Peroxisome proliferator-activated receptor (PPAR) alpha-regulated growth responses and their importance to hepatocarcinogenesis

Peroxisome proliferators (PPs) are a class of non-genotoxic rodent hepatoca rcinogens that act by perturbing liver growth regulation. We have demonstra ted previously that PPs suppress both spontaneous rat hepatocyte apoptosis and that induced by exogenous stimuli such as transforming growth factor-be ta 1 (TGF beta 1). More recently, we have demonstrated that PPs can suppres s apoptosis induced by more diverse stimuli such as DNA damage or ligation of Fas, a receptor related to the tumour necrosis factor alpha (TNF alpha) family of cell surface receptors. PPs transcriptionally activate the peroxi some proliferator activated receptor-alpha, PPAR alpha, a member of the nuc lear hormone receptor superfamily. We investigated whether activation of PP AR alpha mediates the suppression of rat hepatocyte apoptosis induced by PP s. We isolated a naturally occurring variant form of PPAR alpha (hPPAR alph a-6/29) from human liver by PCR cloning. hPPAR alpha-6/29 shared the abilit y of mPPAR alpha to bind to DNA but, unlike mPPAR alpha, could not be activ ated by PPs. Furthermore, hPPAR alpha-6/29 could act as a dominant negative regulator of PPAR-mediated gene transcription. When introduced into primar y rat liver cell cultures by transient transfection, hPPAR alpha-6/29 preve nted the suppression of hepatocyte apoptosis by the PP nafenopin, but not t hat seen in response to phenobarbitone (PB), a non-genotoxic carcinogen who se action does not involve PPAR alpha. The suppression of hepatocyte apopto sis was abrogated completely even though only 30% of hepatocytes were trans fected, suggesting the involvement of a soluble factor. Recent data have su ggested that TNF alpha, perhaps released by liver Kupffer cells in response to PPs, may play a key role in mediating the effects of PPs on hepatocyte growth regulation. (C) 1998 Elsevier Science Ireland Ltd. All rights reserv ed.