Differential regulation of the human versus the mouse apolipoprotein AV gene by PPARalpha. Implications for the study of pharmaceutical modifiers of hypertriglyceridemia in mice.
Mice have been used widely to define the mechanism of action of fibric acid derivatives. The fibrates are pharmacological agonists of the peroxisome proliferator-activated receptor alpha (PPARalpha), whose activation in human subjects promotes potent reduction in plasma levels of triglycerides (TG) with concomitant increase in those of HDL-cholesterol. The impact of PPARalpha agonists on gene expression in humans and rodents is however distinct; such distinctions include differential regulation of key genes of lipid metabolism. We evaluated the question as to whether the human and murine genes encoding apolipoprotein apoAV, a regulator of plasma concentrations of TG-rich lipoproteins, might be differentially regulated in response to fibrates. Fenofibrate, a classic PPARalpha agonist, repressed expression of mouse Apoa5 in vivo in a mouse model transgenic for the human APOA5 gene; by contrast, expression of the human ortholog was up-regulated. Our findings are consistent with the presence of a functional PPAR-binding element in the promoter of the human APOA5 gene; this element is however degenerate and non-functional in the corresponding mouse Apoa5 sequence, as demonstrated by reporter assays and gel shift analyses. These data further highlights the distinct mechanisms which are implicated in the metabolism of TG-rich lipoproteins in mice as compared to man. They equally emphasize the importance of the choice of a mouse model for investigation of the impact of pharmaceutical modifiers on hypertriglyceridemia.
INSERM UMR-S, Hôpital de la Pitié, Paris, France.
Xavier
X
Prieur
Philippe
P
Lesnik
Martine
M
Moreau
Joan C
JC
Rodríguez
Chantal
C
Doucet
M John
MJ
Chapman
Thierry
T
Huby
D000818:Animals; D000072040:Apolipoprotein A-V; D001053:Apolipoproteins / Q000235:genetics*; D001054:Apolipoproteins A / Q000235:genetics*; D001483:Base Sequence; D045744:Cell Line, Tumor; D002995:Clofibric Acid / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D015228:Hypertriglyceridemia / Q000188:drug therapy*; D008074:Lipoproteins / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D047493:PPAR alpha / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects
C437704:APOA5 protein, human; C499058:Apoa5 protein, mouse; D000072040:Apolipoprotein A-V; D001053:Apolipoproteins; D001054:Apolipoproteins A; D008074:Lipoproteins; D047493:PPAR alpha; D002995:Clofibric Acid