PPAR alpha and the regulation of cell division and apoptosis

Peroxisome proliferators (PPs) such as the hypolipidaemic drug, nafenopin and the phthalate plasticiser 2-diethylhexylphthalate induce rodent hepatocyte cell proliferation and suppress apoptosis leading to tumours. PPs act via the nuclear hormone receptor peroxisome proliferator activated receptor alpha (PPAR alpha) which directly regulates genes implicated in the response to PPs such as the peroxisomal gene acyl CoA oxidase. As expected for xenobiotics that perturb proliferation, PPs alter expression of cell cycle regulatory proteins. However, the ability to alter expression of cyclins and cyclin-dependent kinases is shared by physiological hepatic mitogens such as epidermal growth factor and is thus unlikely to be specific to the PP-induced aberrant growth associated with hepatocarcinogenesis. Recent evidence suggests that the response of hepatocytes to PPs is not only dependent upon PPAR alpha but also on the trophic environment provided by nonparenchymal cells and by cytokines such as tumour necrosis factor alpha. Additionally, the ability of PPs to suppress apoptosis and induce proliferation depends upon survival signalling mediated by p38 mitogen activated protein kinase. The cross talk between PPAR alpha-mediated transcription, survival signalling and cell cycle will be discussed with particular emphasis on relevance to toxicology.