The Regulatory Effect And Mechanism Of Selenoprotein T On Glucose And Lipid Metabolism

Type 2 diabetes mellitus(T2DM)is a chronic metabolic disease that not only threatens human health,but also increases the global economic burden.Some trace elements in minerals have potential insulin-like effects and glycemic control effects,which are directly involved in the treatment of T2 DM.Selenium is an essential trace element in human body and has insulin-like effects.Selenium performs an important biological function through selenoprotein.The two sides of selenium in the development of diabetes mellitus have been proved to be closely related to several selenoproteins,including selenoproteins P,selenoproteins S,and glutathione peroxidase 1.Selenoprotein T(SELENOT),as a thioredoxin-like enzyme,plays an important role in oxidoreductase activity in the endoplasmic reticulum.However,there are few studies on the relationship between SELENOT and glucose metabolism.The relationship between SELENOT and lipid metabolism and T2 DM is still unclear.Therefore,in this study,adenovirus-mediated SELENOT overexpression models were used to explore the relatisohip between SELENOT and glycolipid metabolism in vitro and in vivo.In addition,a conventional global Selenot knockout(KO)mouse model was used in this study.Then Tandem mass tag(TMT)proteomics analysis was conducted to explore the differentially expressed proteins(DEPs)in the liver and pancrease of male mice.The main results are as follows:(1)HepG2 cells were used to investigate the effect of SELENOT overexpression on palmitic acid-induced insulin resistance in vitro.The results showed that overexpression of SELENOT could improve insulin signaling pathway transduction and lipid accumulation in Hep G2 cells under insulin resistance.Adenovirus-mediated liver SELENOT overexpression was used in C57BL/6J mice to study the regulatory effect of liver specifical overexpression on glucose and lipid metabolism under normal diet.The results showed that the fasting blood glucose and body weight were decreased after SELENOT-overexpressed,but the food intake was increased.SELENOT overexpression increased glucose clearance,improved insulin sensitivity,and inhibited gluconeogenesis in liver,but had no significant effect on lipid metabolism.T2 DM model mice induced by high fat diet(HFD)were used to investigate whether hepatic SELENOT overexpression could improve glucose and lipid metabolism and its possible mechanism.The results showed fasting blood glucose was significantly reduced,glycogen content and glucose clearance rate in liver were increased,insulin sensitivity was improved,and gluconeogenesis was inhibited after SELENOT overexpression.In the aspect of lipid metabolism,hepatic lipid accumulation was improved,serum lipid levels were decreased,and adipose tissue cell size was decreased after SELENOT overexpression.The protective effect of SELENOT on glycolipid metabolism disorders was realized by improving endoplasmic reticulum stress.(2)Hepatic proteomics analysis in male Selenot-KO mice was performed by TMT technology,which was also used for the explanation of the phenotype in KO mice.TMT proteomics analysis showed 60 up-regulated and 94 down-regulated DEPs in the liver of male Selenot-KO mice.The increased expression of glycogen synthase 2 was consistent with the hypoglycemic phenotype in KO mice.The decrease in type 1 iodothyronine deiodinase expression was consistent with the phenotype of body weight loss in KO mice.Furthermore,the bioinformatics analysis showed that Selenot-KO-induced DEPs were mainly related to lipid metabolism,cancer,peroxisome proliferator-activated receptor(PPAR)signaling pathway,complement and coagulation cascades,and protein digestion and absorption.(3)Pancreatic proteomics analysis in Selenot-KO mice was performed by TMT technology.TMT proteomics analysis revealed 21 up-regulated and 46 down-regulated DEPs in KO mice.The reduced inslin 2 protein/m RNA level and insulin-like growth factor 2 m RNA-binding protein 2 protein level are consistent with the reduced insulin secretion and reduced body weight as well as infertility in KO mice,respectively.Moreover,the elevated protein levels of mitogen-activated protein kinase kinase kinase 11 and reactive oxygen species modulator 1 are consistent with the smaller islets in KO mice.The bioinformatics analysis suggested that DEPs caused by Selenot KO were mainly related to prostate cancer,non-alcoholic fatty liver disease,regulation of lipolysis in adipocytes,and some immunologic process,suggesting SELENOT are involved in cancer,disorders of lipid metabolism as well as disorders of immune process.