Atorvastatin and fenofibrate increase apolipoprotein AV and decrease triglycerides by up-regulating peroxisome proliferator-activated receptor-alpha.
OBJECTIVE
Combining statin and fibrate in clinical practice provides a greater reduction of triglycerides than either drug given alone, but the mechanism for this effect is poorly understood. Apolipoprotein AV (apoAV) has been implicated in triglyceride metabolism. This study was designed to investigate the effect of the combination of statin and fibrate on apoAV and the underlying mechanism(s).


METHODS
Hypertriglyceridaemia was induced in rats by giving them 10% fructose in drinking water for 2 weeks. They were then treated with atorvastatin, fenofibrate or the two agents combined for 4 weeks, and plasma triglyceride and apoAV measured. We also tested the effects of these two agents on triglycerides and apoAV in HepG2 cells in culture. Western blot and reverse transcription polymerase chain reaction was used to measure apoAV and peroxisome proliferator-activated receptor-alpha (PPARalpha) expression.


RESULTS
The combination of atorvastatin and fenofibrate resulted in a greater decrease in plasma triglycerides and a greater increase in plasma and hepatic apoAV than either agent given alone. Hepatic expression of the PPARalpha was also more extensively up-regulated in rats treated with the combination. A similar, greater increase in apoAV and a greater decrease in triglycerides were observed following treatment of HepG2 cells pre-exposed to fructose), with the combination. Adding an inhibitor of PPARalpha (MK886) abolished the effects of atorvastatin on HepG2 cells.


CONCLUSIONS
A combination of atorvastatin and fenofibrate increased apoAV and decreased triglycerides through up-regulation of PPARalpha.
Huang
Xian-sheng
XS
Department of Cardiology, The Second Xiang Ya Hospital, Central South University, Changsha, Hunan, China.
Zhao
Shui-ping
SP
Bai
Lin
L
Hu
Min
M
Zhao
Wang
W
Zhang
Qian
Q
D000818:Animals; D000072040:Apolipoprotein A-V; D001053:Apolipoproteins / Q000097:blood / Q000378:metabolism*; D000069059:Atorvastatin; D045744:Cell Line, Tumor; D004357:Drug Synergism; D011345:Fenofibrate / Q000494:pharmacology*; D006538:Heptanoic Acids / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D015228:Hypertriglyceridemia / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D047493:PPAR alpha / Q000096:biosynthesis*; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014280:Triglycerides / Q000097:blood*; D015854:Up-Regulation
C514818:Apoa5 protein, rat; D000072040:Apolipoprotein A-V; D001053:Apolipoproteins; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents; D047493:PPAR alpha; D011758:Pyrroles; D014280:Triglycerides; D000069059:Atorvastatin; D011345:Fenofibrate
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