The Effect And Mechanism Of IL-6 In Exercise-induced Improvement In Nonalcoholic Fatty Liver Disease

Background:Nonalcoholic fatty liver disease(NAFLD)is one of the most common chronic liver diseases.The prevalence rate of NAFLD is increasing year by year,but effective drugs to treat NAFLD are lacking.Exercise is considered to be the most cost-effective treatment.During exercise,skeletal muscle can secrete a variety of myokine to participate in the regulation of the body.Interleukin-6,as a myokine,has been proved to be involved in the protective regulation of exercise on a variety of metabolic diseases.However,the effect of IL-6 in exercise-induced improvement in nonalcoholic fatty liver disease is not fully clear.Objective:Through the study of this topic,we can further confirm the effect of exercise in the improvement of NAFLD and on the expression of IL-6 regulation,fully prove whether IL-6 mediates the improvement of exercise on NAFLD and deeply elucidate of the relevant molecular mechanisms.Methods:Experiments were carried out in 8-10 week old male IL-6 KO and WT littermate control mice and they were randomly divided into normal diet control group,high-fat diet model group and high-fat diet exercise group.The normal diet control group was given ordinary diet,the high-fat diet model group and the high-fat diet exercise group were given high-fat diet.After 20 weeks,the high-fat diet exercise group was trained on the treadmill at 12m/min,l hour/day,5days/week,for a total of 8 weeks.The changes of body weight and blood glucose in mice were monitored,and the blood,liver and adipose tissue were collected to detect.Results:Exercise could improve insulin resistance,elevation of plasma cholesterol and triglyceride induced by high-fat diet,but there was no significant difference of the improvement between IL-6 KO mice and wild-type mice.In wild type mice,exercise significantly improved ballooning,inflammatory cell infiltration and triglyceride accumulation in liver tissue,but in IL-6 KO mice,Exercise only partially improved ballooning,inflammatory cell infiltration and triglyceride accumulation in liver tissue,there were significant differences between IL-6 knockout mice exercise group and wild type mice exercise group.The results of related genes and proteins showed that the improvement of liver lipid accumulation by exercise was possibly achieved by IL-6 via down-regulating PPARy and its downstream lipid transport related gene CD36 and lipid droplet formation related gene Fsp27.The improvement of inflammation by exercise is possibly achieved by IL-6 via down-regulating chemokine MCP1 to reduce intrahepatic macrophage recruitment.In addition,compared with IL-6 knockout mice,exercise had a more significant down-regulation of visceral adipose tissue weight and subcutaneous adipose tissue weight in wild-type mice.Further study on the molecular mechanism confirmed that IL-6 mediated the up-regulation of lipolysis related genes(ATGL and HSL)and energy metabolism related genes(PGC-1 a and UCP1)in subcutaneous adipose tissue and visceral adipose tissue.Conclusion:IL-6 can partly mediate exercise-induced improvement in nonalcoholic fatty liver disease.The mechanism may be that IL-6 on one hand reduces intrahepatic lipid accumulation by down-regulating PPARγ and its downstream gene CD36 and Fsp27,on the other hand,reduces the accumulation of inflammatory cells in the liver by down-regulating MCP1 to mediate exercise-induced improvement in nonalcoholic fatty liver disease.In addition,IL-6 also promoted lipolysis and browning of white adipose tissue by upregulating lipolysis related genes(ATGL and HSL)and energy metabolism related genes(PGC-1α and UCP1).