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

Abstract Peroxisome proliferators (PPs) induce liver tumors in rodents through an unknown mechanism requiring PP-activated receptor (PPAR) α. 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 PPARα-mediated response induced by PPs in cultured rat primary hepatocytes. Pretreatment with the differentiation-promoting agent dimethylsulfoxide (DMSO) increased PPARα mRNA/protein and enhanced the expression of PPARα-regulated genes [fatty acyl Co-A oxidase ( FACO ), cytochrome P 450 4A1 ( CYP4A1 )] induced by PPs. In contrast, DMSO reduced the expression of immediate early genes (IEG) expression (c- myc , c- jun , c- fos , jun B, 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/ERKs 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 PPARα activation, thus suggesting that PPs could activate growth regulatory pathways largely via PPARα-independent mechanisms.