Regulation of genes encoding enzymes involved in carnitine biosynthesis by peroxisome proliferator-activated receptor of alpha (PPARalpha)

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Recent studies strongly support the hypothesis that genes encoding enzymes involved incarnitine synthesis are directly regulated by peroxisome proliferator-activated receptor α(PPARα). PPARα is a ligand-activated transcription factor that acts as an important regulatorof lipid metabolism and energy homeostasis in mammals. Transcriptional regulation of genesby PPARα is mediated by binding of activated PPAR/retinoid X receptor heterodimers tospecific DNA sequences, called peroxisome proliferator response elements (PPRE) presentin and around the promoter of target genes. The presence of a functional PPRE within apromoter region has been accepted as the best criterion to classify a gene as a PPARαtarget gene. So far, functional PPRE have not yet been described for the promoters of genesencoding enzymes involved in carnitine biosynthesis such as trimethyllysine dioxygenase(TMLD), trimethylaminoaldehyde dehydrogenase (TMABA-DH) and γ-butyrobetainedioxygenase (γ-BBD). Therefore, the aim of this project is to explore the transcriptionalregulation of TMLD, TMABA-DH and BBD by PPARα. For this purpose, reporter gene assayswith wild-type and mutant TMLD, TMABA-DH and BBD promoter reporter truncationconstructs, electrophoretic mobility shift assays, and chromatin immuno-precipitation assayswill be performed. The investigations of the present project are original and will provide directproof whether genes encoding enzymes involved in carnitine synthesis are PPARα targetgenes with functional PPRE or not. Because PPARα has been mostly considered as a keyregulator of fatty acid catabolism and glucose homeostasis, the results of this project willshow whether PPARα also functions directly as an essential regulator of carnitine synthesis.