Peroxisome proliferators activate growth regulatory pathways largely via peroxisome proliferator-activated receptor α-independent mechanisms

Peroxisome proliferators (PPs) induce liver tumors in rodents through an unknown mechanism requiring PP-activated receptor (PPAR) alpha. Since PPs possess growth modulatory activities that may be important to their hepatocarcinogenicity, we aimed at dissociating the activation of growth signaling pathways from the PPARalpha-mediated response induced by PPs in cultured rat primary hepatocytes. Pretreatment with the differentiation-promoting agent dimethylsulfoxide (DMSO) increased PPARalpha mRNA/protein and enhanced the expression of PPARalpha-regulated genes [fatty acyl Co-A oxidase (FACO), cytochrome P450 4A1 (CyT4A1)] induced by PPs. In contrast, DMSO reduced the expression of immediate early genes (IEG) expression (c-myc, c-jun, c-fos, junB, egr-1) and inhibited mitogen-activated protein Kinase (MEK) kinase/extracellular signal-regulated kinases (ERKs) and p38 phosphorylation. Furthermore, the inhibitors Tyrphostin and PD98059 dowregulated IEG/EFKs induction and slightly enhanced the FACO/CYP4A1 response induced by the PP WY-14,643 The stimulation of signal transduction pathways by PPs can be dissociated from PPARa activation, thus suggesting that PPs could activate growth regulatory pathways largely via PPARalpha-independent mechanisms. (C) 2002 Elsevier Science Inc. All rights reserved.