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

Background: The aldehyde dehydrogenase 2 (ALDH2) promoter contains a nuclea r receptor response element (NRRE) that represents an overlapping direct re peat-1 (DR-1) and -5 (DR-S) element. Because DR-1 elements are preferred bi nding sites for peroxisome proliferator-activated receptors (PPARs), we tes ted 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 tr anscription of promoter-reporter constructs containing this NRRE, the effec t of PPAR ligands on ALDH2 expression in liver, and the role of the PPAR al pha on the expression of ALDH2 by using PPAR alpha -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 elemen t. Cotransfection of PPAR expression plasmids showed that PPAR alpha had no effect on expression of heterologous promoter constructs containing the NR RE. PPAR gamma slightly induced expression, whereas PPAR delta repressed ba sal activity of the promoter and blocked induction by hepatocyte nuclear fa ctor 4. Treatment of rats with the PPAR ligand clofibrate repressed express ion of ALDH2 in rats fed either stock rodent chow or a low-protein diet. Co nsistent with the transfection data, expression of ALDH2 protein was not di fferent in PPAR alpha -null mice. Treatment of the mice with the PPAR alpha agonist WY14643 slightly decreased the level of ALDH2 protein in both wild -type and PPAR alpha -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 l ipid metabolizing enzymes and proteins regulated by PPAR alpha.