Liraglutide Improves Non-alcoholic Fatty Liver Disease In Diabetic Mice Through Inflammatory Signaling Pathway

In recent years,with the rapid increase in the prevalence of type 2 diabetes(T2DM),the incidence of nonalcoholic fatty liver disease(NAFLD)has also increased.In addition,NAFLD significantly increases the risk of T2 DM events.T2 DM may also contribute to the progress of NAFLD.Liraglutide is a glucagon-like peptide-1(GLP-1)analogue which has been recognized for its ability to reduce body weight and improve insulin resistance,but the specific mechanism is not clear.This has made the detailed mechanisms elucidating the development of pharmacological treatment and disease progression more urgent.Many chronic metabolic diseases such as T2 DM,obesity,hypertension,and atherosclerosis,are closely related to the chronic low-grade inflammatory state of tissues.A large body of evidence supports the role of inflammatory factors in metabolic disorders.Inhibition of inflammatory signaling pathways is associated with improved insulin sensitivity.In this study,we investigated the role of GLP-1 in improving the glucose and lipid metabolism disorder through the inflammatory signaling pathway,which prevent the occurrence and development of nonalcoholic fatty liver disease,thereby providing new ideas for the treatment of NAFLD.Objective: Based on the high fat diet induced obese diabetic model mice and normal diet induced control mice,this study explored the relationship between inflammatory signaling pathways and nonalcoholic fatty liver disease,and whether GLP-1 improves nonalcoholic fatty liver in diabetic mice through inflammatory signaling pathways.Methods: Five-week-old male C57BL/6J mice were selected.After 1 week of adaptive feeding,the mice were randomly divided into 2 groups(control group and obese diabetic group),12 in each group.The obese diabetic group was fed with high fat diet(60% fat),and the control group was fed with normal diet(5%fat).When the obese diabetic group had blood glucose levels higher than 13.9mmol/L for 3 consecutive days and the body weight was at least 20% higher than the control group,it was identified as an obese diabetic model.Body weight and tail vein random blood glucose were measured weekly.After 10 weeks of normal and high-fat diet,the obese diabetic mice were randomly divided into two subgroups(obese diabetic mice + liraglutide treated group,obese diabetic mice + saline treated group).Liraglutide treatment group was given subcutaneous injection of liraglutide 0.2 mg/kg,saline treatment group was given the same amount of normal saline as a control.After 10 weeks,the angular vein blood was taken from the eyeball,and the serum insulin level of the mice was determined by ELISA;the liver tissue of mice was quickly taken out and HE staining was performed to observe the morphology of liver tissue.Real-time quantitative PCR(RT q PCR)and Western blot(WB)techniques were used to detect the expression levels of the nuclear factor-kappa B(NF-κB),tumor necrosis factor α(TNF-α),inhibitory protein of NF-κB(IκB),and interleukin 1(IL-1β)in the liver.Results:1.Liraglutide improved the metabolism of high fat diet-induced obese diabetic mice: After 10 weeks of treatment with liraglutide,body weight,blood glucose and HOMA-IR were significantly increased in the saline-treated group compared with the control group(p<0.05).Body weight,blood glucose and HOMA-IR were significantly decreased in the liraglutide-treated group than in the saline-treated group(p<0.05).2.Liver histopathological changes: In the control group,the liver tissue structure was normal,the hepatic lobule structure was obvious,the hepatocyte cords were arranged radially,and no balloon-like degeneration was observed in the liver cells.In the saline-treated group,hepatocytes diffuse vesicular fat vacuolar degeneration,severe watery degeneration,the nucleus was partially deformed by extrusion,the hepatic cell line was disordered,and the hepatic sinus was narrowed or disappeared.A small amount of steatosis and watery degeneration were observed in the liver tissue of the liraglutide-treated group,which was significantly less than that of the control group.3.Comparison of expression levels of NF-κB,TNF-α,IL-1β and IκB in liver tissue: Compared with the control group,the levels of NF-κB,TNF-α,IL-1βprotein were increased and IκB were decreased significantly in the saline-treated group(p<0.05).Compared with the saline-treated group,the levels of NF-κB,TNF-α,IL-1β protein were decreased and IκB were increased significantly in the liraglutide-treated group(p<0.05).Conclusion: The high fat diet can induce C57BL/6J mice to be obese diabeteic model.High-fat diet can induce diabetes and obesity by up-regulating the expression of NF-κB,TNFα,IL-1β proteins and down-regulating the expression of IκB protein in the liver tissue inflammation pathway.Liraglutide intervention can reduce the expression of inflammatory genes in liver tissue and relieve non-alcoholic fatty liver in diabetic mice,thereby improving weight gain and blood glucose disorders in mice.