Abnormal suppression of 3-hydroxy-3-methylglutaryl-CoA reductase activity in cultured human fibroblasts by hypertriglyceridemic very low density lipoprotein subclasses

Sandra H. Gianturco, Christopher J. Packard, James Shepherd, Louis C. Smith, Alberico L. Catapano, Harley D. Sybers, Antonio M. Gotto

Research output: Contribution to journalArticle

Abstract

Our previous studies showed that hypertriglyceridemic very low density lipoproteins (HTG VLDL) are functionally abnormal. HTG VLDL, but not normal VLDL, suppress HMG-CoA reductase in cultured normal human fibroblasts. To determine if the suppression by HTG VLDL resulted from a subpopulation of smaller suppressive particles, more homogeneous subclasses of VLDL-VLDL1 (Sf 100-400), VLDL2 (Sf 60-100), and VLDL3 (Sf 20-60) were obtained from the d-1) fraction of normal and hypertriglyceridemic plasma by flotation through a discontinuous salt gradient and tested for suppression in normal human fibroblasts. VLDL1 and VLDL2 from each of the 12 normolipemic subjects tested failed to suppress HMG-CoA reductase activity in normal fibroblasts. Eleven out of 12 preparations of normal VLDL3 suppressed HMG-CoA reductase, but only one-third as effectively as LDL. By contrast, the VLDL1, VLDL2 and VLDL3 from 15 out of 17 hypertriglyceridemic patients (hyperlipoproteinemia Types IIb, III, IV and V) were highly effective in suppression, with half-maximal suppression at 0.1-2.0 μg VLDL protein/ml. The VLDL abnormality is apparently associated with hypertriglyceridemia and not hypercholesterolemia, since VLDL from a homozygous familial hypercholesterolemia patient with a Type IIa pattern did not suppress whereas each of the VLDL subclasses from a Type IIb patient suppressed. Suppression by HTG VLDL in normal cells is apparently a consequence of interaction of the protein portion of the VLDL with the specific LDL cell surface receptor since HTG VLDL1 treated with 0.1 M 1,2-cyclohexanedione to block arginyl residues failed to suppress the enzyme. Moreover, hypertriglyceridemic Sf 60-400 VLDL failed to suppress HMG-CoA reductase activity in LDL receptor-negative fibroblasts. There were no consistent major compositional differences between comparable normal and hypertriglyceridemic VLDL subclasses which could account for differences in suppression. All VLDL subclasses from Type III subjects were enriched in cholesteryl esters and depleted in triglyceride, relative to the corresponding normal VLDL subclasses. However, Type IV and Type V VLDL subclasses were normal in this repect. We conclude from these studies that small particle diameter is not required for suppression, since HTG VLDL1 and VLDL2 which contained few, if any, small particles were effective in suppression.

Original languageEnglish
Pages (from-to)456-463
Number of pages8
JournalLipids
Volume15
Issue number6
DOIs
Publication statusPublished - Jun 1980

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Biochemistry
  • Biochemistry, Genetics and Molecular Biology(all)
  • Food Science

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