Effects of different doses of atorvastatin on human apolipoprotein B-100, B-48, and A-I metabolism

Margaret R. Diffenderfer,Aaron Buchsbaum,Ernst J. Schaefer,Nirupa R. Matthan,P. Hugh R. Barrett,Bela F. Asztalos,Valeria Zago,Stefania Lamon-Fava,Gregory G. Dolnikowski,Katalin Horvath,Alice H. Lichtenstein

doi:10.1194/jlr.m700067-jlr200

Abstract

Nine hypercholesterolemic and hypertriglyceridemic subjects were enrolled in a randomized, placebo-controlled, double-blind, crossover study to test the effect of atorvastatin 20 mg/day and 80 mg/day on the kinetics of apolipoprotein B-100 (apoB-100) in triglyceride-rich lipoprotein (TRL), intermediate density lipoprotein (IDL), and LDL, of apoB-48 in TRL, and of apoA-I in HDL. Compared with placebo, atorvastatin 20 mg/day was associated with significant reductions in TRL, IDL, and LDL apoB-100 pool size as a result of significant increases in fractional catabolic rate (FCR) without changes in production rate (PR). Compared with the 20 mg/day dose, atorvastatin 80 mg/day caused a further significant reduction in the LDL apoB-100 pool size as a result of a further increase in FCR. ApoB-48 pool size was reduced significantly by both atorvastatin doses, and this reduction was associated with nonsignificant increases in FCR. The lathosterol-campesterol ratio was decreased by atorvastatin treatment, and changes in this ratio were inversely correlated with changes in TRL apoB-100 and apoB-48 PR. No significant effect on apoA-I kinetics was observed at either dose of atorvastatin. Our data indicate that atorvastatin reduces apoB-100- and apoB-48-containing lipoproteins by increasing their catabolism and has a dose-dependent effect on LDL apoB-100 kinetics. Atorvastatin-mediated changes in cholesterol homeostasis may contribute to apoB PR regulation.

Highlights

Nine hypercholesterolemic and hypertriglyceridemic subjects were enrolled in a randomized, placebocontrolled, double-blind, crossover study to test the effect of atorvastatin 20 mg/day and 80 mg/day on the kinetics of apolipoprotein B-100 in triglyceride-rich lipoprotein (TRL), intermediate density lipoprotein (IDL), and LDL, of apoB-48 in TRL, and of apoA-I in HDL
The objective of our study was to assess the effect of two different doses of atorvastatin on the kinetic parameters of apoB-100 in triglyceride-rich lipoprotein (TRL), intermediate density lipoprotein (IDL), and LDL, of apoB-48 in chylomicrons, and of apoA-I in HDL in the nonfasting state in healthy subjects with mixed hyperlipidemia
Significant reductions were observed for IDL apoB-100 (P, 0.01)

Summary

Introduction

Nine hypercholesterolemic and hypertriglyceridemic subjects were enrolled in a randomized, placebocontrolled, double-blind, crossover study to test the effect of atorvastatin 20 mg/day and 80 mg/day on the kinetics of apolipoprotein B-100 (apoB-100) in triglyceride-rich lipoprotein (TRL), intermediate density lipoprotein (IDL), and LDL, of apoB-48 in TRL, and of apoA-I in HDL. Compared with the 20 mg/day dose, atorvastatin 80 mg/day caused a further significant reduction in the LDL apoB-100 pool size as a result of a further increase in FCR. Atorvastatin, one of the most potent statins, has a dose-dependent effect on LDL-C, with the 80 mg/day dose decreasing plasma LDL-C by ?10–14% more than the 20 mg/day dose [7, 8] It is not known whether the further reduction in LDL-C levels achieved at higher doses of atorvastatin is mediated by the same mechanism that causes the reduction at lower doses. The objective of our study was to assess the effect of two different doses of atorvastatin on the kinetic parameters of apoB-100 in triglyceride-rich lipoprotein (TRL), intermediate density lipoprotein (IDL), and LDL, of apoB-48 in chylomicrons, and of apoA-I in HDL in the nonfasting state in healthy subjects with mixed hyperlipidemia. This article is available online at http://www.jlr.org

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