The Mechanism Of G0S2 In The Pathogenesis Of Non-alcoholic Fatty Liver Disease And Its Role In Metformin Treatment

Objective The study mainly explored the mechanism of G0S2 in the pathogenesis of NAFLD and metformin treatment,found the relationship between G0S2 and the pathogenesis of NAFLD,therefore providing the theoretical basis for the treatment of NAFLD.Methods First we examined the expression levels of endoplasmic reticulum stress related protein and G0S2 in high fat diet induced fatty liver model and ob/ob mice fatty liver model as well as the human hepatic tissue of people in the non-alcoholic fatty liver disease.Then we detected the expression of G0S2 after endoplasmic reticulum stress agonist Tm and inhibitor TUDCA changed the endoplasmic reticulum stress “on and off”.silence ATF4 or ATF6 pathway in HepG2 cell or use primary hepatic cell in IRE1α LKO mice to detect which endoplasmic reticulum stress signal path specificly or whether the three all mediated the regulation of G0S2.Dual luciferase report gene detection was implied to assay the regulation of ATF4 on G0S2 promoter and findout the exact regulation area on its promoter.At the same time Giving merformin treatment to ob/ob mice to detect the mechnism of G0S2 in metformin’s improvement on nonalcoholic fatty liver disease.Results The activation of endoplasmic reticulum stress and the up-regulation of G0S2 during the process of fatty liver development in high fat diet induced fatty liver model and ob/ob mice fatty liver model as well as the human hepatic tissue of people in the non-alcoholic fatty liver disease.Endoplasmic reticulum stress inhibitors TUDCA could reverse the up-regulation of G0S2 by endoplasmic reticulum stress.All of these suggested that endoplasmic reticulum stress may participate in the regulation of G0S2.PERK-eIF2α-ATF4 signaling pathways may regulate the expression of G0S2 and ATF4 can directly combine the core sequence "TTGCAT" area at G0S2 promoter and trans-activate the expression of G0S2.G0S2 inhibited the activity of ATGL to decrease triglycerides decomposition,promote the occurrence of lipid accumulation in the liver.These results are a good explain about the phenotype of G0S2 transgenic mice who showed the progressive obesity and fatty liver disease.These results suggested that G0S2 gene as a directly target gene of the PERK-eIF2α-ATF4 pathway played a key role in the pathogenesis of NAFLD,which further enrich the mechnism of endoplasmic reticulum stress in the pathogenesis of nonalcoholic fatty liver and provide new targets for the treatment of nonalcoholic fatty liver disease.SREBP1 c and G0S2 expression decreased following the treatment of merformin in ob/ob mouse liver tissue and HepG2 cells,which was reversed by Compound C.Conclusion G0S2 gene as a directly target gene of the PERK-eIF2α-ATF4 pathway played a key role in the pathogenesis of NAFLD.Besides G0S2 regulated by AMPK-SREBP1 c pathways may mediate the improvement of metformin on NAFLD.