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Constitutive Coactivator of Peroxisome Proliferator-Activated Receptor (PPAR), a Novel Coactivator of PPAR that Promotes Adipogenesis

Division of Pulmonary, Critical Care, and Sleep Medicine, Departments of Internal Medicine (D.L., Q.K., D.-M.W.) and Biochemistry and Molecular Biology (D.L.), Saint Louis University, St. Louis, Missouri 63110-0250

Address all correspondence and requests for reprints to: Dechun Li, M.D., Ph.D., Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, Saint Louis University, Desloge Towers, Seventh Floor, 3635 Vista Avenue, St. Louis, Missouri 63110-0250. E-mail: dli2{at}slu.edu.

Peroxisome proliferator-activated receptor (PPAR) plays essential roles in adipogenesis by transcriptionally regulating adipocyte-specific genes through recruitment of coregulators including coactivators and corepressors. However, the precise repertoire of coactivators required for PPAR transactivation remains unresolved. In this report, we cloned and characterized a novel PPAR interacting protein, constitutive coactivator of PPAR (CCPG), which is expressed in multiple adult tissues and throughout embryonic development. CCPG is localized in nucleus and contains four LXXLL motifs, which are characteristic for nuclear receptor coactivators. A delineation of CCPG-PPAR interaction by glutathione-S-transferase pull-down and coimmunoprecipitation assays indicated that CCPG interacts with the hinge region of PPAR in a ligand-independent manner. However, mutation of four motifs of LXXLL to LXXAA in CCPG does not compromise its interaction with PPAR, suggesting LXXLL motif is not required for the interaction. Glutathione-S-transferase pull-down assays showed that CCPG binds to retinoic X receptor- and estrogen receptor- independent of their ligands, but not to thyroid hormone receptor-ß. CCPG coactivates PPAR in PPAR response element reporter assays, and the N terminus (amino acids 1–561) of CCPG acts to significantly augment the transactivation of PPAR, whereas the C terminus (amino acids 562–786) represses PPAR activity, indicating the N terminus possesses the activation domain. Using an adenoviral-mediated system, we also revealed that overexpression of CCPG promoted differentiation of OP9 preadipocyte into adipocyte, and knockdown of CCPG by RNA interference blocked this process, as examined by Oil Red O staining and Western blots of adipocyte-specific protein, adiponectin, and perilipin. Taken together, our data indicate that CCPG is a bona fide coactivator and promotes adipogenesis in a PPAR-dependent manner.