Peroxisome proliferator-activated receptors (PPAR) and the mitochondrial aldehyde dehydrogenase (ALDH2) promoter in vitro and in vivo

David W. Crabb, Jane Pinaire, Wan Yin Chou, Sean Sissom, Jeffrey M. Peters, Robert A. Harris, Mark Stewart

Research output: Contribution to journalArticle

19 Scopus citations

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 PPARα on the expression of ALDH2 by using PPARα-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 PPARα had no effect on expression of heterologous promoter constructs containing the NRRE. PPARγ slightly induced expression, whereas PPARδ 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 PPARα-null mice. Treatment of the mice with the PPARα agonist WY14643 slightly decreased the level of ALDH2 protein in both wild-type and PPARα-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 PPARα.

Original languageEnglish (US)
Pages (from-to)945-952
Number of pages8
JournalAlcoholism: Clinical and Experimental Research
Volume25
Issue number7
DOIs
StatePublished - 2001

All Science Journal Classification (ASJC) codes

  • Medicine (miscellaneous)
  • Toxicology
  • Psychiatry and Mental health

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