414 - Selenium deficiency decreases hepatic selenoprotein S expression and exacerbates the hepatic endoplasmic reticulum (ER) stress response after endotoxemia

Selenium (Se) deficiency increases morbidities and mortality in critically ill patients with sepsis but underlying mechanisms are poorly understood. The endoplasmic reticulum (ER) selenoprotein, selenoprotein S (selenoS), is reported to regulate the ER stress response and pro-inflammatory cytokine expression in vitro. SelenoS is highly expressed in the liver, an organ that is pivotal in coordinating the host response to inflammatory insults. However, whether dietary Se deficiency or decreased hepatic selenoS can exacerbate the in vivo hepatic ER stress response or increase pro-inflammatory signaling are unknown.  

Objective: To test if dietary selenium deficiency alters the hepatic ER stress response after innate immune challenge with endotoxemia.

Design/Methods:

C57Bl/6 mice received Se sufficient (SeS, 0.4 ppm Se) or Se deficient (SeD, < 0.01 ppm Se) diets to induce Se deficiency. Intraperitoneal lipopolysaccharide (LPS) or PBS were given and mice sacrificed after 5 and 24 hours. Hepatic mRNA was assessed by qPCR for ER stress genes (Xbp1, Chop and Ddit3) and pro-inflammatory cytokines  reported to be regulated by selenoS (Tnf, Il-6 and Il-1b). Hepatic protein content of selenoS and the ER stress protein, binding immunoglobulin protein (BIP) were measured by Western blot. F and M mice were analyzed separately then combined as mixed sex as no sex differences were observed in initial assessments.  (p < 0.05, n=4-10). 

Results:

SelenoS protein content was decreased by 90% in SeD control livers compared to SeS control livers. There was no difference in the expression of ER stress genes or BIP protein content between SeS and SeD control livers. SelenoS protein content increased after LPS in both dietary groups, and was significantly higher in the SeS livers.  LPS exposure increased expression of ER stress genes Xbp1, Chop and Ddit3 in both SeS and SeD livers at 5 hours, and remained elevated at 24 hours only in the SeD livers. LPS exposure increased protein content of BIP at 24 hours in SeD livers only. LPS exposure increased the hepatic expression of Tnf, Il-6 and Il-1b for both dietary groups at 5 hours. These only remained significantly increased at 24 hours in SeD livers.

Conclusion(s):

Dietary SeD decreases the hepatic expression of an ER protein, SelenoS, at baseline. After LPS exposure, the acute hepatic ER stress response assessed at 5 hours is similar in SeS and SeD mice. However, the later hepatic ER stress response is exacerbated by SeD.  We speculate that impaired hepatic expression of SelenoS may contribute to persistent inflammation after inflammatory insults, which may worsen organ function.