The effects of simvastatin on plasma lipoproteins and cholesterol homeostasis in patients with heterozygous familial hypercholesterolaemia

F. C. Hagemenas, Anuradha Pappu, D. R. Illingworth

Research output: Contribution to journalArticle

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Abstract

We have examined the influence of simvastatin, a competitive inhibitor of 3-hydroxy-3-methyl glutaryl coenzyme A reductase on plasma concentrations of lipids and lipoproteins, the rates of cholesterol biosynthesis and degradation of 125I-labelled LDL by freshly isolated mononuclear leucocytes and the 24h urinary excretion of mevalonic acid in patients with heterozygous familial hypercholesterolaemia. Patients were treated with progressively increasing doses of simvastatin (20, 40, and 80 mg day-1) taken in a twice-daily dosage for a period of 6 weeks on each dose. Plasma concentrations of LDL cholesterol decreased by 36.6%, 45.6% and 47.1% respectively on the three doses. High-affinity degradation of 125I-LDL by freshly isolated mononuclear leucocytes increased significantly on the 20 mg day-1 dosage but no further increase was observed on doses of 40 and 80 mg of simvastatin per day. Rates of 2-14C acetate incorporation into cholesterol by freshly isolated mononuclear leucocytes (obtained 12-15h after the last dose of simvastatin) increased by 62%, 71% and 29% in cells isolated from patients on 20, 40, and 80 mg day-1 of simvastatin compared with value at baseline. In contrast, the 24h excretion of mevalonic acid in the urine fell by 16.9%, 31.4% and 31.9% respectively on these three doses. Our results indicate that the potent hypocholesterolaemic effects of simvastatin are accompanied by increase in high-affinity LDL receptor-mediated degradation of LDL and a compensatory increase in cholesterol biosynthesis in freshly isolated mononuclear leucocytes but that rates of mevalonic acid excretion in the urine decrease.

Original languageEnglish (US)
Pages (from-to)150-157
Number of pages8
JournalEuropean Journal of Clinical Investigation
Volume20
Issue number2
StatePublished - 1990

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Hyperlipoproteinemia Type II
Simvastatin
Mononuclear Leukocytes
Homeostasis
Plasmas
Mevalonic Acid
Biosynthesis
Degradation
Cholesterol
Urine
LDL Receptors
LDL Cholesterol
lipoprotein cholesterol
Oxidoreductases
Acetates
Lipids
oxidized low density lipoprotein

Keywords

  • cholesterol biosynthesis
  • familial hypercholesterolaemia
  • hypolipidaemic agents
  • low density lipoprotein
  • mevalonic acid
  • mononuclear leucocytes
  • simvastatin

ASJC Scopus subject areas

  • Medicine(all)

Cite this

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title = "The effects of simvastatin on plasma lipoproteins and cholesterol homeostasis in patients with heterozygous familial hypercholesterolaemia",
abstract = "We have examined the influence of simvastatin, a competitive inhibitor of 3-hydroxy-3-methyl glutaryl coenzyme A reductase on plasma concentrations of lipids and lipoproteins, the rates of cholesterol biosynthesis and degradation of 125I-labelled LDL by freshly isolated mononuclear leucocytes and the 24h urinary excretion of mevalonic acid in patients with heterozygous familial hypercholesterolaemia. Patients were treated with progressively increasing doses of simvastatin (20, 40, and 80 mg day-1) taken in a twice-daily dosage for a period of 6 weeks on each dose. Plasma concentrations of LDL cholesterol decreased by 36.6{\%}, 45.6{\%} and 47.1{\%} respectively on the three doses. High-affinity degradation of 125I-LDL by freshly isolated mononuclear leucocytes increased significantly on the 20 mg day-1 dosage but no further increase was observed on doses of 40 and 80 mg of simvastatin per day. Rates of 2-14C acetate incorporation into cholesterol by freshly isolated mononuclear leucocytes (obtained 12-15h after the last dose of simvastatin) increased by 62{\%}, 71{\%} and 29{\%} in cells isolated from patients on 20, 40, and 80 mg day-1 of simvastatin compared with value at baseline. In contrast, the 24h excretion of mevalonic acid in the urine fell by 16.9{\%}, 31.4{\%} and 31.9{\%} respectively on these three doses. Our results indicate that the potent hypocholesterolaemic effects of simvastatin are accompanied by increase in high-affinity LDL receptor-mediated degradation of LDL and a compensatory increase in cholesterol biosynthesis in freshly isolated mononuclear leucocytes but that rates of mevalonic acid excretion in the urine decrease.",
keywords = "cholesterol biosynthesis, familial hypercholesterolaemia, hypolipidaemic agents, low density lipoprotein, mevalonic acid, mononuclear leucocytes, simvastatin",
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AU - Pappu, Anuradha

AU - Illingworth, D. R.

PY - 1990

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N2 - We have examined the influence of simvastatin, a competitive inhibitor of 3-hydroxy-3-methyl glutaryl coenzyme A reductase on plasma concentrations of lipids and lipoproteins, the rates of cholesterol biosynthesis and degradation of 125I-labelled LDL by freshly isolated mononuclear leucocytes and the 24h urinary excretion of mevalonic acid in patients with heterozygous familial hypercholesterolaemia. Patients were treated with progressively increasing doses of simvastatin (20, 40, and 80 mg day-1) taken in a twice-daily dosage for a period of 6 weeks on each dose. Plasma concentrations of LDL cholesterol decreased by 36.6%, 45.6% and 47.1% respectively on the three doses. High-affinity degradation of 125I-LDL by freshly isolated mononuclear leucocytes increased significantly on the 20 mg day-1 dosage but no further increase was observed on doses of 40 and 80 mg of simvastatin per day. Rates of 2-14C acetate incorporation into cholesterol by freshly isolated mononuclear leucocytes (obtained 12-15h after the last dose of simvastatin) increased by 62%, 71% and 29% in cells isolated from patients on 20, 40, and 80 mg day-1 of simvastatin compared with value at baseline. In contrast, the 24h excretion of mevalonic acid in the urine fell by 16.9%, 31.4% and 31.9% respectively on these three doses. Our results indicate that the potent hypocholesterolaemic effects of simvastatin are accompanied by increase in high-affinity LDL receptor-mediated degradation of LDL and a compensatory increase in cholesterol biosynthesis in freshly isolated mononuclear leucocytes but that rates of mevalonic acid excretion in the urine decrease.

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