The Role And Mechanism Of Znf638 In Liver Glucose And Lipid Metabolism

Background and Objective:Glucose and lipid metabolism are an indispensable process for cells and organisms.The liver plays a key role in regulation of systemic metabolic homeostasis.Previous studies have shown that zinc finger protein Znf638 was identified as a novel coactivator with domain homology to Pgc-1α and regulated adipogenesis.The purpose of present study is to investigate the effect and mechanism of Znf638 in hepatic glucose and lipid metabolism,providing new ideas for the study of non-alcoholic fatty liver disease(NAFLD).Materials and methods:1.A variety of NAFLD models characterized by lipid accumulation in the liver were established,including animal and cell models.We isolate the livers of wild type mice fed with high-fat diet(HFD)and fasted for 24 hours to extract RNA.In addition,we isolated the primary liver cells of wild-type mice fed a normal diet,collect the cells after treatment with palmitic acid(PA)and glucose combined with insulin,and detect the expression of Znf638 and glycolipid related genes in the above samples using qPCR to investigate the relationship between Znf638 and hepatic glycolipid metabolism.2.The Znf638 liver-specific knockout mice were constructed and then was fed an HFD diet.The insulin sensitivity was measured using insulin tolerance test(ITT)and glucose tolerance test(GTT).Pyruvate tolerance test(PTT)was used to detect the ability of hepatic glucose production.qPCR or Western Blot were used to detect the gene expression of glucose and lipid metabolism.The biochemical parameters were detected by Commercial kits.3.Methionine-choline-deficient diet(MCD)was used to induce non-alcoholic steatohepatitis(NASH)in mice.The ALT and AST levels were detected by biochemical methods.Results:1.The mRNA level of Znf638 significantly increased in HFD-fed mice,feeding-starvation model and PA-treated cell.The gluconeogenesis and lipid metabolism gene mRNA expression also significantly increased.In the cell model treated with high glucose and insulin,mRNA expression of Znf638 and gluconeogenic genes significantly decreased.Meanwhile,the mRNA expression of de novo synthesis genes significantly increased.2.Compared to the control,physical parameters,blood lipid levels,liver TG and liver pathology in the Znf638 liver-specific knockout mice showed no difference.In addition,the mRNA expression of lipid metabolism related gene was significantly downregulated.The insulin sensitivity in the Znf638 liver-specific knockout mice was improved,and the mRNA and protein level of G6Pase and Pepck gene were significantly decreased.3.Znf638 liver-specific knockout mice on an MCD diet had high ALT and AST levels,aggravated liver fibrosis,and increased mRNA expression of genes involved in inflammation and fibrosis.Conclusion:Our finding showed that the Znf638 gene did not influence hepatic lipid metabolism in HFD-fed mice,however,it inhibits hepatic gluconeogenesis by downregulating the expression of G6Pase and Pepck.In addition,deletion of hepatic Znf638 aggravated hepatic inflammation and fibrosis in MCD-fed mice.