Functional analysis of new PPARγ coactivator and elucidation of emergence mechanism of diabetes.

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Thyroid hormone receptor interacting protein 3(TRIP3) is a protein with unknown function that interacts with thyroid hormone receptor(TR) and retinoid hormone X receptor(RXR), but not with glucocorticoid receptor(GR). We have recently doned the full length TRIP3 cDNA and identified that TRIP3 also directly interacts with hepatocyte nuclear factor-4α (HNF-4α) and activated the transactivation activity of HNF-4α Peroxisome proliferators-activated receptor γ (PPARγ) is another transcription factor, belonging to the nuclear receptor factor family. PPARγ is a master regulator for adipocyte differentiation and is important in regulation of genes involved in lipid and glucose metabolism. In the present study, we examined the effect of TRIP3 on PPARγ transactivation activity. TRIP3 mRNA was expressed in human visceral and subcutaneous fat tissues. GST pull-down assay and mammalian two-hybrid assay showed that TRIP3 directly bound to PPARγ. Deletion studies indicated that TRIP3 interacted with the AF-2 domain of PPARγ. TRIP3 contains a short conserved LXXLL motif, in the C terminus. However, deletion experiments suggested that N terminus of ThIP3 was important for the interaction with PPARγ. A reporter gene assay showed that TRIP3 significantly increased the transcriptional activation activity of PPARγ in dose dependent manner in the presence(2.0-5.0 fold, p<0.05) or absence(2.4-5.0 fold, p<0.05) of its synthetic ligand. TRIP3 may act as a coactivator of PPAR γ.