PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-ALPHA REQUIRED FOR GENE INDUCTION BY DEHYDROEPIANDROSTERONE-3-BETA-SULFATE

Peroxisome proliferator-activated receptor alpha (PPAR alpha) mediates the effects of foreign chemical peroxisome proliferators on liver and kidney, including the induction of peroxisomal, mitochondrial, and mi crosomal enzymes involved in beta-oxidation of fatty acids. However, t he role of this receptor in the peroxisome proliferative effects of th e endogenous steroid dehydroepiandrosterone (DHEA) is not known. DHEA- 3 beta-sulfate (DHEA-S) is shown to induce a liver peroxisome prolifer ative response in rats in vivo at a dose at which DHEA is much less ac tive, which is consistent with cultured hepatocyte studies indicating a requirement for sulfation for the activation of DHEA. Transient tran sfection experiments demonstrated that in contrast to the prototypic f oreign chemical peroxisome proliferator pirinixic acid, DHEA-S and its 17 beta-reduced metabolite, 5-androstene-3 beta, 17 beta-diol-3 beta- sulfate, are inactive in mediating trans-activation by PPAR alpha in C OS-1 cells. Two other mammalian PPAR isoforms, gamma and delta/Nuc1, w ere also inactive with respect to DHEA-S trans-activation. To test whe ther PPAR alpha mediates peroxisomal gene induction by DHEA-S in intac t animals, we administered DHEA-S or clofibrate to mice lacking a func tional PPAR alpha gene. Both peroxisome proliferators markedly increas ed hepatic expression of two microsomal cytochrome P450 4A proteins as well as six mRNAs known to be associated with the peroxisomal prolife rative response in wild-type mice. In contrast, neither DHEA-S nor clo fibrate induced these hepatic proteins and mRNAs in PPAR alpha-deficie nt mice. Clofibrate-induced expression of kidney CYP4A mRNAs was also blocked in the PPAR alpha gene knockout mice. Thus, despite its unresp onsiveness to steroidal peroxisome proliferators in transfection assay s, PPAR alpha is obligatory for DHEA-S-stimulated hepatic peroxisomal gene induction. DHEA-S, or one of its metabolites, may thus serve as a n important endogenous regulator of liver peroxisomal enzyme expressio n via a PPAR alpha-mediated pathway.