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 det ermined, and its promoters and tissue-specific expression were functio nally characterized. Similar to the mouse, two PPAR isoforms, PPAR gam ma 1 and PPAR gamma 2, were detected in man. The relative expression o f human PPAR gamma was studied by a newly developed and sensitive reve rse transcriptase-competitive polymerase chain reaction method, which allowed us to distinguish between PPAR gamma 1 and gamma 2 mRNA. In al l tissues analyzed, PPAR gamma 2 was much less abundant than PPAR gamm a 1. Adipose tissue and large intestine have the highest levels of PPA R gamma mRNA; kidney, liver, and small intestine have intermediate lev els; whereas PPAR gamma is barely detectable in muscle. This high leve l expression of PPAR gamma in colon warrants further study in view of the well established role of fatty acid and arachidonic acid derivativ es in colonic disease. Similarly as mouse PPAR gamma s, the human PPAR gamma s are activated by thiazolidinediones and prostaglandin J and b ind with high affinity to a PPRE. The human PPAR gamma gene has nine e xons and extends over more than 100 kilobases of genomic DNA. Alternat e transcription start sites and alternate splicing generate the PPAR g amma 1 and PPAR gamma 2 mRNAs, which differ at their 6'-ends. PPAR gam ma 1 is encoded by eight exons, and PPAR gamma 2 is encoded by seven e xons. The 5'-untranslated sequence of PPAR gamma 1 is comprised of exo ns A1 and A2, whereas that of PPAR gamma 2 plus the additional PPAR ga mma 2-specific N-terminal amino acids are encoded by exon B, located b etween exons A2 and A1. The remaining six exons, termed 1 to 6, are co mmon 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 re gulating its expression could be of major importance in understanding its biology.