Expansion Of New Indication NASH Of Candidate Hypoglycemic New Drug LSH01

Background:Non-alcoholic fatty liver disease(NAFLD)refers to a clinicopathological syndrome characterized by excessive lipid accumulation in the liver after the elimination of excessive alcohol intake and other factors that can cause liver damage.It is the most common chronic liver disease.Among them,non-alcoholic steatohepatitis(NASH),which is characterized by hepatocellular bullous steatosis with hepatocyte damage and lobular inflammation,is more likely to develop into cirrhosis.The incidence of NASH is increasing year by year around the world,but there is currently no drug approved by the FDA or EMA on the market,and the huge treatment needs of patients cannot be met.Regarding the pathogenic mechanism of NASH,scholars currently recognize the "multiple hit" theory,which is believed to be caused by multiple factors,such as obesity and metabolic syndrome,dysfunction of adipose tissue cell,disorder of intestinal microbiota,functional changes of Kupffer cell and hepatic stellate cell,and ions overload,promote the occurrence and development of diseases in parallel.Glucagon-like peptide-1(GLP-1)is a polypeptide secreted by endocrine cells in the ileum.It can exert its physiological effects by acting on GLP-1 receptors.It is currently mainly used as a medicine for type 2 diabetes(T2 DM).In addition to the stable and safe hypoglycemic effect and pancreatic islet protection,GLP-1 also has a wide range of metabolic regulation effects,such as appetite control and weight reduction,as well as a certain reduction in blood lipids and hepatic lipid.At present.Novo Nordisk’s GLP-1 receptor agonists,Liraglutide and Semaglutide,have completed phase 2 clinical trials.Compared with placebo,they can significantly improve or even eliminate the patients’ histological symptoms of NASH without aggravating liver fibrosis.In the preliminary study of our laboratory,LSH01 is a candidate compound for a new hypoglycemic drug.When it is used in the chronic treatment of db/db diabetic mouse model,it is found that it has a significant hypoglycemic effect and can improve insulin sensitivity.At the same time,LSH01 can improve lipid accumulation and inflammation in the liver of db/db mice.When investigating the mechanism of this drug effect,it was found that LSH01 has a good effect of promoting GLP-1 secretion at the level of cells and animals in vivo and in vitro,and its hypoglycemic effect can be blocked by the GLP-1 receptor antagonist(Exendin 9-39).preliminarily indicating that the efficacy of LSH01 on diabetic mouse models is achieved by promoting the secretion of GLP-1.Purpose:Combining the effects of LSH01 on improving insulin sensitivity,liver lipid accumulation and inflammation in mice,we plan to evaluate the efficacy of compound LSH01 on new indications of NASH in different animal models.Method:This project constructs the insulin resistance phenotype of c57 mice induced by short-term high-fat diet(HFD)feeding,the NASH model of mice induced by HFD combined with streptozotocin(STZ)c57,and carbon tetrachloride(CCl4)induced mouse liver fibrosis model,the efficacy of compound LSH01 is evaluated on the three levels of insulin resistance phenotype,overall NASH model,and fibrosis model.Oral glucose tolerance,insulin tolerance and other indicators are evaluated during treatment,and each is evaluated after treatment.The improvement of model serological indexes,fat accumulation degree or fibrosis indexes.Results:The chronic administration of compound LSH01 improved oral sugar tolerance and insulin tolerance in short-term high-fat mice,and significantly improved metabolic disorders and related indicators caused by high-fat feeding.In the NASH model of mice induced by high-fat combined STZ,the compound LSH01 showed some improvement effect on liver inflammation and lipid accumulation abnormalities.In the CCl4-induced mouse liver fibrosis model,the compound LSH01 can significantly improve the level of fibrosis marker genes,but no improvement effect is seen at the level of hydroxyproline and histopathology.The results suggest that the efficacy of compound LSH01 for NASH may be derived from the relief of metabolic stress without aggravating fibrosis.Conclusion:The compound LSH01,as a GLP-1 pro-secretion agent,has the potential to treat NASH,its long-term administration can reduce liver fat deposition,improve inflammation,reduce blood lipid levels and liver fibrosis gene levels,and regulate imbalance of intestinal flora.The results of this study can provide a theoretical basis for GLP-1 pro-secretion agents to improve NASH.