Leptin regulation of the immune response and the immunodeficiency of malnutrition1

Abstract

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