Regulation of peroxisome proliferator-activated receptor-alpha mRNA in rat liver.

Chemical-induced peroxisome proliferation in rodent liver is postulated to occur via activation of members of the steroid hormone receptor superfamily, the peroxisome proliferation-activated receptors (PPARs). In the present study, the expression of the predominant liver subtype PPAR alpha was examined and compared to that of acyl-CoA oxidase (ACO), a marker for peroxisome proliferation and a prototype for genes regulated via PPARs. Despite the induction of both mRNA species in vivo by the peroxisome proliferator perfluorodecanoic acid (PFDA), dose response and time course indicate PPAR alpha and ACO are not controlled similarly. Messenger RNA levels for ACO increased rapidly in rat liver and declined over the subsequent 7 days following PFDA administration, while PPAR alpha mRNA increased slower and remained elevated over this period. In addition, PPAR alpha mRNA accumulation in PFDA-treated rats appears to be due primarily to hypophagia as pair feeding and complete caloric restriction result in a large increase in the concentration of this messenger RNA. Nuclear run-on experiments in vivo suggest that, unlike ACO, PFDA as well as caloric restriction results in accumulation of PPAR alpha mRNA which cannot be explained solely by transcriptional activation. These data indicated that PPAR alpha mRNA accumulation has a very small peroxisome proliferator-dependent component and that other factors may be involved. A rat hepatoma cell line was examined to determine the direct effect on peroxisome proliferators on PPAR alpha mRNA. PPAR alpha and ACO mRNA levels were increased rapidly in the rat hepatoma cell line FaO after treatment with PFDA or the prototypical peroxisome proliferator Wy 14,643. In this cell line, PPAR alpha mRNA levels are not affected by glucagon or insulin and in addition to peroxisome proliferators are induced in this cell line by oleic acid and dexamethasone. The latter treatment had the greatest effect on PPAR alpha mRNA accumulation while having a minimal effect on ACO mRNA. Treatment of FaO cells with actinomycin D prior to Wy 14,643 abolished ACO and PPAR alpha mRNA accumulation, demonstrating that there must be a transcriptional component of the peroxisome proliferator response. Therefore, although PPAR alpha is responsive to peroxisome proliferators and direct effects are observed in cell cultures, mRNA accumulation in vivo is predominantly posttranscriptional, and endogenous regulators such as glucocorticoids may play critical roles in the tissue- and developmentally specific expression of this steroid hormone receptor.