Recent studies demonstrated that inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase lower plasma triglyceride primarily by decreasing hepatic secretion of very low density lipoproteins (VLDL). A possible mechanism is that inhibition of cholesterol synthesis interferes with the assembly of VLDL particles. Since one molecule of apolipoprotein (apo) B is required for the proper assembly and secretion of each VLDL and secretion of apo B may be regulated by various lipid components of the lipoproteins, question arises whether HMG-CoA reductase inhibitors also decrease the secretion of apo B. To address this issue, we investigated the effect of lovastatin on the secretion rate of VLDL-apo B and on the composition of VLDL in the Zucker obese rat; a model for genetic hypertriglyceridemia. Lovastatin treatment (4 mg/kg day × 13 days), as compared with placebo, decreased the concentrations of fasting plasma triglyceride (1740 ± 170 vs. 3130 ± 790 μg/ml) and VLDL-triglyceride (1379 ± 59 vs. 3082 ± 715 μg/ml). There was a small but non-significant decrease in VLDL-apo B (19 ± 2 μg/ml vs. 26 ± 7 μg/ml). Thus, lovastatin significantly decreased the ratio of triglyceride to apo B in VLDL (76 in lovastatin vs. 124 in placebo group). Secretion rates of VLDL-lipids and VLDL-apo B were measured after intravenous injection of Triton WR-1339. Lovastatin, as compared with placebo, decreased the secretion rates of plasma triglyceride (78 vs. 123 μg/ml per min) and VLDL-triglyceride (102 vs. 167 μg/ml per min) significantly, but not of VLDL-phospholipid (11 vs. 14 μg/ml per min), VLDL-free cholesterol (5.3 vs. 6.6 μg/ml per min) or VLDL-apo B (1.1 vs. 1.0 μg/ml per min). Consequently, newly-secreted VLDL particles had a significantly smaller ratio of triglyceride to apo B (91 vs. 184) and smaller estimated particle sizes (46 + 2.4 nm vs. 58 + 2.6 nm in diameter). In summary, the present study demonstrated that, in the hypertriglyceridemic state, lovastatin interfered with the secretion of VLDL-triglyceride but not of VLDL-apo B, resulting in the production of smaller, triglyceride-depleted VLDL particles.
- HMG-CoA reductase inhibitors
- VLDL-apo B
- Zucker fa/fa rat
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine