Small Heterodimer Partner, an Orphan Nuclear Receptor, Augments Peroxisome Proliferator-activated Receptor γ Transactivation*

Small heterodimer partner (SHP, NR0B2) is an atypical orphan nuclear receptor that inhibits transcriptional activation by several other nuclear receptors. We recently reported that mutations in the SHP gene are associated with insulin resistance. In the present study, we demonstrated that theSHP gene is expressed in adipose tissues. A reporter gene assay showed that a gene product of SHP increased the transcriptional activation of peroxisome proliferator-activated receptor (PPAR) γ. SHP-mediated activation of PPARγ was observed both in the presence and absence of the ligand of PPARγ. Immunoprecipitation and glutathione S-transferase pull-down assay showed that SHP directly bound to PPARγ and competed with nuclear receptor corepressor for binding to PPARγ. Serial deletion studies indicated that the C terminus of SHP is important for PPARγ activation. Mutant SHP proteins, which are found in naturally occurring mutation, showed less enhancing activity for PPARγ than wild-type SHP. Our results suggest that SHP may act as an endogenous enhancer of PPARγ.

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