title: The mouse gene encoding the carnitine biosynthetic enzyme 4-N-trimethylaminobutyraldehyde dehydrogenase is regulated by peroxisome proliferator-activated receptor α.
abstract: Genes involved in carnitine uptake and synthesis, such as organic cation transporter-2 (OCTN2) and γ-butyrobetaine dioxygenase (BBD), have been shown to be regulated by peroxisome proliferator-activated receptor (PPAR)α directly. Whether other genes encoding enzymes involved in the carnitine synthesis pathway, such as 4-N-trimethylaminobutyraldehyde dehydrogenase (TMABA-DH) and trimethyllysine dioxygenase (TMLD), are also direct PPARα target genes is less clear. In silico-analysis of the mouse TMLD promoter and first intron and the TMABA-DH promoter revealed several putative peroxisome proliferator response elements (PPRE) with high similarity to the consensus PPRE. Luciferase reporter gene assays using either a 2kb TMLD promoter or a 4kb TMLD first intron reporter constructs revealed no functional PPRE. In contrast, reporter gene assays using wild-type and mutated 5´-truncation TMABA-DH promoter reporter constructs showed that one PPRE located at position -132 in the proximal promoter is probably functional. Using gel shift assays we observed in vitro-binding of PPARα to this PPRE. Moreover, using chromatin immunoprecipitation assays we found that PPARα also binds in vivo to a nucleotide sequence spanning the PPRE at -132, which confirms that this PPRE is functional. In conclusion, the present study shows that the mouse TMABA-DH gene is a direct PPARα target gene. Together with the recent identification of the mouse BBD and the mouse OCTN2 genes as PPARα target genes this finding confirm that PPARα plays a key role in the regulation of carnitine homeostasis by controlling genes involved in carnitine synthesis and carnitine uptake.
authors.affiliation: Justus-Liebig-Universitat, Giessen, Germany.
authors.forename: Gaiping
authors.initials: G
authors.lastname: Wen
authors.forename: Robert
authors.initials: R
authors.lastname: Ringseis
authors.forename: Christine
authors.initials: C
authors.lastname: Rauer
authors.forename: Klaus
authors.initials: K
authors.lastname: Eder
mesh_terms: D000445:Aldehyde Oxidoreductases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002331:Carnitine / Q000096:biosynthesis / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D051379:Mice; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism; D059372:Nucleotide Motifs / Q000235:genetics; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D020218:Response Elements / Q000235:genetics
chemical_list: D047493:PPAR alpha; D006899:Mixed Function Oxygenases; C436318:epsilon-N-trimethyllysine hydroxylase; C023095:4-N-trimethylaminobutyraldehyde dehydrogenase; D000445:Aldehyde Oxidoreductases; D002331:Carnitine