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Molecular Endocrinology 13 (9): 1535-1549
Copyright © 1999 by The Endocrine Society

A Truncated Human Peroxisome Proliferator-Activated Receptor {alpha} Splice Variant with Dominant Negative Activity

Philippe Gervois, Inés Pineda Torra, Giulia Chinetti, Thilo Grötzinger, Guillaume Dubois, Jean-Charles Fruchart, Jamila Fruchart-Najib, Eran Leitersdorf1 and Bart Staels

U.325 INSERM Département d’Athérosclérose Institut Pasteur de Lille 59019 Lille, France
Faculté de Pharmacie Université de Lille II 59006 Lille, France

The peroxisome proliferator-activated receptor {alpha} (PPAR{alpha}) plays a key role in lipid and lipoprotein metabolism. However, important inter- and intraspecies differences exist in the response to PPAR{alpha} activators. This incited us to screen for PPAR{alpha} variants with different signaling functions. In the present study, using a RT-PCR approach a variant human PPAR{alpha} mRNA species was identified, which lacks the entire exon 6 due to alternative splicing. This deletion leads to the introduction of a premature stop codon, resulting in the formation of a truncated PPAR{alpha} protein (PPAR{alpha}tr) lacking part of the hinge region and the entire ligand-binding domain. RNase protection analysis demonstrated that PPAR{alpha}tr mRNA is expressed in several human tissues and cells, representing between 20–50% of total PPAR{alpha} mRNA. By contrast, PPAR{alpha}tr mRNA could not be detected in rodent tissues. Western blot analysis using PPAR{alpha}-specific antibodies demonstrated the presence of an immunoreactive protein migrating at the size of in vitro produced PPAR{alpha}tr protein both in human hepatoma HepG2 cells and in human hepatocytes. Both in the presence or absence of 9-cis-retinoic acid receptor, PPAR{alpha}tr did not bind to DNA in gel shift assays. Immunocytochemical analysis of transfected CV-1 cells indicated that, whereas transfected PPAR{alpha}wt was mainly nuclear localized, the majority of PPAR{alpha}tr resided in the cytoplasm, with presence in the nucleus depending on cell culture conditions. Whereas a chimeric PPAR{alpha}tr protein containing a nuclear localization signal cloned at its N-terminal localized into the nucleus and exhibited strong negative activity on PPAR{alpha}wt transactivation function, PPAR{alpha}tr interfered with PPAR{alpha}wt transactivation function only under culture conditions inducing its nuclear localization. Cotransfection of the coactivator CREB-binding protein relieved the transcriptional repression of PPAR{alpha}wt by PPAR{alpha}tr, suggesting that the dominant negative effect of PPAR{alpha}tr might occur through competition for essential coactivators. In addition, PPAR{alpha}tr interfered with transcriptional activity of other nuclear receptors such as PPAR{gamma}, hepatic nuclear factor-4, and glucocorticoid receptor-{alpha}, which share CREB-binding protein/p300 as a coactivator. Thus, we have identified a human PPAR{alpha} splice variant that may negatively interfere with PPAR{alpha}wt function. Factors regulating either the ratio of PPAR{alpha}wt vs. PPAR{alpha}tr mRNA or the nuclear entry of PPAR{alpha}tr protein should therefore lead to altered signaling via the PPAR{alpha} and, possibly also, other nuclear receptor pathways.




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