title: Negative regulation of the human apolipoprotein A-I promoter by fibrates can be attenuated by the interaction of the peroxisome proliferator-activated receptor with its response element.
abstract: Fibrates have been reported to modulate plasma high density lipoprotein cholesterol and apolipoprotein (apo) A-I concentrations. Therefore, the molecular mechanisms underlying the regulation of human apoA-I gene expression by fibrates was investigated. Fenofibrate reduced the expression of a reporter gene driven by the DNA sequences between -192 and +91 (BC-P-chloramphenicol acetyltransferase; CAT) relative to the apoA-I gene transcription start site approximately 3-fold. The sequences involved in the down-regulation of apoA-I gene transcription by fenofibrate were localized between -41 and +91 (P-CAT) relative to the transcription start site. The reduction of the expression of BC-P-CAT was dose-dependent and maximal at 500 microM (20 +/- 7%). Different peroxisome proliferators showed different levels of repression varying from 39 +/- 4% for fenofibrate, 43 +/- 5% for tetradecylthioacetic acid, 48 +/- 4% for bezafibrate, 54 +/- 2% for 5,8,11,14-eicotetraynoic acid, 76 +/- 2% for ciprofibrate, whereas Wy 14643 only marginally inhibited the expression of BC-P-CAT. By contrast, inclusion of sequences between -256 and -192 (ABC-P-CAT) attenuated the repression by fenofibrate. Furthermore, the apoA-IA site (-214 to -192; Awt-P-CAT) could counteract the repression of P-CAT by fenofibrate in the presence of cotransfected mPPAR alpha (peroxisome proliferator-activated receptor). In addition, the acyl-CoA oxidase-peroxisome proliferator response element (PPRE) could substitute the wild-type A-site in blocking the fenofibrate-induced reduction of the apoA-I promoter by mPPAR alpha. The protective effect of PPAR on fenofibrate induced inhibition of apoA-I expression was abolished after mutation of the direct repeat in the A site (Am-P-CAT). Consistent with these functional data only the wild-type, but not the mutated A site bound PPAR/retinoic X receptor heterodimers in gel shift assays. These data suggest that certain peroxisome proliferators can reduce the expression of the apoA-I promoter in a PPAR-independent fashion, through modulation of factors interacting with sequences localized between -41 and +91 of the apoA-I gene transcription initiation site. This inhibitory effect can be overcome when PPAR interacts with a functional PPRE, such as the apoA-I A site or the acyl-CoA oxidase-PPRE.
authors.affiliation: U. 325 INSERM, Département d'Athérosclérose, Institut Pasteur, Lille, France.
authors.forename: N
authors.initials: N
authors.lastname: Vu-Dac
authors.forename: K
authors.initials: K
authors.lastname: Schoonjans
authors.forename: B
authors.initials: B
authors.lastname: Laine
authors.forename: J C
authors.initials: JC
authors.lastname: Fruchart
authors.forename: J
authors.initials: J
authors.lastname: Auwerx
authors.forename: B
authors.initials: B
authors.lastname: Staels
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites; D015536:Down-Regulation; D005227:Fatty Acids / Q000494:pharmacology; D011345:Fenofibrate / Q000494:pharmacology; D006801:Humans; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D011401:Promoter Regions, Genetic; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D016632:Apolipoprotein A-I; D005227:Fatty Acids; D009838:Oligodeoxyribonucleotides; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D011345:Fenofibrate