Expression of the mRNA encoding truncated PPARα does not correlate with hepatic insensitivity to peroxisome proliferators

Two alternatively spliced forms of human PPARα mRNA, PPARα1 and PPARα2, have been identified. PPARα1 mRNA gives rise to an active PPARα protein while PPARα2 mRNA gives rise to a form of PPAR which lacks the ligand-binding domain. PPARα2 is unable to activate a peroxisome proliferator response element (PPRE) reporter gene construct in transient transfection assays. Both PPARα1 and PPARα2 mRNA are present in human liver, kidney, testes, heart, small intestine, and smooth muscle. In human liver, PPARα2 mRNA abundance is approximately half that of PPARα1 mRNA; a correlation analysis of PPARα1 and PPARα2 mRNA mass revealed an r-value of 0.75 (n = 18). Additional studies with intact liver from various species, showed that the PPARα2/PPARα1 mRNA ratios in rat, rabbit, and mouse liver were less than 0.10; significantly lower than the 0.3 and 0.5 ratios observed in monkey and human livers, respectively. To determine if a high PPARα2/PPARα1 mRNA ratio was associated with insensitivity to peroxisome proliferators, we treated human, rat, and rabbit hepatocytes with WY14643, a potent PPARa activator, and measured acyl CoA oxidase (ACO) mRNA levels. Rat ACO mRNA levels increased markedly in response to WY14643 while human and rabbit hepatocytes were unresponsive. Thus, although the PPARα2/PPARα1 mRNA ratio is low in rabbits, this species is not responsive to peroxisome proliferators. Further studies with male and female rats, which vary significantly in their response to peroxisome proliferators, showed little difference in the ratio of PPARα2/PPARα1 mRNA. These data suggest that selective PPARα2 mRNA expression is not the basis for differential species or gender responses to peroxisome proliferators.