Identification of peroxisome proliferator-responsive human genes by elevated expression of the peroxisome proliferator-activated receptor a in HepG2 cells

In mice and other sensitive species, PPAR alpha mediates the induction of mitochondrial, microsomal, and peroxisomal fatty acid oxidation, peroxisome proliferation, liver enlargement, and tumors by peroxisome proliferators. In order to identify PPAR alpha -responsive human genes, HepG2 cells were engineered to express PPAR alpha at concentrations similar to mouse liver. This resulted in the dramatic induction of mRNAs encoding the mitochondrial HMG-CoA synthase and increases in fatty aryl-CoA synthetase (3-8-fold) and carnitine palmitoyl-CoA transferase IA (2-4-fold) mRNAs that were dependent on PPAR alpha expression and enhanced by exposure to the PPAR alpha agonist Wy14643. A PPAR response element was identified in the proximal promoter of the human HMG-COA synthase gene that is functional in its native context. These data suggest that humans retain a capacity for PPAR alpha regulation of mitochondrial fatty acid oxidation and ketogenesis. Human liver is refractory to peroxisome proliferation, and increased expression of mRNAs for the peroxisomal fatty acyl-CoA oxidase, bifunctional enzyme, or thiolase, which accompanies peroxisome proliferation in responsive species, was not evident following Wy14643 treatment of cells expressing elevated levels of PPAR alpha. Additionally, no significant differences were seen for the expression of apolipoprotein AI, All, or CIII; medium chain acyl-CoA dehydrogenase; or stearoyl-CoA desaturase mRNAs.