Response of primary hepatocytes to GW7647

Activation of PPARa pathways by some environmental chemicals causes hepatocyte proliferation and cancer in rodents. While these responses do not seem to occur in humans, the biological basis of these species differences remains uncertain. We systematically evaluated multiple readouts in rat and human hepatocytes and gene expression in intact rat livers using a PPARa-selective agonist, GW7467. In vitro rat hepatocytes had more genes significantly altered by GW7647 than did human (2320 versus 192). There were common pathways of fatty acid metabolism, amino acid metabolism and lipid transport, mostly represented by upregulated genes, shared between species. In rat hepatocytes, there were many downregulated genes enriched for processes including apoptosis, inflammation, response to hormones and chemical stimuli. In vivo, gene expression signatures for proliferation were present at high doses. In both species, a third of the genes with altered expression had direct binding of PPARa to a nearby peroxisome proliferator response element (PPRE). While the PPRE associated with upregulated genes in both species, was similar, the downregulated genes in the rat had altered flanking region conservation of nucleotides. Among the down regulated genes with direct PPARa binding in the rat were two key transcription factors – Hnf6 (onecut1) and Ets. Our results support a qualitative difference in biology of PPARa activation between human and rats. The secondary downregulated pathways, in the rat, appear to be reversion to an earlier lineage more responsive to proliferative signals that likely arise from interactions between the PPARa activated hepatocytes and other cell types in the intact liver.