Selenoprotein S regulates adipogenesis through IRE1α-XBP1 pathway.

The induction of endoplasmic reticulum (ER) stress is associated with adipogenesis, during which the inositol-requiring enzyme 1 alpha (IRE1α) -X-box binding protein 1 (XBP1) pathway is involved. Selenoprotein S (SelS), which is an ER resident selenoprotein, is involved in ER homeostasis regulation, however, little is known about the role of SelS in regulating adipogenesis. In vivo studies showed that SelS protein levels in white adipose tissue were increased in obese patients and high-fat diet (HFD) fed mice. Moreover, we identified that SelS protein levels increased in the early phase of adipogenesis, then decreased in the late phase during adipogenesis. Overexpression of SelS promoted adipogenesis. Conversely, knockdown (KD) of SelS resulted in the inhibition of adipogenesis, which was related to increasing cell death, decreased mitotic clonal expansion and cell cycle G1 arrest. In vivo studies also showed that endoplasmic reticulum (ER) stress markers (p-IRE1α/IRE1α, XBP1s, Grp78) were significantly increased with up-regulating of SelS expression in subcutaneous and visceral adipose tissues in the obese subjects and HFD fed mice. Furthermore, in SelS KD cells, the levels of Grp78 were increased, the levels of p-IRE1α/IRE1α were unchanged , but mRNA levels of spliced XBP1 (XBP1s) produced by IRE1α-mediated splicing were decreased, suggesting a role of SelS in the modulation of IRE1α-XBP1 pathway. Moreover, inhibition of adipogenesis by SelS suppression can be rescued by overexpression of XBP1s. Thus, SelS appears to function as a novel regulator of adipogenesis through IRE1α-XBP1 signaling pathway.