The Role And Mechanism Of SGLT2 Inhibitors In The Prevention And Treatment Of Non-alcoholic Fatty Liver Disease

Background and ObjectiveNon-alcoholic fatty liver disease(NAFLD)is the most common chronic liver disease in the world,which affects ~25% of the adult population worldwide.It is closely related to metabolic syndromes such as type 2 diabetes(T2DM),obesity,and insulin resistance(IR).T2 DM patients have a higher prevalence of NAFLD than the general population.So far,NAFLD has no specific effective treatment.Sodium-glucose cotransporter 2(SGLT2)inhibitors,which are known to reduce blood glucose by inhibiting the reabsorption of renal glucose and promoting the excretion of urine glucose,are a kind of novel anti-diabetic drugs for the treatment of type 2 diabetes and clinical research showed that the heart and kidney benefits were obvious.At present,some clinical studies have shown that SGLT2 inhibitors can reduce weight,improve fasting blood glucose,hepatic steatosis and liver fibrosis.However,related experimental researches on NAFLD were rare.Therefore,the purpose of this study aimed to explore the effects and mechanisms of SGLT2 inhibitors on NAFLD.MethodsEight-week-old male C57BL/6J and ob/ob mice were used as subjects.Model one: C57BL/6J received a 16-week high fat diet to induce mouse model of NAFLD.After the diet induction,each dietary intervention was randomly divided into 2 groups,and was administered with SGLT2 inhibitor empagliflozin(EMPA)or an equivalent amount of co-solvent hydroxyethyl cellulose as a control for 4 weeks.Model two: ob/ob mice and wild-type control mice were randomly divided into 2 groups(n=7-8),and were administered with empagliflozin or the same amount of cosolvent for 4 weeks.The body weight,blood glucose,and food intake were monitored every weeks,and abdominal glucose tolerance and insulin sensitivity tests were performed at the end of the intervention.24 h urine volume was collected in a mouse metabolic cage.In the end,the mice were anesthetized with isoflurane,and liver samples were collected and weighed.The morphology of liver was observed by HE staining.Liver fat deposition was detected by oil red O staining.Liver tissue fibrosis were detected by Sirius red staining.The mRNA and protein related to liver lipid metabolism,inflammation,and fibrosis were examined by Real-time PCR and Western Blot.Results(1)Empagliflozin treatment alleviated glucose tolerance and insulin resistance in DIO mice and ob/ob mice,while reduced body weight in DIO mice.(2)Empagliflozin treatment promoted urine glucose excretion and increased water intake and urine volume in DIO mice and ob/ob mice.(3)Empagliflozin treatment improved liver lipid metabolism in DIO mice,but not in ob/ob mice.(4)Empagliflozin treatment improved inflammation and fibrosis of liver tissue in DIO mice.ConclusionSGLT2 inhibitors not only improve glucose metabolism in DIO and ob/ob mice,but also improve obesity-related lipid metabolism disorders in DIO mice.Moreover,SGLT2 inhibitors could alleviate liver inflammation and fibrosis in DIO mice.This study will provide strong theoretical support and basis for the clinical treatment of SGLT2 inhibitors for diabetes with NAFLD.Background and Objective Non-alcoholic steatohepatitis(NASH)is a progressive stage of NAFLD.NASH can progress to liver fibrosis,cirrhosis and hepatocellular carcinoma.It is unclear whether SGLT2 inhibitor could attenuate nonalcoholic steatohepatitis(NASH).Therefore,this study aimed to explore the effect and mechanism of SGLT2 inhibitor Canagliflozin on NASH.Methods Eight-week-old male ob/ob mice were induced by methionine and choline deficiency(MCD)diet to establish NASH animal models.ob/ob mice were randomly divided into three groups: chow diet group,MCD diet group,MCD diet + Canagliflozin group(CANA).Dietary intervention and Canagliflozin intervention were carried out simultaneously for 8 weeks.The body weight,blood glucose and food intake of the mice were monitored every week,and abdominal glucose tolerance and insulin tolerance tests were performed to evaluate the sensitivity of insulin at the end of the intervention.In the end,the mice were anesthetized with isoflurane,and liver samples were collected and weighed.The morphology of liver was observed by HE staining.Liver fat deposition was detected by oil red O staining.Liver tissue fibrosis were detected by masson and Sirius Red staining.The m RNA and protein related to liver inflammation,and fibrosis were examined by Real-time PCR and Western Blot.Results(1)ob/ob mice which were induced by MCD diet showed significant cachexia;(2)Canagliflozin improved liver inflammation and fibrosis in the ob/ob mouse model by MCD diet induced.Conclusion Canagliflozin improved inflammation and fibrosis of liver tissues in ob/ob mice by MCD diet-induced.This study will provide possibilities for SGLT2 inhibitors to treat NASH.