THE PEROXISOME PROLIFERATORS ARE HEPATOCYTE MITOGENS IN CHEMICALLY-DEFINED MEDIA - GLUCOCORTICOID-INDUCED PPAR-ALPHA IS LINKED TO PEROXISOME PROLIFERATOR MITOGENESIS

Peroxisome proliferator-induced mitogenesis is believed to play a role in hepatocarcinogenesis, but it has not been possible to demonstrate high level induction of DNA synthesis by peroxisome proliferators in c ultured hepatocytes, We now show that four structurally dissimilar per oxisome proliferators (methylclofenapate, Wy-14 643, tetradecyl-3-thia acetic acid and clofibrate)cause high level induction of DNA synthesi s in primary cultures of rat hepatocytes, routinely 7-9 fold above con trol, with up to 29% of cells undergoing S-phase, Peroxisome prolifera tors induce DNA synthesis rapidly, with maximal response 24 h after do sing [compared with 48 h for epidermal growth factor (EGF)]; indeed, p eroxisome proliferators were mitogenic in a chemically defined medium, i.e. with no added exogenous growth factors. EGF-treated hepatocytes that had undergone DNA synthesis comprised 23% binucleated cells, wher eas hepatocytes induced into S-phase by peroxisome proliferators conta ined only 3% binucleated cells, demonstrating a distinct response of h epatocytes to peroxisome proliferators and EGF, The presence of a gluc ocorticoid was essential for peroxisome proliferator induced DNA synth esis, but not for EGF-induced DNA synthesis, demonstrating that the re quirement for glucocorticoids is selective for peroxisome proliferator s. Hydrocortisone was shown to induce the expression of peroxisome pro liferator activated receptor-alpha (PPAR alpha), and we propose that i t is the glucocorticoid-induced expression of PPAR alpha that is essen tial for peroxisome proliferator mitogenesis. This in vitro system pro vides a powerful tool for investigating the mechanism and role of pero xisome proliferator-induced mitogenesis in liver growth and carcinogen esis.