The peroxisome proliferator-activated receptor is a ligand-activated transcription factor that plays an important role in the regulation of lipid homeostasis. PPAR mediates the effects of fibrates, which are potent hypolipidemic drugs, on gene expression. To better understand the biological effects of fibrates and PPAR, we searched for genes regulated by PPAR using oligonucleotide microarray and subtractive hybridization. By comparing liver RNA from wild-type and PPAR null mice, it was found that PPAR decreases the mRNA expression of enzymes involved in the metabolism of amino acids. Further analysis by Northern blot revealed that PPAR influences the expression of several genes involved in trans- and deamination of amino acids, and urea synthesis. Direct activation of PPAR using the synthetic PPAR ligand WY14643 decreased mRNA levels of these genes, suggesting that PPAR is directly implicated in the regulation of their expression. Consistent with these data, plasma urea concentrations are modulated by PPAR in vivo. It is concluded that in addition to oxidation of fatty acids, PPAR also regulates metabolism of amino acids in liver, indicating that PPAR is a key controller of intermediary metabolism during fasting.—Kersten, S., Mandard, S., Escher, P., Gonzalez, F. J., Tafuri, S., Desvergne, B., Wahli, W. The peroxisome proliferator-activated receptor regulates amino acid metabolism.