title: Mouse γ-butyrobetaine dioxygenase is regulated by peroxisome proliferator-activated receptor α through a PPRE located in the proximal promoter.
abstract: Convincing evidence from studies with peroxisome proliferator-activated receptor (PPAR)α-deficient mice suggested that the carnitine biosynthetic enzyme γ-butyrobetaine dioxygenase (BBD) is regulated by PPARα. However, the identification of BBD as a direct PPARα target gene as well as its exact regulation remained to be demonstrated. In silico-analysis of the mouse BBD promoter revealed seven putative peroxisome proliferator response elements (PPRE) with high similarity to the consensus PPRE. Luciferase reporter gene assays using mutated and non-mutated serial 5'-truncation BBD promoter reporter constructs revealed that one PPRE located at -75 to -87 relative to the transcription start site in the proximal BBD promoter is probably functional. Using gel shift assays we observed in vitro-binding of PPARα/RXRα heterodimer to this PPRE confirming that it is functional. In conclusion, the present study clearly shows that mouse BBD is a direct PPARα target gene and that transcriptional up-regulation of mouse BBD by PPARα is likely mediated by binding of the PPARα/RXR heterodimer to one PPRE located in its proximal promoter region. The results confirm emerging evidence from recent studies that PPARα plays a key role in the regulation of carnitine homeostasis by controlling genes involved in both, carnitine synthesis and carnitine uptake.
authors.affiliation: Institute of Animal Nutrition and Nutritional Physiology, Justus-Liebig-Universität, Heinrich-Buff-Ring Giessen, Germany.
authors.forename: Gaiping
authors.initials: G
authors.lastname: Wen
authors.forename: Hagen
authors.initials: H
authors.lastname: Kühne
authors.forename: Christine
authors.initials: C
authors.lastname: Rauer
authors.forename: Robert
authors.initials: R
authors.lastname: Ringseis
authors.forename: Klaus
authors.initials: K
authors.lastname: Eder
mesh_terms: D000818:Animals; D002331:Carnitine / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D051379:Mice; D047493:PPAR alpha / Q000502:physiology*; D011401:Promoter Regions, Genetic; D055503:Protein Multimerization; D020218:Response Elements / Q000502:physiology*; D047490:Retinoid X Receptor alpha / Q000502:physiology; D050563:gamma-Butyrobetaine Dioxygenase / Q000235:genetics*
chemical_list: D047493:PPAR alpha; D047490:Retinoid X Receptor alpha; D050563:gamma-Butyrobetaine Dioxygenase; D002331:Carnitine