ROLE OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-ALPHA IN ALTERED CELL-CYCLE REGULATION IN MOUSE-LIVER

The mechanisms underlying peroxisome proliferator-induced hepatocarcin ogenesis are unclear but are mediated by the peroxisome proliferator-a ctivated receptor a (PPAR alpha), To determine the role of PPAR alpha in the mechanisms of hepatocarcinogenesis, the effect of Wy-14,643 on expression patterns of acyl CoA oxidase (ACO) and proteins involved in cell proliferation in the PPAR alpha-null mouse were evaluated. AGO, CDK-1, CDK-2, CDK-4, PCNA and c-myc proteins were significantly increa sed in wild-type mice fed Wy-14,643 for 5 weeks or 11 months, as compa red with controls. This effect was not observed in Wy-14,643-treated P PARa-null mice. Expression patterns of cyclin B1, cyclin D, cyclin E a nd p53 were not different in any of the groups. mRNAs encoding CDK-1, CDK-4, cyclin D1 and c-myc were also increased in wild-type mice fed W y-14,643 but not in PPARa-null mice. These results indicate that the i ncrease in CDK-1, CDK-4 and c-myc may be caused by an increase in tran scription that is mediated directly or indirectly by PPAR alpha. Thus PPAR alpha-dependent alterations in cell cycle regulatory proteins ind uced by peroxisome proliferators are likely to contribute to the hepat ocarcinogenicity of peroxisome proliferators.