Effects And Mechanism Of Selenoprotein F Knockout On Glucose And Lipid Metabolism In High-fat-fed Aged C57/BL6 Mice

Selenium is a trace element that is necessary for human health,it mainly carrys out its biological function through selenoproteins in the form of selenocysteine.Selenoprotein F is one of 25 mammalian selenoproteins that have been reported.Selenoprotein F combines with UDP-glucose: glycoprotein glucosyltransferase(UGGT)to realize its residence in the endoplasmic reticulum.According to the current research results,selenoprotein F participates in the quality control process of protein folding in the endoplasmic reticulum in the form of molecular chaperones,and it even may catalyze the formation of disulfide bonds directly to participate in protein folding.The latest research found that knockout of selenoprotein F caused endoplasmic reticulum stress in mouse pancreas,and published studies have shown that long-term high-fat feeding can cause oxidative stress in mice.The current reports have not studied endoplasmic reticulum stress and oxidative stress in high-fat-fed selenoprotein F aged mice.We hypothesize that the liver cells and pancreas cells of high-fat-fed selenoprotein F knockout aged mice may be damaged under the combined action of endoplasmic reticulum stress and oxidative stress,leading to changes in glucose and lipid metabolism.10-12 weeks old selenoprotein F knockout male mice(using C57/BL6 mice as genetic Background mice)were fed with 45% fat content feedstuff for 32 weeks to construct an obese aged mouse model(42-44 weeks old).We used this model to study the effects of selenoprotein F gene knockout on glucose metabolism and lipid metabolism,endoplasmic reticulum stress and redox balance.The main results are as follows:(1)Using blood glucose detection,blood lipid kit detection,glycogen kit detection,q PCR,western blotting and other methods,we have studied the effects of selenoprotein F knockout on glucose and lipid metabolism in obese aged mice.The results showed that selenoprotein F knockout increased the liver glycogen content of aged mice(including normal and obese type),alleviated the blood glucose drop caused by long-term fasting(10hrs)in obese aged mice,and did not affect the insulin sensitivity of aged mice.Knockout of selenoprotein F in aged mice increased the cholesterol content in serum,increased the m RNA level of cholesterol synthesis genes in the liver,decreased the m RNA level of cholesterol synthesis genes in the liver,and increased N-glycosylation lipid metabolism protein carboxylesterase(Ces1d)and lipoprotein lipase(LPL)in the liver.(2)Using Western blotting and Tunel staining,we have studied the effects of selenoprotein F knockout on endoplasmic reticulum stress and endoplasmic reticulum stress-induced apoptosis in the pancreas and liver of obese aged mice.The results showed that selenoprotein F knockout activated the endoplasmic reticulum stress in the pancreas and liver of normal aged mice,and aggravated the endoplasmic reticulum stress in obese aged mice.The selenoprotein F knockout activated the apoptosis signal induced by endoplasmic reticulum stress in the pancreas and liver of aged mice.(3)Using biochemical kit detection such as glutathione peroxidase activity,glutathione and malondialdehyde,we have studied the effects of selenoprotein F knockout on the redox balance in the liver,spleen,kidney,heart and brain tissues of obese aged mice.The results showed that knockout of selenoprotein F had no effects on redox levels of the liver,spleen,kidney and heart in aged mice,but increased brain oxidation level in normal aged mice.In summary,knockout of selenoprotein F caused endoplasmic reticulum stress in the pancreas and liver of aged mice and activated the apoptosis signal induced by endoplasmic reticulum stress,which in turn affected the glucose metabolism and lipid metabolism in aged mice.In addition,knockout of selenoprotein F also increased the level of oxidation in the brain of normal aged mice.In this study,we made a further inquiry on the biological function of selenoproteins F,our results may provide certain theoretical basis for the prevention of age-related diseases such as hyperglycemia and hyperlipidemia.