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Characterization of the Human PPAR Promoter: Identification of a Functional Nuclear Receptor Response Element

U.545 Institut National de la Santé et de la Recherche Médicale (I.P.T., J.-C.F., B.S.), Département d’Athérosclérose, Institut Pasteur de Lille, 59019 Lille, and the Faculté de Pharmacie, Université de Lille II, 59006 Lille, France; and Centre for Cardiovascular Genetics (Y.J., D.M.F.), Department of Medicine, Royal Free and University College London Medical School, The Rayne Institute, London WC1E 6JJ, United Kingdom

Address all correspondence and requests for reprints to: Bart Staels, U.545 INSERM, Institut Pasteur de Lille, 1 Rue Calmette BP245, 59019 Lille, France. E-mail: Bart.Staels{at}pasteur-lille.fr.

PPAR is a nuclear receptor that controls lipid and glucose metabolism and exerts antiinflammatory activities. The factors regulating human PPAR (hPPAR) gene expression remain largely unexplored. To study the mechanisms controlling hPPAR expression, the hPPAR gene promoter was identified and characterized. First, an alternatively spliced exon within the 5'-untranslated region of the hPPAR gene was identified by RT-PCR. Next, the transcription start site was mapped and the hPPAR gene promoter was cloned and functionally analyzed. Because PPAR levels are elevated in tissues expressing the hepatocyte nuclear factor-4 (HNF4), such as liver, the regulation of hPPAR by HNF4 was examined. Transient transfections in HepG2 and Cos cells showed that HNF4 enhances hPPAR promoter activity. 5'-Deletion and mutation analysis of the hPPAR promoter identified a regulatory element (RE) consisting of a degenerate hexamer repeat with a single nucleotide spacer (direct repeat 1), termed HNF4-RE. Gel shift assays demonstrated that HNF4 binds to this HNF4-RE. Furthermore, HNF4 increased the activity of a heterologous promoter driven by two copies of the HNF4-RE. The nuclear receptor COUP-TFII also bound this site and down-regulated basal as well as HNF4-induced hPPAR promoter activity. Finally, PPAR was shown to bind the HNF4-RE, leading to an induction of PPAR expression in hepatocytes. In summary, the organization of the 5'-flanking and untranslated region of the hPPAR gene was characterized and the hPPAR promoter region has been identified. Furthermore, these data demonstrate that the hPPAR gene is regulated by nuclear receptors, such as HNF-4, COUP-TFII, and PPAR.

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