FORUM Evidence for Cross Talk between PPAR and p38 MAP Kinase

The evidence implicating the peroxisome proliferator activated receptor (PPAR ) in peroxisome proliferator (PP)-induced rodent hepatocarcinogenesis is compelling. However, the question that remains is “Which genes are regulated by PPAR to perturb hepatocyte proliferation and apoptosis leading to PP-induced rodent hepatocarcinogenesis? ” Despite extensive research, there are no convincing gene targets that display the required link with causality and sufficient specificity. However, some laboratories suggest a role for p38 mitogen-activated protein (MAP) kinase in mediating PP-induced hepatocyte survival and proliferation but not peroxisome proliferation. Thus, cross talk between the p38 and PPAR signaling pathways may facilitate the growth but not the biochemical changes seen in response to this important class of xenobiotics. The discovery of the PPAR in 1990 (Issemann and Green, 1990) stimulated much research worldwide aimed at elucidating its role in mediating the response to the PP class of nongenotoxic hepatocarcinogens (reviewed in Auwerx, 1992; Kliewer et al., 1997; Roberts et al., in press; Roberts and Moffat, 2001; Vanden Heuvel, 1998). Many articles published over the next 5 years described PPAR structure, activation profile, and function as a ligand-dependent transcription factor (Auwerx, 1992; Bardot et al., 1993; Dreyer et al., 1993; Green, 1992; Issemann et al., 1993; Kliewer et al., 1995; Mukherjee et al., 1994; Palmer et al., 1995; Schoonjans et al., 1996; Tugwood et al., 1992). Specific PP response elements were described within the promoters of microsomal and peroxisomal genes known to be upregulated during peroxisome proliferation such as CYP4A1 (Aldridge et al., 1995), CYP4A6 (Muerhoff et al., 1992), and acyl CoA oxidase (Tugwood et al., 1992). Further international interest was sparked when PPAR was implicated in mediating not only the rodent hepatic peroxisome proliferation but also the hypolipidemic response to pharmaceutical PPs such as clofibrate and gemfibrozil given to patients to lower blood cholesterol (reviewed in Roberts and Moffat, 2001). This evidence was based on observations that PPAR can regulate the expression of several genes implicated in lipid transport and storage (Gulick et al., 1994; Hertz et al., 1995; Keller et al., 1993; Lehmann et al., 1995; Peters et al., 1997; Schoonjans et al., 1996) (reviewed in Roberts and Moffat, 2001). Thus, it was clear that PPAR could regulate the expression of genes from different functional families. Conclusive proof of a role for PPAR in PP-induced rodent peroxisome proliferation, liver growth changes, and hepatocarcinogenesis came with the creation of a PPAR null mouse (Lee et al., 1995) that was refractory to the effects of PPs, including hepatic peroxisome proliferation (Lee et al., 1995), liver hyperplasia (Lee et al., 1995), and carcinogenesis (Peters et al., 1997). Thus, by 1998, a virtually complete picture had emerged of the mechanism by which PPAR mediates the expression of enzymes involved in peroxisome proliferation and hypolipidemia. Additionally, the evidence implicating PPAR in rodent hepatocarcinogenesis was compelling. Despite these significant advances, one major question remained: How does activation of PPAR lead to the growth changes associated with rodent hepatocarcinogenesis? Some progress was made when it was demonstrated that PPAR is responsible for suppression of hepatocyte apoptosis, which would normally act to remove damaged or unwanted cells from the liver (Christensen et al., 1998; Hasmall et al., 2000; Holden et al., 2000). Coupled with evidence of a role for PPAR in mediating PP-induced hepatocyte DNA synthesis (Lee et al., 1995; Hasmall et al., 2000), these data provided a mode of action for PP-induced hepatocarcinogenesis based on mitogenic stimulation and clonal expansion of cells protected from deletion by apoptosis (reviewed in Roberts, 1999; Roberts et al., 2001b). Although the role of PPAR in regulating hepatocyte growth and survival was established, the mechanism of this regulation was unclear. However, because PPAR is a ligandactivated transcription factor, it is reasonable to attribute the observed biology to altered gene expression. From about 1997 onward, many laboratories concentrated on determining the identity of putative PPAR -regulated genes that may be involved in growth control and cancer. Techniques such as 1 Present address: Aventis Pharma S.A. , 13 quai Jules Guesde, F94400 Vitry-sur-Seine, France. Fax: 3 3158 938164. E-mail: ruth.roberts@ aventis.com. TOXICOLOGICAL SCIENCES 68, 270–274 (2002) Copyright © 2002 by the Society of Toxicology