Pharmacodynamic Study Of FTZ Modulation Of Liver-gut Axis To Improve Liver Pathological Injury In NASH Mice

Background: Non-alcoholic fatty liver disease(NAFLD)has become the most common and highly prevalent metabolic liver disease in clinical practice.It can transform from simple NAFLD to non-alcoholic steatohepatitis(NASH),which can progress to liver fibrosis,cirrhosis,and even hepatocellular carcinoma,and has become a serious public health problem worldwide.In particular,NASH has become a significant event in liver transplantation and death from liver disease.However,there are no effective treatments or drugs for NAFLD in clinical practice.As an innovative Chinese medicine for the treatment of glucolipid metabolic diseases,Fuzhengzhi Lipid Regulating Capsules(FTZ)has achieved excellent performance in previous basic research and clinical practice and is a promising candidate for the treatment of NASH.Method: We used a high-fat diet(HFD)-induced obese mice to establish an in vivo NASH model and observed the effects of FTZ on their systemic metabolic homeostasis by monitoring body weight changes,body fat rate,and blood glucose levels.In addition,we observed the effects of FTZ on liver lipid deposition,metabolic inflammation,and progressive liver fibrosis in NASH mice by means of histopathological staining,serum biochemical and molecular biology experiments,as well as the restoration of intestinal mucosal barrier function.Finally,we used 16 S r DNA gene sequencing together with metabolomics to resolve the material basis of FTZ to restore intestinal microecological disorders in NASH mice.Results: The results of NASH mice showed that FTZ effectively reduced HFD-induced increase in body weight and body fat percentage and improved insulin resistance in NASH mice.Follow-up experiments showed that FTZ effectively improved the homeostatic imbalance of hepatic lipid metabolism in NASH mice,mainly by reducing hepatic and serum triglyceride levels,improving histopathology,lowering serum transaminase levels,and restoring dysregulated expression of lipid metabolism gene clusters.In addition,FTZ similarly attenuated hepatic metabolic inflammation and progressive liver fibrosis in NASH mice,reducing the expression of inflammation and fibrosisrelated factor genes and proteins.Finally,FTZ restored HFD-induced intestinal mucosal barrier damage in mice,increased the expression of tight junctionrelated molecules,inhibited intestinal inflammation and modulated abnormal lipid transport,and restored intestinal microecological structure and metabolite disorders in NASH mice.Conclusion: FTZ could effectively improve the systemic metabolic stress,hepatic steatosis,metabolic inflammation,and progressive liver fibrosis in NASH mice with disorders of glucolipid metabolism,which may be achieved by restoring intestinal mucosal barrier function and regulating intestinal flora homeostasis.FTZ may be a potential drug for the treatment of NASH.