title: Apolipoprotein A5, a crucial determinant of plasma triglyceride levels, is highly responsive to peroxisome proliferator-activated receptor alpha activators.
abstract: 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.
authors.affiliation: 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
authors.forename: Ngoc
authors.initials: N
authors.lastname: Vu-Dac
authors.forename: Philippe
authors.initials: P
authors.lastname: Gervois
authors.forename: Heidi
authors.initials: H
authors.lastname: Jakel
authors.forename: Maxime
authors.initials: M
authors.lastname: Nowak
authors.forename: Eric
authors.initials: E
authors.lastname: Bauge
authors.forename: Helene
authors.initials: H
authors.lastname: Dehondt
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
authors.forename: Len A
authors.initials: LA
authors.lastname: Pennacchio
authors.forename: Edward M
authors.initials: EM
authors.lastname: Rubin
authors.forename: Jamila
authors.initials: J
authors.lastname: Fruchart-Najib
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Fruchart
mesh_terms: 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
chemical_list: 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