Regulation of genes encoding enzymes involved in carnitine biosynthesis by peroxisome proliferator-activated receptor of alpha (PPARalpha)
Final Report Abstract
Results from previous studies with rats, pigs and PPARα-knockout mice strongly supported the hypothesis that genes encoding enzymes involved in carnitine synthesis, namely TMLD, TMABA-DH and BBD, are directly regulated by PPARα. However, the existence of functional PPRE within their promoter regions, which has been accepted as the best criterion to classify a gene as a PPARα target gene, remained to be demonstrated. The aim of this project therefore was to explore the transcriptional regulation of mouse TMLD, TMABA-DH and BBD by PPARα. The investigations of the present project therefore should provide evidence for the first time whether genes encoding enzymes involved in carnitine synthesis are PPARα target genes or not. The results of the project show that both, the mouse BBD and the mouse TMABA-DH are direct PPARα target genes and that transcriptional up-regulation by PPARα is mediated by binding of the PPARα/RXRα heterodimer to a PPRE located in their proximal promoter region. In contrast, our results regarding the regulation of mouse TMLD by PPARα do not suggest that mouse TMLD is a direct PPARα target gene. Collectively, the results of this project together with the recent identification of the mouse OCTN2 gene as a PPARα target gene confirm emerging evidence from animal studies that PPARα plays a key role in the regulation of carnitine homeostasis by controlling genes involved in both, carnitine synthesis and carnitine uptake. From a practical point of view, this study indicates that fibrates, synthetic agonists of PPARα used in the therapy of hyperlipidemia, might stimulate the synthesis of carnitine.
Publications
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(2011) Mouse γ-butyrobetaine dioxygenase is regulated by peroxisome proliferator-activated receptor α through a PPRE located in the proximal promoter. Biochemical Pharmacology 82: 175-183
Wen G, Kühne H, Rauer C, Ringseis R, Eder K
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(2012) The mouse gene encoding the carnitine biosynthetic enzyme 4-N-trimethylaminobutyraldehyde dehydrogenase is regulated by peroxisome proliferator-activated receptor α. Biochimica et Biophysica Acta - Gene regulatory mechanisms 1819: 357-365
Wen G, Ringseis R, Rauer C, Eder K
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(2012): Gene der Carnitinbiosynthese werden durch den Fettsäure-sensitiven Transkriptionsfaktor PPARa reguliert. Proceedings of the German Nutrition Society 17: 37
Ringseis R, Rauer C, Kühne H, Wen G, Eder K
