Loss of epithelium-specific GPx2 results in aberrant cell fate decisions during intestinal differentiation

Abstract

The selenoprotein glutathione peroxidase 2 (GPx2) is expressed in the epithelium of the gastrointestinal tract, where it is thought to be involved in maintaining mucosal homeostasis. To gain novel insights into the role of GPx2, proteomic profiles of colonic tissues either derived from wild type (WT) or GPx2 knockout (KO) mice, maintained under selenium (Se) deficiency or adequate Se supplementation conditions were established and analyzed. Amongst the panel of differentially expressed proteins, the calcium-activated chloride channel regulator 1 (CLCA1) was significantly down-regulated in GPx2 KO versus WT mice regardless of the given Se status. Moreover, transcript levels of the isoforms CLCA2 and CLCA3 showed a similar expression pattern. In the intestine, CLCA1 is usually restricted to mucin-producing goblet cells. However, although -SeKO mice had the highest numbers of goblet cells as confirmed by significantly enhanced mRNA expression levels of the goblet cell marker mucin-2, the observed expression pattern suggests that GPx2 KO goblet cells might be limited in synthesizing CLCA1. Furthermore, transcript levels of differentiation markers such as chromogranin-1 (Chga) for enteroendocrine cells and leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5) for stem cells were also downregulated in GPx2 KO mice. Moreover, this was accompanied by a downregulation of the mRNA expression levels of the intestinal hormones glucagon-like peptide 1 (Glp1), ghrelin (Ghrl) and somatostatin (Sst). Thus, it seems that GPx2 might be important for the modulation of cell fate decisions in the murine intestinal epithelium.

Distinct and overlapping functions of glutathione peroxidases 1 and 2 in limiting NF-κB-driven inflammation through redox-active mechanisms

“…Thus, H 2 O 2 generated by NADPH oxidases provides antimicrobial defense and, vice versa , loss-of-function mutations in NOX1 result in mucus layer disruption with bacterial penetration into crypts and subsequent intestinal inflammation [54]. Besides this, we have previously shown that another important mediator of mucus composition, the calcium-activated chloride channel regulator 1 (CLCA1), was decreased in GPx2 KO mice irrespective of the selenium status and associated shifts in GPx1 expression [55]. Based on that, there might be a specific function of the isoform GPx2 in modulating the immune response towards the intestinal microbiota.…”

Loss of Selenov predisposes mice to extra fat accumulation and attenuated energy expenditure

“…Our new findings not only help explain the strong correlation between the Selenov expression and the high-fat diet-induced obesity in pigs [ 24 ], but also qualify SELENOV to join a special group of selenoproteins involved in body energy metabolism [ 5 ]. To our best knowledge, 19 selenoprotein genes were inactivated in mice [ 10 , [12] , [13] , [14] , [15] , [66] , [67] , [68] , [69] , [70] , [71] , [72] , [73] , [74] , [75] , [76] , [77] , [78] , [79] ], and 9 of them displayed roles in glucose, lipid, and energy metabolism [ 10 , [12] , [13] , [14] , [15] , [67] , [68] , [69] , [70] ]. Null of Gpx1 and Selenop [ 10 , 12 ] protected mice from adiposity and/or insulin resistance, whereas deficiencies of Dio2, Selenom, Selenot , and Selenof [ [13] , [14] , [15] , 69 ] exerted opposite impacts.…”

The clinical significance of glutathione peroxidase 2 in glioblastoma multiforme

“…Several studies have pointed out the association of GPX2 with GPCR. For example, Lennicke et al [ 25 ] found that the depletion of GPX2 downregulates the expression of leucine-rich repeat-containing GPCR 5 (Lgr5). Following receptor activation, the alpha- and beta-gamma subunits of G protein dissociate to activate the diverse downstream pathways in cellular polarization and actin reorganization, which are important functions for tumor formation and development [ 26 ].…”