Roles for selenium and selenoprotein P in the development, progression, and prevention of intestinal disease

Abstract

Selenium (Se) is a micronutrient essential to human health, the function of which is mediated in part by incorporation into a class of proteins known as selenoproteins (SePs). As many SePs serve antioxidant functions, Se has long been postulated to protect against inflammation and cancer development in the gut by attenuating oxidative stress. Indeed, numerous studies over the years have correlated Se levels with incidence and severity of intestinal diseases such as inflammatory bowel disease (IBD) and colorectal cancer (CRC). Similar results have been obtained with the Se transport protein, selenoprotein P (SELENOP), which is decreased in the plasma of both IBD and CRC patients. While animal models further suggest that decreases in Se or SELENOP augment colitis and intestinal tumorigenesis, large-scale clinical trials have yet to show a protective effect in patient populations. In this review, we discuss the function of Se and SELENOP in intestinal diseases and how research into these mechanisms may impact patient treatment.

Keywords: Colitis; Colitis-associated carcinoma; Colorectal cancer; Selenium; Selenoprotein P; Selenoproteins.

Figure 1. SELENOP’s role in Se transport

SELENOP contains 10 Sec residues (U; white circles): one in an N-terminal redox domain (red outline) and 9 in a C-terminal Se transport domain (brown outlines). Extracellular SELENOP can bind to megalin or apoER2 receptors. After binding to apoER2, the receptor is endocytosed and SELENOP is lysosomally degraded. The freed Sec then undergoes a series of metabolism steps by selenocysteine lyase (SCLY) and selenophosphate synthetase (SPS2) to yield hydrogen selenide (HS; H₂Se) and monoselenophosphate (MSP; H₂O₃PSe). The monoselenophosphate then serves as the Se donor to convert a tRNA-associated serine into Sec for incorporation into nascent selenoproteins. Sec insertion is also mediated by a 3′ SECIS sequence in SeP mRNA that recruits the Sec-tRNA and dedicated transcription factors such the as Sec-tRNA specific elongation factor (EFSec) and SECIS-binding protein 2 (SBP2).

Figure 2. Additional roles proposed for SELENOP

SELENOP can be synthesized by intestinal epithelial cells and has been found experimentally to inhibit WNT and TGF-β signaling pathways, as well as modify secretion of cytokines such as TNF-α. Secreted SELENOP can also serve as an extracellular antioxidant in the tissue microenvironment. However, much is unknown about SELENOP’s expression patterns and functions in the intestine, such as whether SELENOP binds additional LRP receptors or modifies receptor-mediated signaling, which isoforms are expressed, and whether SELENOP has additional roles in intracellular signaling pathways.