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Abnormal suppression of 3‐hydroxy‐3‐methylglutaryl‐CoA reductase activity in cultured human fibroblasts by hypertriglyceridemic very low density lipoprotein subclasses
Author(s) -
Gianturco Sandra H.,
Packard Christopher J.,
Shepherd James,
Smith Louis C.,
Catapano Alberico L.,
Sybers Harley D.,
Gotto Antonio M.
Publication year - 1980
Publication title -
lipids
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.601
H-Index - 120
eISSN - 1558-9307
pISSN - 0024-4201
DOI - 10.1007/bf02534072
Subject(s) - very low density lipoprotein , endocrinology , medicine , reductase , chemistry , lipoprotein , hmg coa reductase , hypertriglyceridemia , cholesterol , biochemistry , enzyme , biology , triglyceride
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‐VLDL 1 (S f 100–400), VLDL 2 (S f 60–100), and VLDL 3 (S f 20–60) were obtained from the d<1.006 (g°ml −1 ) fraction of normal and hypertriglyceridemic plasma by flotation through a discontinuous salt gradient and tested for suppression in normal human fibroblasts. VLDL 1 and VLDL 2 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 VLDL 3 suppressed HMG‐CoA reductase, but only one‐third as effectively as LDL. By contrast, the VLDL 1 , VLDL 2 and VLDL 3 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 VLDL 1 treated with 0.1 M 1,2‐cyclohexanedione to block arginyl residues failed to suppress the enzyme. Moreover, hypertriglyceridemic S f 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 VLDL 1 and VLDL 2 which contained few, if any, small particles were effective in suppression.