Regulation of Peroxisome Proliferator-Activated Receptor-α mRNA in Rat Liver

Abstract

Chemical-induced peroxisome proliferation in rodent liver is postulated to occur via activation of members of the steroid hormone receptor superfamily, the peroxisome proliferator-activated receptors (PPARs). In the present study, the expression of the predominant liver subtype PPARα 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 speciesin vivoby the peroxisome proliferator perfluorodecanoic acid (PFDA), dose response and time course indicate PPARα 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 PPARα mRNA increased slower and remained elevated over this period. In addition, PPARα 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 experimentsin vivosuggest that, unlike ACO, PFDA as well as caloric restriction results in accumulation of PPARα mRNA which cannot be explained solely by transcriptional activation. These data indicate that PPARα 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 of peroxisome proliferators on PPARα mRNA. PPARα 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, PPARα 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 PPARα 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 PPARα mRNA accumulation, demonstrating that there must be a transcriptional component of the peroxisome proliferator response. Therefore, although PPARα is responsive to peroxisome proliferators and direct effects are observed in cell culture, mRNA accumulationin vivois predominantly posttranscriptional, and endogenous regulators such as glucocorticoids may play critical roles in the tissue- and developmentally specific expression of this steroid hormone receptor.