A single amino acid change in the mouse peroxisome proliferator-activated receptor α alters transcriptional responses to peroxisome proliferators

The mouse peroxisome proliferator-activated receptor α (mP-PARα) can activate transcription from the CYP4A6 promoter in transient cotransfection experiments in the absence (intrinsic transactivation) or presence of added peroxisome proliferator. However, mPPARα-G, in which glycine is substituted for Glu²⁸², exhibits very low intrinsic transactivation and responds fully to added peroxisome proliferators. The two receptors, when expressed in COS- 1 cells, are nuclear in localization, are expressed at similar levels, have similar stability, and bind DNA in vitro with similar efficiency. The phenotypic difference in intrinsic transactivation is not altered by overexpression of the human retinoid X receptor α. The mPPARα-G mutant receptor displays a higher EC₅₀ for pirinixic acid and for 5,8,11,14- eicosatetraynoic acid than the wild-type PPARα. This difference in the apparent EC₅₀ value is independent of the cell lines used and indicates that the Glu²⁸² to glycine substitution alters the response of mPPARα to peroxisome proliferators. The EC₅₀ values obtained for each receptor with the CYP4A6 reporter construct are lower than those for a reporter derived from the acyl-CoA oxidase gene. In general, an inverse relation is evident between the apparent EC₅₀ values and the extent of intrinsic transactivation observed. The difference in intrinsic transactivation may reflect the presence of an endogenous activator at a concentration that is not sufficient to activate the mPPARα-G but that is sufficient to effect the intrinsic transactivation seen for the wild-type mPPARα.