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Effects of atorvastatin on high-density lipoprotein apolipoprotein A-I metabolism in dogs

Authors


  • Centre de Recherche en Nutrition Humaine, INSERM U539, CHU Nantes (F. Briand, T. Magot, M. Krempf, K. Ouguerram); USC INRA de Nutrition et Endocrinologie, Ecole Nationale Vétérinaire de Nantes, Nantes (P. Nguyen), France.

Khadija Ouguerram, PhD, Centre de Recherche en Nutrition Humaine, INSERM U539, CHU Nantes, 1 Place Alexis Ricordeau, 44093 Nantes Cedex 01, France. Tel.: +33 240087535; fax: +33 240087544; e-mail: khadija.ouguerram@university-nantes.fr

Abstract

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 (3·56 ± 0·24 vs. 2·64 ± 0·15 mmol L−1, P < 0·05). HDL-triglycerides were not affected. HDL-phospholipids levels were decreased (4·28 ± 0·13 vs. 3·29 ± 0·13 mmol L−1, P < 0·05), as well as phospholipids transfer protein (PLTP) activity (0·83 ± 0·05 vs. 0·60 ± 0·05 pmol µL−1 min−1, P < 0·05). 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 < 0·05) as well as fractional catabolic rate (FCR) (threefold, P < 0·05). This resulted in lower HDL-apo A-I levels (2·36 ± 0·03 vs. 1·55 ± 0·04 g l−1, P < 0·05). 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.

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