The Effect And Mechanism Of Liraglutide On Type2Daibetic Non-alcoholic Fatty Liver

Objective:Liraglutide as a novel antidiabetic drug has been widely used in clinical treatment.More and more evidences showed that Liraglutide plays a role in other fields besides anti-hyperglycemia. For example liraglutide has protective effect on endothelia cells and it could also inhibit inflammatory cytokine production by diabetic kidneys. It was reported recently, Liraglutide can significantly reduce the amount of lipids in the liver of diabetic rats, and reduce diabetic rat liver steatosis. Basic fibroblast growth factor-19(FGF-19) and FGF-21were newly reported adipokines secreted mainly by gut and liver cells respectively. Both of them play important role in glucose and lipid metabolism especially on energy metabolism in liver. In this study we planned to identify whether liragrutide affect blood levels of FGF-19and FGF-21and then activate AMPK pathway to further regulate critical enzymes related to lipids metabolism.Methods:High glucose and high fat food feeding and small dose of STZ injection were used to build diabetic non-alcoholic fatty liver diseases (NADLDs) rat models. The levels of blood glucose, TG, TC, fasting insulin was detected, as well as serum FGF-19and FGF-21were measured by ELISA. The liver index was calculated. HE staining and Red oil staining were used to measure the changes of diabetic liver and amount of lipids in liver. The relationship between blood levels of FGF-19, FGF-21and other biochemic indexs were analyzed. Real-time PCR and western blot were use to clarify the expression on CREBH, PPAR-a which were the transcript activators of FGF-19and FGF-21.The expression of FGFRs were measured as well.We further detected the activation status of AMPK pathway and the expression of lipid metabolism critical enzymes in liverResults:1. Liraglutide could significantly reduced the levels of blood glucose, TG, TC and markedly ameliorate body weight as well as liver index.2. There was significant liver steatosis in diabetic rats, while Liraglutide could decrease the scores of inflammatory activity in liver and lipid amount in liver cells and significantly reduced liver steatosis. 3. Liraglutide could increase the levels of blood FGF-19and FGF-21.It also promoted the expression of FGF-21in liver4. The levels of blood FGF-19and FGF-21were negatively related to the levels of TG, TC as well as liver steatosis.5. The expression levels of CREBH、PPAR-a were decreased in diabetic liver while Liraglutide could partly restore the expression of CREBH、PPAR-a in liver.6. Liraglutide could increase the expression of FGFRs in diabetic livers.In high dose liraglutide group the expression levels of FGFR1,FGFR3,FGFR4was increased by57%、49%、82%respectively.While there were no significant difference between each group.7. Liraglutide could up-regulated the expression of AMPKal while there was no statistic significant difference for AMPKa28. Liraglutide could obviously promote lipid acid oxidation critical enzyme CPT-1mRNA expression and inhibit lipid synthesis critical enzymes FAS、SREBP-1、 HMGR mRNA expression.9. Liraglutide could markly promote the levels of blood FGF19,FGF21as well as L/S ratial in type2diabetic patients.Conclusions:Liraglutide could play a protective role on NAFLD through increasing the levels of blood FGF19and FGF-21,up-regulation the expression of FGFRs then to activate AMPK pathway and further to regulate lipid metabolism critical enzymes expression.