Expression of PPARα in human hepatocytes and activation by trichloroacetate and dichloroacetate

Dichloroacetate (DCA) and trichloroacetate (TCA) are carcinogenic metabolites of trichloroethylene (TCE), a known hepatocarcinogen in B6C3F₁ mice. This hepatocarcinogenesis is believed to result from peroxisome proliferation viaPPARα and/or stimulation of hepatocyte replication. In this study hPPARα levels in six human liver tissues and in a long-term human hepatocyte cell line are compared. PPARα levels varied significantly between individual tissues and are generally lower than PPARα levels detected in mouse liver. Long-term cultured human hepatocytes display PPARα levels only slightly lower than cultured mouse hepatocytes. Transfection studies examining the endogenous hPPARα activity revealed little or no receptor activation, even following treatment with high concentrations of peroxisome proliferators. In contrast human hepatocytes transfected with mPPARα and mRXRα display increased expression of PPARα, and increased PPRE-reporter activity when treated with WY-14,643, TCA, and DCA. This human hepatocyte transfection system is a promising tool for examining the regulation of genes by PPARα from different species.