The Regulatory Effect And Mechanism Of SelT Gene Knockout On Lipid Metabolism And Insulin Resistance

Selenin T（SelT）is a thioredoxin with important oxidoreductase activity.SelT is located in the endoplasmic reticulum and participates in redox reactions through metabolic pathways to control homeostasis and cell survival.It has been found that conditional knockout of SelT in the brain can cause elevated levels of oxidative stress in tissues and aggravate Parkinson’s disease;conditional knockout of SelT in the pancreas can cause damage to pancreatic tissue and cause impaired glucose tolerance.Therefore,SelT also has a certain relationship with metabolic diseases such as diabetes and fatty liver.To explore this relationship,we constructed SelT systemic knockout mice to study the relationship between SelT gene and glycolipid metabolism.This has important scientific significance and application value for revealing the role of SelT in metabolic diseases such as diabetes and fatty liver.This article first describes the function of known selenoproteins,glycolipid metabolism,oxidative stress,insulin signaling pathway and insulin resistance in the liver.On this basis,the effects of systemic knockdown of SelT gene on glycolipid metabolism were investigated in normal normal physiological models and obesity models.The main results are as follows:（1）The effects of SelT gene knockout on glucose and lipid metabolism in mice under normal physiological conditions were studied by QPCR and Western blotting.The results showed that under normal physiological conditions,the daily intake of mice after SelT gene knockout decreased significantly,the random blood glucose decreased significantly,and the fasting blood glucose decreased significantly.The glucose clearance ability of SelT knockout mice was significantly enhanced,the insulin sensitivity was significantly improved,the pyruvate tolerance was significantly decreased,the liver glycogen content of mice was significantly increased,and the G6PASE and PEPCK gene contents were significantly decreased.After the SelT gene knockout,the islet shape in the mouse pancreas was small and irregular,and the contents of MAFA,PDX1 and PPINS1 were significantly decreased.The phosphorylation levels of IR,Akt,FoxO1 and GSK-3βwere significantly increased in mice.The ratio of GSH/GSSG in the liver of mice was significantly increased,the content of MDA was significantly increased,the degree of carbonylation of white matter was significantly increased,and the content of H₂O₂ in muscle was significantly increased.After SelT knockout,the TG,TC in the serum of the mice decreased significantly,and the LDL-C decreased significantly.However,there was no difference in TG,TC,and liver HE staining in the liver of the mice after knockout,and there was no lipid accumulation;in the adipose tissue section staining,the fat cell size did not change significantly.These results indicate that SelT knockdown enhances the mouse insulin signaling pathway under normal physiological conditions but has no effect on steatosis.（2）The effects of SelT gene knockout on glucose and lipid metabolism in obese model mice were studied by QPCR and Western blotting.The results showed that fasting blood glucose was significantly decreased in obese mice after SelT gene knockout,glucose tolerance was improved,and insulin sensitivity was enhanced.After knockout,the serum insulin content and insulin resistance index of mice were significantly decreased.The shape of the pancreas of the knockout group was significantly smaller and the number was increased.Fluorescence staining of the pancreas showed a decrease in insulin content in the knockout group.TUNNEL staining showed that the number of dead cells in the pancreas of the knockout group increased significantly.In the knockout group,the degree of phosphorylation of AKT was increased in the liver,and the degree of AKT phosphorylation was increased in the KO+HFD group.The GSSG content in the liver of the knockout group was significantly decreased,and the GSH content was slightly increased but there was no significant difference.The GSH/GSSG ratio increased to some extent but there was no significant difference,the MDA content increased significantly,and the protein carbonylation increased significantly.In the knockout group,the serum TC decreased to a certain extent,and the LDL-C content decreased significantly,but the HDL-C did not change significantly,and the TG and TC contents in the liver were significantly decreased.In the knockout group,the white lipid droplets in the liver tissue were significantly reduced,the oil red O staining was alleviated,and the shape of white fat cells was not significantly changed.After knockout,the FAS in the liver decreased to some extent,SREBP-1c showed no significant change,PPARαincreased significantly,IL-1B and TNFαlevels decreased significantly,and IL-6 and MCP1 also decreased to some extent.These results indicate that SelT gene knockdown can alleviate lipid accumulation in the liver and enhance insulin signaling pathway.