UNDERSTANDING OF FUNCTIONS OF SELENOPROTEINS AND DIETARY SELENIUM BY USING ANIMAL MODELS

Abstract

Selenium (Se) is a trace element that is incorporated into proteins in the form of the 21st amino acid, selenocysteine (Sec). Se supplementation was reported to have beneficial roles in prevention of cardiovascular and muscle disorders, cancer prevention and enhancement of the immune function. However, recent studies also showed that excessive dietary Se increases the risk of development of type 2 diabetes mellitus. Thus, better understanding of Se and selenoprotein functions is required. We used three approaches to address this problem. First, we used high-throughput sequencing to examine composition of the gut microflora in mice maintained on selenium-deficient, selenium-sufficient, and selenium-enriched diets, and then link information to selenoprotein expression and function. Our data indicate that Se supplementation affects both the composition of the intestinal microflora and the colonization of the gastrointestinal tract in germ-free mice, which in turn, influence the host selenium status and selenoproteome expression. Second, we characterized the phenotype of the 15 kDa selenoprotein (Sep15) knockout (KO) mice. Sep15 is a thioredoxin-like, endoplasmic reticulum (ER)-resident protein involved in the quality control of glycoprotein folding through its interaction with UDP-glucose:glycoprotein glucosyltransferase. We found that Sep15 KO mice develop nuclear cataracts at an early age. We suggest that the cataracts resulted from improper folding status of lens proteins caused by Sep15 deficiency. Third, we evaluated the role of Se and selenoproteins in naked mole rat (MR) Heterocephalus glaber, a rodent model of delayed aging due to its unusually long lifespan (\u3e28 years). Tissue imaging by X-ray fluorescence microscopy and direct analyses of trace elements revealed low levels of selenium in the MR tissues. Metabolic labeling of MR cells with 75Se followed by sequencing and assembly of the MR transcriptome revealed the loss of expression of glutathione peroxidase 1 (GPx1), whereas expression of other selenoproteins was preserved. Thus, MR is characterized by reduced utilization of selenium due to a specific defect in GPx1 expression. Overall, the use of rodent models allowed us to obtain insights into interplay of dietary selenium, gut microbiota, and expression and function of several selenoproteins. Advisors: Vadim N. Gladyshev, Dmitri E. Fomenk