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

Two alternatively spliced forms of human PPAR alpha mRNA, PPAR alpha1 and P PAR alpha2, have been identified. PPAR alpha1 mRNA gives rise to an active PPAR alpha protein while PPAR alpha2 mRNA gives rise to a form of PPAR whic h lacks the ligand-binding domain. PPAR alpha2 is unable to activate a pero xisome proliferator response element (PPRE) reporter gene construct in tran sient transfection assays. Both PPAR alpha1 and PPAR alpha2 mRNA are presen t in human liver, kidney, testes, heart, small intestine, and smooth muscle . In human liver, PPAR alpha2 mRNA abundance is approximately half that of PPAR alpha1 mRNA; a correlation analysis of PPAR alpha1 and PPAR alpha2 mRN A mass revealed an r-value of 0.75 (n = 18). Additional studies with intact liver from various species, showed that the PPAR alpha2/PPAR alpha1 mRNA r atios in rat, rabbit, and mouse liver were less than 0.10; significantly lo wer than the 0.3 and 0.5 ratios observed in monkey and human livers, respec tively. To determine if a high PPAR alpha2/PPAR alpha1 mRNA ratio was assoc iated with insensitivity to peroxisome proliferators, we treated human, rat , and rabbit hepatocytes with WY14643, a potent PPARa activator, and measur ed acyl CoA oxidase (ACO) mRNA levels. Rat ACO mRNA levels increased marked ly in response to WY14643 while human and rabbit hepatocytes were unrespons ive. Thus, although the PPAR alpha2/PPAR alpha1 mRNA ratio is low in rabbit s, this species is not responsive to peroxisome proliferators. Further stud ies with male and female rats, which vary significantly in their response t o peroxisome proliferators, showed little difference in the ratio of PPAR a lpha2/PPAR alpha1 mRNA. These data suggest that selective PPAR alpha2 mRNA expression is not the basis for differential species or gender responses to peroxisome proliferators.