| First Author | Wen G | Year | 2012 |
| Journal | Biochim Biophys Acta | Volume | 1819 |
| Issue | 5 | Pages | 357-65 |
| PubMed ID | 22285688 | Mgi Jnum | J:185081 |
| Mgi Id | MGI:5427316 | Doi | 10.1016/j.bbagrm.2012.01.004 |
| Citation | Wen G, et al. (2012) The mouse gene encoding the carnitine biosynthetic enzyme 4-N-trimethylaminobutyraldehyde dehydrogenase is regulated by peroxisome proliferator-activated receptor alpha. Biochim Biophys Acta 1819(5):357-65 |
| abstractText | Genes involved in carnitine uptake and synthesis, such as organic cation transporter-2 (OCTN2) and gamma-butyrobetaine dioxygenase (BBD), have been shown to be regulated by peroxisome proliferator-activated receptor (PPAR)alpha 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 PPARalpha 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 PPARalpha to this PPRE. Moreover, using chromatin immunoprecipitation assays we found that PPARalpha 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 PPARalpha target gene. Together with the recent identification of the mouse BBD and the mouse OCTN2 genes as PPARalpha target genes this finding confirm that PPARalpha plays a key role in the regulation of carnitine homeostasis by controlling genes involved in carnitine synthesis and carnitine uptake. |
