In vivo regulation of human mononuclear leukocyte 3-hydroxy-3-methylglutaryl coenzyme A reductase: Decreased enzyme catalytic efficiency in familial hypercholesterolemia

P. W. Stacpoole, D. M. Bridge, I. M. Alvarez, R. B. Goldberg, H. J. Harwood

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase) controls the rate of cholesterol biosynthesis and is itself modulated through feedback suppression by internalized low density lipoprotein (LDL) cholesterol. We measured HMG CoA reductase protein concentration and microsomal enzyme activity in freshly isolated mononuclear leukocytes from normal individuals and patients with heterozygous or homozygous familial hypercholesterolemia (FH). Reductase protein concentration was similar in normal and heterozygous subjects, but was over twofold elevated in patients with homozygous FH. Reductase protein concentration was inversely related to LDL receptor status. Total activity and catalytic efficiency of reductase, however, were decreased in heterozygous and homozygous FH patients. The decrease in catalytic efficiency was not due to enzyme phosphorylation or thiol-disulfide formation. Reduction of plasma cholesterol concentration over 2 h by plasmapheresis increased reductase activity, the degree of which was directly proportional to the LDL-receptor status of the subjects. Decreased HMG CoA reductase activity and catalytic efficiency in mononuclear leukocytes and perhaps other cells in FH may represent a fundamental abnormality in the regulation of this enzyme independent of that induced by the LDL-receptor defect and may provide new insight into the control of cholesterol metabolism in FH.

Original languageEnglish (US)
Pages (from-to)1401-1408
Number of pages8
JournalJournal of Clinical Investigation
Volume80
Issue number5
DOIs
StatePublished - 1987

ASJC Scopus subject areas

  • Medicine(all)

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