Study On The Mechanism Of Chronic Arsenic Exposure Induced Abnormal Lipid Metabolism Through Endoplasmic Reticulum Stress In Mice

Objective:Arsenic is a definite carcinogen that exists in the environment.The liver is one of the important target organs of arsenic and an important place for the accumulation of metabolites.Now,the epidemiological investigation of arsenic and lipid metabolism is relatively extensive,but the specific mechanism of the increase of triglyceride,cholesterol and LDL in blood and the decrease of HDL caused by arsenic and lipid metabolism in liver are relatively rare.This study is intended to provide ideas for the study of arsenic-induced lipid metabolism abnormalities by studying whether NaAsO₂ exposure causes the functional changes of the INSIG-SCAP-SREBP complex through endoplasmic reticulum stress,resulting in abnormal adipogenesis in mice.Methods:Healthy 4-week-old C57BL/6J mice were randomly divided into dose groups:NaAsO₂（0,10,20,40 mg/L）;Treatment group:normal saline group,4-PBA inhibitor group,NaAsO₂ 40mg/L+normal saline group,NaAsO₂ 40mg/L+4-PBA inhibitor group,the duration of exposure was 12 weeks,and normal saline and 4-PBA were injected intraperitoneally,during which the drinking water,body weight,growth and development of mice were recorded;Collect serum and liver tissue samples of mice after exposure and intervention;The levels of total cholesterol and triglyceride in liver and serum of mice in each group were measured;The liver tissue of mice was stained with tissue sections to determine the accumulation of lipid in the liver of mice in each group;Western blot was used to detect the expression of fatty acid synthesis-related protein,endoplasmic reticulum stress signal protein and the expression of n SREBP in liver nuclei of mice in each group;The expression of INSIG-SCAP-SREBP complex in mouse hepatocytes was detected by immunoprecipitation;The difference was statistically significant at P<0.05.Result:（1）Long-term NaAsO₂ exposure and 4-PBA intervention had no significant effect on water consumption and body weight of mice;（2）Long-term exposure to NaAsO₂ can cause lipid accumulation in the liver of mice;（3）Long-term exposure to NaAsO₂ could cause the overexpression of the endoplasmic reticulum stress marker proteins GRP78 and CHOP in mice,which could be inhibited by the endoplasmic reticulum stress intervention agent 4-PBA,with a statistically significant difference（P<0.05）;（4）Long-term exposure to NaAsO₂ could increase the expression of FAS,ACC1 and SCD,which were related to fatty acid synthesis in mice.This process could be inhibited by the endoplasmic reticulum stress intervention agent 4-PBA,,with a statistically significant difference（P<0.05）;（5）Long-term exposure to NaAsO₂ can cause abnormal binding of INSIG-SCAP-SREBP,a lipid metabolism feedback regulatory complex in mouse hepatocytes,which can be inhibited by the endoplasmic reticulum stress intervener 4-PBA,with a statistically significant difference（P<0.05）;（6）Long-term exposure to NaAsO₂ could causes overexpression of n SREBP1 and n SREBP2,two isoforms of the mature sterol regulatory element binding protein n SREBP,in the nucleus of mouse hepatocytes,with statistically significant differences（P<0.05）;（7）Long-term exposure to NaAsO₂ could increase the content of TG and LDL in serum of mice,with statistically significant differences（P<0.05）.Conclusion:（1）Long-term NaAsO₂ exposure can cause lipid accumulation in liver tissue of mice;（2）Long-term NaAsO₂ exposure leads to dysfunction of INSIG-SCAP-SREBP complex through endoplasmic reticulum stress,which leads to abnormal fatty acid metabolism.