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

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

Lipid Metabolism Laboratory, Jean Mayer USDA HNRCA, Boston, MA 02111

Corresponding Author: stefania.lamon-fava{at}tufts.edu

This study was designed to determine the contribution of changes in apolipoprotein (apo) B and A-I kinetics to the dose-dependent effects of atorvastatin on LDL and HDL cholesterol levels. 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 apoB-100 in triglyceride-rich lipoproteins (TRL), IDL and LDL, of apoB-48 in TRL, and of apoA-I in HDL. Compared with placebo, treatment with 20 mg/day atorvastatin was associated with significant reductions in the TRL, IDL, and LDL apoB-100 pool size (-22%, -35%, and -41%, respectively, all P<0.02), due to significant increases in fractional catabolic rates (FCR) (47%, 72%, and 81%, respectively, all P<0.03) without changes in production rates (PR). Compared with the 20 mg/day dose, atorvastatin 80 mg/day caused a further reduction in the LDL apoB-100 pool size (-12%, P<0.05) due to a further increase in FCR (27%, P<0.05). ApoB-48 pool size was significantly reduced by both atorvastatin doses (-24% and -31%, respectively, P<0.05), and this reduction was associated with increases in FCR (+11% and +34%, respectively, P<0.13). The lathosterol/campesterol ratio, an indicator of cholesterol synthesis/absorption, was lowered by atorvastatin treatment and this change was inversely associated with the 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 moderate and high doses of atorvastatin reduce apoB-100- and apoB-48-containing lipoproteins by increasing their catabolism, and that the atorvastatin-mediated changes in cholesterol homeostasis may contribute to apoB PR regulation.

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