The organization, promoter analysis, and expression of the human PPAR gamma gene

PPAR gamma is a member of the PPAR subfamily of nuclear receptors. In this work, the structure of the human PPAR gamma cDNA and gene was determined, and its promoters and tissue-specific expression were functionally characterized. Similar to the mouse, two PPAR isoforms, PPAR gamma 1 and PPAR gamma 2, were detected in man. The relative expression of human PPAR gamma was studied by a newly developed and sensitive reverse transcriptase-competitive polymerase chain reaction method, which allowed us to distinguish between PPAR gamma 1 and gamma 2 mRNA. In all tissues analyzed, PPAR gamma 2 was much less abundant than PPAR gamma 1. Adipose tissue and large intestine have the highest levels of PPAR gamma mRNA; kidney, liver, and small intestine have intermediate levels; whereas PPAR gamma is barely detectable in muscle. This high level expression of PPAR gamma in colon warrants further study in view of the well established role of fatty acid and arachidonic acid derivatives in colonic disease. Similarly as mouse PPAR gamma s, the human PPAR gamma s are activated by thiazolidinediones and prostaglandin J and bind with high affinity to a PPRE. The human PPAR gamma gene has nine exons and extends over more than 100 kilobases of genomic DNA. Alternate transcription start sites and alternate splicing generate the PPAR gamma 1 and PPAR gamma 2 mRNAs, which differ at their 6'-ends. PPAR gamma 1 is encoded by eight exons, and PPAR gamma 2 is encoded by seven exons. The 5'-untranslated sequence of PPAR gamma 1 is comprised of exons A1 and A2, whereas that of PPAR gamma 2 plus the additional PPAR gamma 2-specific N-terminal amino acids are encoded by exon B, located between exons A2 and A1. The remaining six exons, termed 1 to 6, are common to the PPAR gamma 1 and gamma 2. Knowledge of the gene structure will allow screening for PPAR gamma mutations in humans with metabolic disorders, whereas knowledge of its expression pattern and factors regulating its expression could be of major importance in understanding its biology.