Cholesterol homeostasis in mononuclear leukocytes from patients with familial hypercholesterolemia treated with lovastatin.
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)
Hagemenas
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FC
Department of Medicine, Oregon Health Sciences University, Portland 97201.
Illingworth
D R
DR
D002784:Cholesterol / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D006579:Heterozygote; D006706:Homeostasis; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000201:enzymology / Q000378:metabolism*; D008148:Lovastatin / Q000627:therapeutic use*; D014280:Triglycerides / Q000097:blood
D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D014280:Triglycerides; D002784:Cholesterol; D008148:Lovastatin; D006903:Hydroxymethylglutaryl CoA Reductases