Stimulation and suppression of 3-hydroxy-3-methylglutaryl coenzyme a reductase in normal human fibroblasts by high density lipoprotein subclasses

Olfgang H. Daerr, Sandra H. Gianturco, Joseph R. Patsch, Louis C. Smith, Antonio M. Gotto

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

Plasma concentrations of high density lipoproteins3 (HDL3), a subclass of HDL, are relatively constant, while those of HDL2 are variable. We report that HDL2 suppress, while HDL3 stimulate 3-hydroxy-3-methylglutaryl-CoA reductase (EC 1.1.1.34) activity in normal human fibroblasts. HDL3, which contained no detectable HDL2 or low density lipoproteins, stimulated 3-hydroxy-3-methylglutaryl-CoA reductase activity 2-fold from 60 to 120 pmol/mg per min. The induction, which exhibited saturation kinetics with maximum stimulation at 150 μg HDL phospholipid/ml medium, occurred only in the late-log and stationary phase of cell growth and was abolished by 0.1 mM actinomycin D or cycloheximide. Apolipoprotein HDL3 did not stimulate enzyme activity, whereas the total lipid extract of HDL3 was about 1.7 times more potent than were the native HDL3 in stimulating enzyme activity. HDL2 consistently suppressed 3-hydroxy-3-methylglutaryl-CoA reductase in normal fibroblasts by 20-50% at 80μg HDL2 protein/ml. Mixtures of HDL3 and HDL3 suppressed when HDL2 were greater than 35% of the total HDL. The suppressive effects of HDL2 were abolished by treatment with 0.1 M cyclohexanedione and restored by regeneration of arginyl residues, suggesting an apolipoprotein-mediated suppressive mechanism. The total lipid extract of HDL2 stimulated 3-hydroxy-3-methylglutaryl-CoA reductase 2-fold at 3 μg lipid phosphorus/ml. Moreover, HDL2 and HDL3 both stimulated 3-hydroxy-3-methylglutaryl-CoA reductase activity in receptor-negative fibroblasts. HDL2 have both the ability to suppress 3-hydroxy-3-methyl-CoA reductase activity in cells which possess low density lipoproteins receptors and to activate the enzyme in receptor-negative cells. These results show that variations in culture conditions and differences in the proportions of DHL subclasses must be considered in the interpretation of studies investigating cellular responses to HDL.

Original languageEnglish (US)
Pages (from-to)287-301
Number of pages15
JournalBiochimica et Biophysica Acta - Lipids and Lipid Metabolism
Volume619
Issue number2
DOIs
StatePublished - 1980

Keywords

  • 3-Hydroxy-3-methylglutaryl-CoA reductase
  • Apolipoprotein
  • Cholesterol biosynthesis
  • HDL
  • HDL
  • HDL
  • HDL
  • HDL
  • HDL
  • Human fibroblasts
  • LDL
  • SDS
  • an apolipoprotein constituent of HDL and HDL
  • apolipoprotein B
  • apolipoprotein E
  • apolipoprotein E-containing lipoproteins induced by cholesterol feeding of dogs and swine
  • high density lipoproteins (d = 1.063–1.125 g/ml)
  • high density lipoproteins (d = 1.063–1.21 g/ml)
  • high density lipoproteins (d = 1.125–1.21 g/ml)
  • low density lipoproteins (d = 1.006–1.063 g/ml)
  • principal apolipoprotein constituent of LDL
  • sodium dodecyl sulfate

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Endocrinology

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