Apolipoprotein A5, a crucial determinant of plasma triglyceride levels, is highly responsive to peroxisome proliferator-activated receptor alpha activators.
The recently discovered APOA5 gene has been shown in humans and mice to be important in determining plasma triglyceride levels, a major cardiovascular disease risk factor. apoAV represents the first described apolipoprotein where overexpression lowers triglyceride levels. Since fibrates represent a commonly used therapy for lowering plasma triglycerides in humans, we investigated their ability to modulate APOA5 gene expression and consequently influence plasma triglyceride levels. Human primary hepatocytes treated with Wy 14,643 or fenofibrate displayed a strong induction of APOA5 mRNA. Deletion and mutagenesis analyses of the proximal APOA5 promoter firmly demonstrate the presence of a functional peroxisome proliferator-activated receptor response element. These findings demonstrate that APOA5 is a highly responsive peroxisome proliferator-activated receptor alpha target gene and support its role as a major mediator for how fibrates reduce plasma triglycerides in humans.
Vu-Dac
Ngoc
N
Département d'Athérosclerose, U.545 INSERM, Institut Pasteur de Lille and Faculté de Pharmacie de Lille, 1 rue Calmette BP 245, 59019 Lille Cédex, France. Ngoc.vu-dac@pasteur-lille.fr
Gervois
Philippe
P
Jakel
Heidi
H
Nowak
Maxime
M
Bauge
Eric
E
Dehondt
Helene
H
Staels
Bart
B
Pennacchio
Len A
LA
Rubin
Edward M
EM
Fruchart-Najib
Jamila
J
Fruchart
Jean-Charles
JC
D000072040:Apolipoprotein A-V; D001053:Apolipoproteins; D001054:Apolipoproteins A / Q000378:metabolism* / Q000502:physiology*; D001483:Base Sequence; D002478:Cells, Cultured; D003001:Cloning, Molecular; D011345:Fenofibrate / Q000494:pharmacology; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology; D008156:Luciferases / Q000378:metabolism; D008969:Molecular Sequence Data; D020025:Peroxisome Proliferators / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011743:Pyrimidines / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry; D020218:Response Elements; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D014280:Triglycerides / Q000097:blood* / Q000378:metabolism
C437704:APOA5 protein, human; D000072040:Apolipoprotein A-V; D001053:Apolipoproteins; D001054:Apolipoproteins A; D000960:Hypolipidemic Agents; D020025:Peroxisome Proliferators; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; D014157:Transcription Factors; D014280:Triglycerides; C006253:pirinixic acid; D008156:Luciferases; D011345:Fenofibrate