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Background: The mechanisms involved in the decline of high-density lipoprotein (HDL) levels at a higher dose of atorvastatin have not yet been elucidated. We investigated the effects of atorvastatin on HDL-apolipoprotein (apo) A-I metabolism in dogs, a species lacking cholesteryl ester transfer protein activity.

Materials and methods: Seven ovariectomized normolipidaemic female Beagle dogs underwent a primed constant infusion of [5,5,5-2H3] leucine to determine HDL-apo A-I kinetics before and after atorvastatin treatment (5 mg kg-1 d-1 for 6 weeks). Plasma lipoprotein profiles, activity of HDL-modifying enzymes involved in reverse cholesterol transport and hepatic scavenger receptor class B type I (SR-BI) expression were also studied.

Results: Atorvastatin treatment decreased HDL-cholesterol levels (3[middle dot]56 /- 0[middle dot]24 vs. 2[middle dot]64 /- 0[middle dot]15 mmol L-1, P < 0[middle dot]05). HDL-triglycerides were not affected. HDL-phospholipids levels were decreased (4[middle dot]28 /- 0[middle dot]13 vs. 3[middle dot]29 /- 0[middle dot]13 mmol L-1, P < 0[middle dot]05), as well as phospholipids transfer protein (PLTP) activity (0[middle dot]83 /- 0[middle dot]05 vs. 0[middle dot]60 /- 0[middle dot]05 pmol [mu]L-1 min-1, P < 0[middle dot]05). Activity of lecithin: cholesterol acyl transferase (LCAT), hepatic lipase (HL) and SR-BI expression did not change. HDL-apo A-I absolute production rate (APR) was higher after treatment (twofold, P < 0[middle dot]05) as well as fractional catabolic rate (FCR) (threefold, P < 0[middle dot]05). This resulted in lower HDL-apo A-I levels (2[middle dot]36 /- 0[middle dot]03 vs. 1[middle dot]55 /- 0[middle dot]04 g l-1, P < 0[middle dot]05). Plasma lipoprotein profiles showed a decrease in large HDL1 levels, with lower apo A-I and higher apo E levels in this subfraction.

Conclusions: Although a high dose of atorvastatin up-regulated HDL-apo A-I production, this drug also increased HDL-apo A-I FCR in dogs. This effect could be explained by a higher uptake of apo E-enriched HDL1 by hepatic lipoprotein receptors.

Copyright (C) 2006 Blackwell Publishing Ltd.