The local region we identified as GRE #1 is within a region that has already demonstrated insulin-dependent attenuation of SEPP1 expression by modulation of HNF-4α activity (Speckmann et al. 2008), and therefore, this could be a critical region that determines the expression levels of SEPP1 based on the affinity and availability of transcriptional regulators in different cell types. Other genes have HNF-4α responsive elements that overlap with GR or RXR responsive elements and perhaps this allows for more intricate modulation of these genes in development (Crestani et al. 1998; Bailly et al. 2001). It is unlikely that the effects on transactivation we observe are related to interactions with HNF-4α since this transcription factor is not expressed in HEK-293 cells (Lucas et al. 2005), and it is unclear how HNF-4α-mediated SEPP1 regulation would account for alterations in serum selenium levels in critically ill patients since insulin sensitivity changes would allow for more SelP expression (Lazzeri et al. 2009).
