagemenas1, D R Illingworth
1Department of Medicine, Oregon Health Sciences University, Portland 97201.
Insights
Lovastatin treatment in patients with familial hypercholesterolemia reduced LDL cholesterol. This was accompanied by increased HMG CoA reductase activity and cholesterol synthesis, along with enhanced LDL degradation in mononuclear cells.
Area of Science:
- Biochemistry
- Pharmacology
- Genetics
Background:
- Familial hypercholesterolemia (FH) is a genetic disorder characterized by high LDL cholesterol levels.
- Statins, like lovastatin, are primary treatments for FH by inhibiting HMG CoA reductase.
- Understanding lovastatin's effects on cholesterol homeostasis in FH is crucial for optimizing treatment.
Purpose of the Study:
- To evaluate the dose-dependent effects of lovastatin on cholesterol homeostasis in patients with heterozygous FH.
- To assess the impact of lovastatin on HMG CoA reductase activity, cholesterol synthesis, and LDL degradation in mononuclear leukocytes.
Main Methods:
- 19 FH patients received sequentially increasing doses of lovastatin (10-80 mg/day).
- In vitro HMG CoA reductase activity and cholesterol synthesis from 2-14C-acetate were measured in mononuclear cells.
- 125I-LDL degradation was assessed at baseline and on 80 mg/day lovastatin.
Main Results:
- Lovastatin progressively reduced LDL cholesterol levels, with a 38% decrease at 80 mg/day (p < 0.005).
- HMG CoA reductase activity increased by 121% (p < 0.05), and cholesterol synthesis rose by 39% (p < 0.005).
- Total and high-affinity 125I-LDL degradation significantly increased in cells from patients on 80 mg/day lovastatin (p < 0.005).
Conclusions:
- Lovastatin effectively lowers LDL cholesterol in FH patients.
- The drug induces compensatory increases in HMG CoA reductase activity and cholesterol synthesis.
- Lovastatin enhances LDL uptake and degradation by mononuclear leukocytes, contributing to its cholesterol-lowering effect.
Abstract:
We evaluated the effects of different doses of lovastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase) and the rate-limiting enzyme in cholesterol biosynthesis, on parameters of cholesterol homeostasis in freshly isolated mononuclear leukocytes from 19 patients with heterozygous familial hypercholesterolemia. Patients were treated with sequentially increasing doses of lovastatin (10 to 80 mg/day in a twice-daily regimen). The in vitro activity of HMG CoA reductase and cholesterol synthesis from 2-14C-acetate was determined in mononuclear cells obtained under steady-state conditions after patients had spent 6 weeks on doses of 20, 40, or 80 mg/day. The total and high affinity degradation of 125I-low density lipoprotein (LDL) was determined at baseline and on lovastatin at a dose of 80 mg/day. LDL cholesterol levels fell progressively on lovastatin (38% reduction on 80 mg daily, p less than 0.005). These changes were paralleled by a 121% increase in the activity of HMG CoA reductase (p less than 0.05) and a 39% increase in cholesterol synthesis from 2-14C-acetate (p less than 0.005). Total and high affinity degradation of 125I-LDL increased from 27 +/- 3.3 and 12.1 +/- 1.6 ng/4 x 10(6) cells/4 hours on the diet only to 69.7 +/- 7.2 and 32.9 +/- 3.6 ng/4 x 10(6) cells/4 hours, respectively, (mean +/- SEM) in mononuclear cells isolated from patients on 80 mg of lovastatin daily (p less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)