Down-regulation of the human secretin gene expression by an atypical nuclear orphan receptor, small heterodimer partner (SHP)

Abstract

Small Heterodimer Partner (SHP) is an orphan nuclear receptor that lacks a DNA-binding domain (DBD). SHP transcription can be enhanced by several nuclear receptors, including farnesoid X receptor (FXR). It has been demonstrated that, FXR is activated by bile acids. Therefore, bile acid can up-regulate SHP expression through FXR. On the other hand, SHP represses the transcriptional activities of NeuroD via physical contacts and displacing the coactivator p300. The transcription of secretin gene is partly driven by the NeuroD and E2A (E47 and E12) heterodimer interacting with the E-box motif, which is potentiated by p300 binding. In view of this, NeuroD-dependent secretin transcription can potentially be regulated by SHP. Furthermore, SHP may confer a novel pathway for secretin transcription in response to bile acids. In regard to the hypothesis, the regulatory role of SHP in human secretin gene expression was confirmed by over-expression of SHP in HuTu-80 cells, which led to dose-dependent decreases of both secretin promoter activities and endogenous secretin transcript levels. In contrast, silencing of endogenous SHP by the siRNA sequences, siRNA-1 and siRNA-2, augmented secretin promoter activity. On top of SHP, our studies have also demonstrated that the bile acid, CDCA, could effectively raise endogenous SHP transcript levels and down-regulate the secretin promoter. These results suggest that binding of CDCA to FXR activates SHP expression which eventually leads to down-regulation of secretin. In summary, the proposed hypothesis provides a negative regulatory loop that the secretin-stimulated bile acids, via SHP, can down-regulate secretin expression to reduce the long-term bile flow.