Evidence for Cross Talk between PPAR{alpha} and p38 MAP Kinase

Ruth A. Roberts,1

Syngenta CTL, Alderley Park, Macclesfield, SK10 4TJ, United Kingdom

Received February 4, 2002; accepted March 27, 2002


    INTRODUCTION
 TOP
 INTRODUCTION
 REFERENCES
 
The evidence implicating the peroxisome proliferator activated receptor (PPAR{alpha}) in peroxisome proliferator (PP)-induced rodent hepatocarcinogenesis is compelling. However, the question that remains is "Which genes are regulated by PPAR{alpha} 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{alpha} 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{alpha} in 1990 (Issemann and Green, 1990Go) stimulated much research worldwide aimed at elucidating its role in mediating the response to the PP class of nongenotoxic hepatocarcinogens (reviewed in Auwerx, 1992Go; Kliewer et al., 1997Go; Roberts et al., in pressGo; Roberts and Moffat, 2001Go; Vanden Heuvel, 1998). Many articles published over the next 5 years described PPAR{alpha} structure, activation profile, and function as a ligand-dependent transcription factor (Auwerx, 1992Go; Bardot et al., 1993Go; Dreyer et al., 1993Go; Green, 1992Go; Issemann et al., 1993Go; Kliewer et al., 1995Go; Mukherjee et al., 1994Go; Palmer et al., 1995Go; Schoonjans et al., 1996Go; Tugwood et al., 1992Go). 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., 1995Go), CYP4A6 (Muerhoff et al., 1992Go), and acyl CoA oxidase (Tugwood et al., 1992Go). Further international interest was sparked when PPAR{alpha} 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, 2001Go). This evidence was based on observations that PPAR{alpha} can regulate the expression of several genes implicated in lipid transport and storage (Gulick et al., 1994Go; Hertz et al., 1995Go; Keller et al., 1993Go; Lehmann et al., 1995Go; Peters et al., 1997Go; Schoonjans et al., 1996Go) (reviewed in Roberts and Moffat, 2001Go). Thus, it was clear that PPAR{alpha} could regulate the expression of genes from different functional families.

Conclusive proof of a role for PPAR{alpha} in PP-induced rodent peroxisome proliferation, liver growth changes, and hepatocarcinogenesis came with the creation of a PPAR{alpha} null mouse (Lee et al., 1995Go) that was refractory to the effects of PPs, including hepatic peroxisome proliferation (Lee et al., 1995Go), liver hyperplasia (Lee et al., 1995Go), and carcinogenesis (Peters et al., 1997Go). Thus, by 1998, a virtually complete picture had emerged of the mechanism by which PPAR{alpha} mediates the expression of enzymes involved in peroxisome proliferation and hypolipidemia. Additionally, the evidence implicating PPAR{alpha} in rodent hepatocarcinogenesis was compelling.

Despite these significant advances, one major question remained: How does activation of PPAR{alpha} lead to the growth changes associated with rodent hepatocarcinogenesis? Some progress was made when it was demonstrated that PPAR{alpha} is responsible for suppression of hepatocyte apoptosis, which would normally act to remove damaged or unwanted cells from the liver (Christensen et al., 1998Go; Hasmall et al., 2000Go; Holden et al., 2000Go). Coupled with evidence of a role for PPAR{alpha} in mediating PP-induced hepatocyte DNA synthesis (Lee et al., 1995Go; Hasmall et al., 2000Go), 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, 1999Go; Roberts et al., 2001bGo).

Although the role of PPAR{alpha} in regulating hepatocyte growth and survival was established, the mechanism of this regulation was unclear. However, because PPAR{alpha} is a ligand-activated 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{alpha}-regulated genes that may be involved in growth control and cancer. Techniques such as differential display (Anderson et al., 1999Go; Corton et al., 1998Go; Vanden Heuvel et al., 1998Go) and genomics (Cherkaoui-Malki et al., 2001Go; Hasmall et al., 2002Go; Yamazaki et al., 2001Go) have yielded many candidate genes such as those for acute phase proteins (Anderson et al., 1999Go), cyclophilin A (Corton et al., 1998Go), and the zinc-finger protein ZFP-37 (Vanden Heuvel et al., 1998Go). More recent studies have used genomics to generate a wider view of the impact of PPAR{alpha} on metabolic and growth signaling pathways in the rodent liver. In one study, expression data highlighted several genes involved in lipid and glucose metabolism as well as those implicated in cell cycle and apoptosis (Cherkaoui-Malki et al., 2001Go). Another study found changes in many genes, including serum amyloid A (SAA), a protein associated with acute phase responses (Yamazaki et al., 2001Go). Interestingly, several of the proteins identified by these studies are associated with inflammation and oxidative stress, and this may be significant in the context of an inferred role for cytokines. However, these studies await follow-up confirmation of the role of these candidate genes in response to PPs. In contrast, studies performed in our laboratory suggest a role for lactoferrin (LF) in the response to PPs, not only from expression data but also from follow-up studies of LF biology (Hasmall et al., in preparation). Despite this, there are as yet no candidate genes for which there is clear causality between PPAR{alpha}-mediated regulation and rodent hepatic growth and cancer. Similarly, there are candidate genes for which regulation plays a role not only in PP-mediated hepatic growth but in response to other stimuli as well. Thus, genes identified to date lack the degree of specificity expected for a PPAR{alpha}-mediated response.

Parallel to attempts to identify PPAR{alpha}-regulated genes that may be a factor in hepatocyte proliferation and growth, other researchers have taken a different approach and asked whether cytokines normally implicated in liver damage could play a role in the response to PPs. In support of this hypothesis, the cytokine tumor necrosis factor-{alpha} (TNF-{alpha}) was found to increase hepatocyte proliferation and suppress apoptosis in cultured rodent hepatocytes (Rolfe et al., 1997Go). Furthermore, the hepatocyte growth response to PPs was prevented by antibodies to either TNF-{alpha} (Bojes et al., 1997Go; Rolfe et al., 1997Go) or TNF-{alpha} receptor 1 (TNFR1) (West et al., 1999Go). In addition, TNF-{alpha} messenger RNA was reported to be increased in some studies (Bojes et al., 1997Go; Rose et al., 1997Go) but not in another (Holden et al., 2000Go). Thus, TNF-{alpha} appears to play a role in the response to PPs, but data on a direct regulation of the TNF-{alpha} gene by PPs are equivocal. Thus, the liver response to PPs may be mediated by bioactivation or release of preexisting TNF-{alpha} protein from hepatic Kupffer cells (Holden et al., 2000Go). However, the proliferative response of hepatocytes to PPs appears to be intact in both TNF-{alpha} null and TNF-{alpha} receptor null mice (Givler et al., 2000Go; Lawrence et al., 2001Go), suggesting some redundancy in cytokine-mediated responses. In support of this, other cytokines such as interleukin (IL)-1 and IL-6 are able to regulate hepatocyte growth and may play a role in a coordinated cytokine-mediated response to PPs (reviewed in Roberts and Kimber, 1999Go; Roberts et al., 2001aGo). Interestingly, both forms of IL-1 (IL-1{alpha} and IL-1ß) act through a single signal transducing membrane receptor, IL-1R1 (Dinarello, 1988Go), that shares many downstream signaling pathways with TNFR1 (Eder, 1997Go).

MAP kinase pathways transduce extracellular signals, resulting in phosphorylation of transcription factors leading to alterations in gene expression (Schaeffer and Weber, 1999Go). Significantly, p38 MAP kinases are associated with enhanced cell survival and are activated by cytokines, growth factors, and a variety of cellular stresses (Mendelson et al., 1996Go; Raingeaud et al., 1995Go). Several lines of evidence implicate p38 MAP kinase in the response to PPs. Both TNF-{alpha} and the PP, nafenopin, can activate p38 MAP kinase in rodent hepatocytes (Cosulich et al., 2000Go). Furthermore, inhibition of p38 MAP kinase with the specific inhibitor SB203580 prevents both the suppression of apoptosis and the induction of DNA synthesis in response to the PP, nafenopin (Cosulich et al., 2000Go). However, inhibition of p38 MAP kinase was unable to prevent the induction of peroxisomal ß-oxidation by nafenopin (Cosulich et al., 2000Go) (Fig. 1Go). As well as having a direct role, p38 MAP kinase is implicated in the synthesis of IL-6 in response to TNF-{alpha} (Beyaert et al., 1996Go), placing it at the center of a putative cytokine signaling cascade (Roberts and Kimber, 1999Go). Additionally, it has been shown that dexamethasone, an inhibitor of cytokine release, can prevent the growth but not the peroxisome proliferation responses to the PP Wyeth-14, 643 (Lawrence et al., 2001Go). These data suggest a pivotal role for p38 MAP kinase in the growth but not the peroxisome proliferation response to PPs.



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FIG. 1. Schematic depicting the role of p38 MAP kinase (MAPK) in the survival and proliferation response of rodent hepatocytes to PPs. The p38 MAPK inhibitor SB203580 can prevent the suppression of apoptosis and induction of proliferation normally seen in response to PPs.

 
The evidence presented so far argues for a role for both PPAR{alpha} and p38 MAP kinase in the growth and carcinogenic response of rodent liver to PPs. However, the key question is "Do these two pathways cross talk, and if so, how?" (Fig. 2Go). Our recent data have demonstrated that p38 MAP kinase is still activated by PPs in PPAR{alpha} null mouse hepatocytes, although the hepatocytes fail to mount a response (unpublished data). This suggests that PPAR{alpha} activation is either downstream of or independent of p38 MAP kinase.



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FIG. 2. The growth response of rodent hepatocytes to PPs depends on both PPAR{alpha} and on p38 MAP kinase. This suggests that there is cross talk between these two pathways, but the nature of this remains to be determined.

 
One reasonable hypothesis is that p38 MAP kinase acts to phosphorylate PPAR{alpha}, contributing to its function. Evidence exists that PPAR{alpha} is a phosphoprotein (Passilly et al., 1999Go; Shalev et al., 1996Go) and that the level of phosphorylation can be increased by insulin (Shalev et al., 1996Go) or the PP ciprofibrate (Passilly et al., 1999Go). More recently, several serine phosphorylation sites were demonstrated in the A/B domain of PPAR{alpha}, a region associated with so-called ligand-independent receptor activity (Fajas et al., 1997Go; reviewed in Tugwood et al., 1996Go; Vanden Heuvel, 1999Go). Furthermore, it was suggested that the ability of PPAR{alpha} to activate reporter gene transcription in the presence of PPs is dependent on p38 MAP kinase (Barger et al., 2001Go), although demonstration of dependency required artificial and prolonged stimulation of p38 activity using a constitutively active MAP kinase kinase (MKK6) (Barger et al., 2001Go).

One fascinating hypothesis is that the activation of p38 MAP kinase by PPs may be required for PPAR{alpha}-mediated hepatocyte growth regulation but not for PPAR{alpha}-mediated peroxisome proliferation (Fig. 3Go). Such a model would explain how the so-called pleiotropic responses to PPs can be dissected into functional pathways by the use of inhibitors such as SB203580. In addition, this could explain why cytokine signaling pathways can reproduce the growth but not the peroxisome proliferation responses to PPs. Another exciting idea is that PPAR{alpha} can orchestrate both transcriptional and nongenomic responses to PPs, perhaps by interacting with components of the cytosolic signaling machinery to regulate cell growth. Such a model has been suggested for estrogen receptor, another member of the nuclear hormone receptor superfamily (Moggs and Orphanides, 2001Go).



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FIG. 3. Inhibitors such as SB203580 suggest that the so-called pleiotropic responses to PPs can be dissected into functional pathways. Thus, the activation of p38 MAP kinase by PPs may be required for PPAR{alpha}-mediated hepatocyte growth regulation but not for PPAR{alpha}-mediated peroxisome proliferation.

 
Evidence for cross talk between survival signaling pathways and PPAR{alpha} comes from studies not only of p38 but of other kinases as well, such as the Janus kinase-signal transducer and activator of transcription (JAK-STAT) (Zhou and Waxman, 1999Go), MEK (MAP kinase kinase) (Cosulich et al., 2000Go), extracellular signal-related kinases (ERK) (Mounho and Thrall, 1999Go), and phosphatidylinositol-3 kinases (PI3 kinase) (Mounho and Thrall, 1999Go). Generally, the p38 MAP kinases and c-Jun N-terminal kinases (JNKs) respond to cellular stress signals, whereas the MEK-ERK pathway is primarily responsible for responding to cellular proliferation signals (reviewed in Schaeffer and Weber, 1999Go). Thus, a requirement for activation of the ERK pathway for the growth response of rodent cells to PPs (Cosulich et al., 2000Go; Mounho and Thrall, 1999Go; Rokos and Ledwith, 1997Go) suggests that PPs may be using both stress and growth pathways. Additional complexity is added by cross talk between the kinases and by the observation that STAT5 activation by growth hormone inhibited PPAR{alpha} activity, suggesting a role for both positive and negative regulation (Zhou and Waxman, 1999Go).

In summary, both p38 MAP kinase and PPAR{alpha} play pivotal roles in the growth and hepatocarcinogenic response of rodent liver to PPs. Various strands of evidence suggest cross talk between these two signaling pathways. Technological developments will provide the opportunity to dissect the components of these pathways, providing invaluable insight into the diverse responses to this important class of xenobiotics.


    NOTES
 
1 Present address: Aventis Pharma S.A., 13 quai Jules Guesde, F94400 Vitry-sur-Seine, France. Fax: 3 3158 938164. E-mail: ruth.roberts{at}aventis.com. Back


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