title: Peroxisome proliferator-activated receptors (PPAR) and the mitochondrial aldehyde dehydrogenase (ALDH2) promoter in vitro and in vivo.
abstract: BACKGROUND
  The aldehyde dehydrogenase 2 (ALDH2) promoter contains a nuclear receptor response element (NRRE) that represents an overlapping direct repeat-1 (DR-1) and -5 (DR-5) element. Because DR-1 elements are preferred binding sites for peroxisome proliferator-activated receptors (PPARs), we tested the hypothesis that PPARs regulate ALDH2 expression.
  
  
  METHODS
  We examined the ability of PPAR isoforms to bind to the ALDH2 NRRE in electrophoretic mobility shift assays, their ability to activate the transcription of promoter-reporter constructs containing this NRRE, the effect of PPAR ligands on ALDH2 expression in liver, and the role of the PPARalpha on the expression of ALDH2 by using PPARalpha-null mice.
  
  
  RESULTS
  In vitro translated PPARs bound the ALDH NRRE with high affinity. Mutation of the NRRE indicated that binding was mediated by the DR-1 element. Cotransfection of PPAR expression plasmids showed that PPARalpha had no effect on expression of heterologous promoter constructs containing the NRRE. PPARgamma slightly induced expression, whereas PPARdelta repressed basal activity of the promoter and blocked induction by hepatocyte nuclear factor 4. Treatment of rats with the PPAR ligand clofibrate repressed expression of ALDH2 in rats fed either stock rodent chow or a low-protein diet. Consistent with the transfection data, expression of ALDH2 protein was not different in PPARalpha-null mice. Treatment of the mice with the PPARalpha agonist WY14643 slightly decreased the level of ALDH2 protein in both wild-type and PPARalpha-null mice, suggesting that the effect of WY14643 was not mediated by the receptor.
  
  
  CONCLUSIONS
  These data indicate that ALDH2 is not part of the battery of lipid metabolizing enzymes and proteins regulated by PPARalpha
authors.affiliation: Departments of Medicine and of Biochemistry and Molecular Biology, Indiana University School of Medicine and VA Medical Center, Indianapolis, USA. dcrabb@iupui.edu
authors.forename: D W
authors.initials: DW
authors.lastname: Crabb
authors.forename: J
authors.initials: J
authors.lastname: Pinaire
authors.forename: W Y
authors.initials: WY
authors.lastname: Chou
authors.forename: S
authors.initials: S
authors.lastname: Sissom
authors.forename: J M
authors.initials: JM
authors.lastname: Peters
authors.forename: R A
authors.initials: RA
authors.lastname: Harris
authors.forename: M
authors.initials: M
authors.lastname: Stewart
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D001483:Base Sequence; D015152:Blotting, Northern; D015153:Blotting, Western; D002994:Clofibrate / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology*; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D000924:Anticholesteremic Agents; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D004247:DNA; C096127:ALDH2 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D002994:Clofibrate