Peroxisome proliferator-activated receptor α required for gene induction by dehydroepiandrosterone-3β-sulfate

Peroxisome proliferator-activated receptor α (PPARα) mediates the effects of foreign chemical peroxisome proliferators on liver and kidney, including the induction of peroxisomal, mitochondrial, and microsomal enzymes involved in β-oxidation of fatty acids. However, the role of this receptor in the peroxisome proliferative effects of the endogenous steroid dehydroepiandrosterone (DHEA) is not known. DHEA-3β-sulfate (DHEA-S) is shown to induce a liver peroxisome proliferative response in rats in vivo at a dose at which DHEA is much less active, which is consistent with cultured hepatocyte studies indicating a requirement for sulfation for the activation of DHEA. Transient transfection experiments demonstrated that in contrast to the prototypic foreign chemical peroxisome proliferator pirinixic acid, DHEA- S and its 17β-reduced metabolite, 5-androstene-3β,17β-diol-3β-sulfate, are inactive in mediating trans-activation by PPARα in COS-1 cells. Two other mammalian PPAR isoforms, γ and δ/Nuc1, were also inactive with respect to DHEA-S trans-activation. To test whether PPARα mediates peroxisomal gene induction by DHEA-S in intact animals, we administered DHEA- S or clofibrate to mice lacking a functional PPARα gene. Both peroxisome proliferators markedly increased hepatic expression of two microsomal cytochrome P450 4A proteins as well as six mRNAs known to be associated with the peroxisomal proliferative response in wild-type mice. In contrast, neither DHEA-S nor clofibrate induced these hepatic proteins and mRNAs in PPARα-deficient mice. Clofibrate-induced expression of kidney CYP4A mRNAs was also blocked in the PPARα gene knockout mice. Thus, despite its unresponsiveness to steroidal peroxisome proliferators in transfection assays, PPARα is obligatory for DHEA-S-stimulated hepatic peroxisomal gene induction. DHEA-S, or one of its metabolites, may thus serve as an important endogenous regulator of liver peroxisomal enzyme expression via a PPARα- mediated pathway.