Peroxisome proliferators are postulated to elicit predictable pleiotropic responses in the liver by activating a peroxisome proliferator-activated receptor (PPAR). PPARs from mouse liver (mPPAR), rat liver (rPPAR), and Xenopus liver (xPPAR gamma) have been cloned recently. We now report the cloning of a new member from mouse liver which we designate mPPAR gamma. mPPAR gamma cDNA contained an open reading frame encoding a 475-amino acid protein exhibiting 75% amino acid similarity to xPPAR gamma, while it showed only 55% identity with mPPAR. The ligand-binding and DNA-binding domains are best conserved between mPPAR gamma, mPPAR, and xPPAR gamma. Like rPPAR, mPPAR gamma is able to impart peroxisome proliferator responsiveness to the promoter of peroxisomal bifunctional gene, which encodes the second enzyme of the peroxisomal fatty acid beta-oxidation system. Northern blot analysis revealed high expression of mPPAR gamma gene in mouse liver, kidney, and heart and low expression in the lung, testis, brain, skeletal muscle, and spleen. In mice treated with ciprofibrate, a peroxisome proliferator, a 2-fold increase in mPPAR gamma mRNA was observed in the liver and kidney. The presence of two PPARs in the mouse liver suggests the possibility of multiple signaling pathways for the peroxisome proliferator-induced pleiotropic responses.