Regulation of low density lipoprotein apoprotein B metabolism by lovastatin and cholestyramine in miniature pigs: Effects on LDL composition and synthesis of LDL subfractions

Abstract

A major factor in the regulation of low density lipoprotein (LDL) apoprotein B (apo B) concentrations in miniature pigs is the direct synthesis of LDL apo B. LDL apo B derived from plasma very low density lipoproteins (VLDL) accounts for only 20% to 30% of total LDL synthesis. Treatment with lovastatin and cholestyramine can inhibit the direct synthesis pathway in this species, thereby lowering LDL apo B concentrations. The present study was carried out to determine if lovastatin alone was as effective as in combination with cholestyramine. The possibility that the direct synthesis pathway was confined to a specific subclass of LDL and the effect of lovastatin and cholestyramine on the metabolism of LDL subfractions were also investigated. Homologous 126I-VLDL and 131I-LDL were injected into miniature pigs during a control period and again following 18 days of treatment with lovastatin (1.2 mg/kg/d, n = 4) or in combination with cholestyramine (1.0 g/kg/d, n = 4). Kinetic analysis of apo B specific activity curves following lovastatin treatment indicated that LDL apo B pool size was decreased by 25% ( P < .025), which was due entirely to a 70% ( P < .025) decrease in the direct synthesis of LDL apo B, since VLDL-derived apo B, and LDL fractional catabolic rate (FCR) were not affected. Parameters of VLDL apo B metabolism were not affected. Lovastatin in combination with cholestyramine was more effective than lovastatin alone. LDL apo B pool size was reduced by 50% ( P < .05) due entirely to a 85% ( P < .025) reduction in the direct synthesis of LDL apo B. LDL apo B FCR was not affected. Combined treatment did not change VLDL apo B pool size, but increased the FCR by 74% ( P < .025) and increased total VLDL apo B flux by 50% ( P < .025), which was reflected primarily in an increased direct removal of VLDL. The direct synthesis of LDL apo B entered the circulation in the LDL 2 (density [d] 1.040 to 1.063 g/mL) fraction entirely, since LDL 1 (d 1.019 to 1.040 g/mL), which comprised approximately 10% of plasma LDL apo B, was completely derived from VLDL catabolism. Only the synthesis of LDL 2 was inhibited (by 60%) by treatment with both drugs. To determine if changes in lipid composition could explain the lack of effect of LDL apo B FCR, the lipid composition of LDL from animals treated with both drugs was analyzed by total lipid profiling. Small increases in the lipid surface to core ratio (0.8 ± 0.03 v 0.7 ± 0.02, P < .025) and decreases in the estimated particle diameter ( 184 ± 5 v 202 ± 6 A ̊ , P < .025 ) were observed. These results indicate that the direct synthesis of LDL 2 apo B can be regulated in this species and that a combination of lovastatin and cholestyramine is more effective than lovastatin alone. The regulation of the direct synthesis of LDL may have a greater effect on LDL concentrations than previously appreciated.