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


METHODS
Seven ovariectomized normolipidaemic female Beagle dogs underwent a primed constant infusion of [5,5,5-(2)H(3)] 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 microL(-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 HDL(1) 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 HDL(1) by hepatic lipoprotein receptors.
Briand
F
F
Centre de Recherche en Nutrition Humaine, INSERM U539, CHU Nantes, France.
Magot
T
T
Krempf
M
M
Nguyen
P
P
Ouguerram
K
K
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D016632:Apolipoprotein A-I / Q000378:metabolism*; D000069059:Atorvastatin; D008076:Cholesterol, HDL / Q000032:analysis*; D002853:Chromatography, Liquid / Q000379:methods; D004285:Dogs / Q000378:metabolism*; D005260:Female; D006538:Heptanoic Acids / Q000494:pharmacology*; D015151:Immunoblotting / Q000379:methods; D008049:Lipase / Q000032:analysis; D008099:Liver / Q000737:chemistry; D010052:Ovariectomy; D049294:Phospholipid Transfer Proteins / Q000097:blood; D010743:Phospholipids / Q000097:blood; D011758:Pyrroles / Q000494:pharmacology*; D051122:Scavenger Receptors, Class B / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
D000924:Anticholesteremic Agents; D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D006538:Heptanoic Acids; D049294:Phospholipid Transfer Proteins; D010743:Phospholipids; D011758:Pyrroles; D051122:Scavenger Receptors, Class B; D014280:Triglycerides; D000069059:Atorvastatin; D008049:Lipase