Hepatic regeneration in peroxisome proliferator-activated receptor alpha-null mice after partial hepatectomy

Peroxisome proliferator activated receptor alpha (PPARalpha), a member of the nuclear hormone receptor superfamily, is essential for hepatic pleiotropic effects induced by peroxisome proliferators including cell proliferation. In a previous study, we have shown that PPARalpha null mice do not show increased hepatocyte proliferation after administration of peroxisome proliferators, confirming that PPARalpha is necessary for peroxisome proliferator-induced cell proliferation. However, the role of PPARalpha, if any, in compensatory liver cell hyperplasia is not known. Therefore, we examined the role of PPARalpha in modulating compensatory liver cell proliferation occurring after partial hepatectomy (PH). Replicative DNA synthesis, as measured by bromodeoxyuridine labeling of liver cell nuclei, was significantly higher after 48 h post-hepatectomy in both wild type and PPARalpha-null mouse livers, as compared to sham-operated control mice. Interestingly, in PPARalpha-null mice labeling index was significantly higher at 60 h after hepatectomy compared to wild-type mice; however, at 72 and 84 h the values were comparable in both the groups. Hepatic levels of mRNAs encoding CDK1, CDK2, CDK4, cyclin B1, cyclin D1 and PCNA were all elevated at 60 and 72 h post-hepatectomy and this effect was similar in both PPARalpha genotypes. Similarly, CDK2, CDK4, cyclin B1, cyclin D1 and PCNA proteins also showed comparable increase in both the groups. These results show that PPARalpha receptor is not essential for increased expression of CDKs, cyclins, PCNA and enhanced cell proliferation that occur after PH. This strongly suggests that the signaling for increased cell proliferation in response to PH is distinctly different from that observed after administration of peroxisome proliferators.