ABSTRACT
BACKGROUND: Many chronic metabolic diseases, such as obesity and type 2 diabetes (T2DM), are closely related to a chronic low-grade inflammatory state in tissues. The high prevalence of non-alcoholic fatty liver disease (NAFLD) in patients with T2DM is related to the role of inflammation in the disease. In this study, we investigated the role of liraglutide in improving lipid metabolism disorders and preventing their progression to NAFLD by modulating inflammatory signaling pathways, thereby providing new treatment options for NAFLD. METHODS: We designed a 2×2 factorial analysis experiment. A mouse model of NAFLD with T2DM was established by feeding the animals a high-fat diet (HFD). The NAFLD mice with HFD-induced diabetes were treated with liraglutide for 10 weeks. Hematoxylin and eosin staining, Oil Red O staining and electron microscopy were used to observe the accumulation of triglycerides in the liver. RT-PCR and Western blotting were used to analyze the expression of α-SMA, IL-1ß, TNF-α, NF-κB and the NF-κB inhibitory protein IκB in the liver at the gene and protein levels, respectively. RESULTS: Liraglutide reduced the body weight and fasting blood glucose levels of HFD-fed mice. The expression of α-SMA, IL-1ß, TNF-α, and NF-κB in the liver of HFD-fed mice was increased at the mRNA and protein levels, but liraglutide treatment decreased the expression of these molecules. The expression of IκB in the liver decreased at the mRNA and protein levels but was upregulated after liraglutide treatment. CONCLUSION: Based on the current findings, liraglutide can significantly improve hepatic steatosis, primarily by downregulating the expression of inflammatory signaling mediators in the TNF-α pathway.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/pharmacology , Inflammation/drug therapy , Liraglutide/pharmacology , Non-alcoholic Fatty Liver Disease/drug therapy , Animals , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Type 2/chemically induced , Diabetes Mellitus, Type 2/metabolism , Diet, High-Fat/adverse effects , Disease Models, Animal , Hypoglycemic Agents/administration & dosage , Inflammation/metabolism , Liraglutide/administration & dosage , Male , Mice , Mice, Inbred C57BL , Non-alcoholic Fatty Liver Disease/chemically induced , Non-alcoholic Fatty Liver Disease/metabolism , Signal Transduction/drug effectsABSTRACT
Purpose: High prevalence of nonalcoholic fatty liver disease (NAFLD) among patients with type 2 diabetes has implicated the role of hepatic insulin resistance (IR) in the diseases. To better understand the underlying mechanism, we have evaluated the pathophysiological effects of Liraglutide on NAFLD via the insulin signaling pathway. Patients and methods: A 2×2 factorial experiment was designed. High-fat diet (HFD)-induced NAFLD mice with diabetes were treated with Liraglutide for 10 weeks, while the control mice were saline-treated. Hepatic expressions of InsR, IGF-1R, IRS2, PI3K and Akt at mRNA and protein levels were analyzed with RT-PCR and Western blotting. Hematoxylin and eosin staining, Oil Red O staining and electron microscopy were used to visualize triglyceride accumulation in liver. Results: Liraglutide significantly decreased body weight, fasting blood glucose levels and HOMA-IR scores in HFD mice. Compared with the control mice fed with chow diet, hepatic expressions of InsR, IRS2, PI3K and Akt at both mRNA and protein levels in HFD mice were significantly reduced, but upregulated after Liraglutide treatment. Furthermore, Liraglutide treatment was found to improve hepatic steatosis. Conclusion: The current study thereby provides evidence that Liraglutide ameliorates NAFLD and improves hepatic steatosis mainly by upregulation of the IRS2/PI3K/Akt signaling mediators.
