Suppression of 3 hydroxy 3 methylglutaryl coenzyme A reductase activity and inhibition of growth of human fibroblasts by 7 ketocholesterol

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Abstract

Of 47 steroid compounds tested for their ability to suppress 3 hydroxy 3 methylglutaryl coenzyme A reductase activity in cultured human fibroblasts, 11 were more potent than cholesterol. The only consistent structural requirement for suppression of enzyme activity was the presence of an unesterified oxygen function at position 3 of the sterol nucleus. The presence of a ketone or hydroxyl group at positions 6, 7 or 25 markedly enhanced inhibitory activity. In fibroblasts from a homozygote with familial hypercholesterolemia, which are genetically resistant to physiological enzyme suppression by cholesterol contained in low density lipoproteins, 3hydroxy 3methylglutaryl coenzyme A reductase activity was suppressed by nonlipoprotein steroids to the same degree as in normal cells. 7 Ketocholesterol, which was 100 times more potent than cholesterol on a weight basis, suppressed enzyme activity in normal cells by more than 90% in 2 hr. This inhibition was reflected in a similarly marked decrease in the rate of incorporation of acetate, but not mevalonate into digitonin precipitable sterols. When normal cells were cultured in the presence of 7ketocholesterol but in the absence of lipoproteins, the suppression of endogenous cholesterol synthesis by 7ketocholesterol resulted in a marked inhibition of cell growth. This inhibition of growth was prevented by the presence in the culture medium of either cholesterol or mevalonate, but not acetate. Thus, the activity of 3hydroxy 3methylglutaryl coenzyme A reducatase became the rate limiting factor both for cholesterogenesis and for growth of fibroblasts under conditions where exogenous cholesterol was not available to the cells. It is concluded that 7ketocholesterol may provide a powerful tool for delineation of the mechanism by which cholesterol and other steroids promote the growth of human cells in culture. (18 references.)

Original languageEnglish (US)
Pages (from-to)7306-7314
Number of pages9
JournalJournal of Biological Chemistry
Volume249
Issue number22
StatePublished - Dec 1 1974

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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