Sunjie Yan1,2, Zhen Jiang1, Ling Cheng1, Youfen Lin1, Beibei Fan1, Liufen Luo1, Yuanli Yan1, Liyong Yang1,2, Ximei Shen3,4. 1. From Endocrinology Department, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, China. 2. Diabetes Research Institute of Fujian Province, Fuzhou, 350005, Fujian, China. 3. From Endocrinology Department, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, China. 641498885@qq.com. 4. Diabetes Research Institute of Fujian Province, Fuzhou, 350005, Fujian, China. 641498885@qq.com.
Abstract
PURPOSE: Studies showed that TLR4 knockout (TLR4KO) could mitigate obesity and insulin resistance induced by high-fat diet in rats. In this study, we further investigated the effects of TLR4KO on islet function and pancreatic proteomics in obese rats by high-fat diet. METHODS: PA-induced lipotoxicity β-cells, SD and TLR4KO rats were used in this study. iTRAQ was used to screen out meaningful differential proteins.The protein expression level was evaluated by Western blotting; the cell apoptosis was detected by TUNEL assay. RESULTS: TLR4KO could reduce inflammatory and regulate body composition in obese rats, and improve β-cells function. The quantitative analysis of protein revealed that TLR4KO rebalanced proteomics disorders in pancreas of obese rats. In addition, the pathways involved in differential proteins were mainly metabolic pathways, arachidonic acid metabolism, ECM-receptor interaction, pancreatic secretion, PI3K-Akt signaling pathway, and FoxO signaling pathway. Further analysis of protein-protein interaction (PPI) revealed that Stk39 and Ass1 interacting through Mapk14-Ywhae were node proteins and participated in inflammatory response, carboxylic acid metabolic process, and small molecule metabolic process. In vitro experiments we confirmed that silencing TLR4 can inhibit PA-induced β-cell apoptosis, insulin secretion disorders, and increase Ass1 expression. While, overexpression of Ass1 in β-cell inhibited PA or LPS-induced β-cell damage. CONCLUSIONS: Our study confirmed that TLR4KO could improve dysfunction of β-cell, and the underlying mechanism might be involved in ebalancing proteomics disorders in pancreas, affecting the expression of Ass1.
PURPOSE: Studies showed that TLR4 knockout (TLR4KO) could mitigate obesity and insulin resistance induced by high-fat diet in rats. In this study, we further investigated the effects of TLR4KO on islet function and pancreatic proteomics in obese rats by high-fat diet. METHODS: PA-induced lipotoxicity β-cells, SD and TLR4KO rats were used in this study. iTRAQ was used to screen out meaningful differential proteins.The protein expression level was evaluated by Western blotting; the cell apoptosis was detected by TUNEL assay. RESULTS: TLR4KO could reduce inflammatory and regulate body composition in obese rats, and improve β-cells function. The quantitative analysis of protein revealed that TLR4KO rebalanced proteomics disorders in pancreas of obese rats. In addition, the pathways involved in differential proteins were mainly metabolic pathways, arachidonic acid metabolism, ECM-receptor interaction, pancreatic secretion, PI3K-Akt signaling pathway, and FoxO signaling pathway. Further analysis of protein-protein interaction (PPI) revealed that Stk39 and Ass1 interacting through Mapk14-Ywhae were node proteins and participated in inflammatory response, carboxylic acid metabolic process, and small molecule metabolic process. In vitro experiments we confirmed that silencing TLR4 can inhibit PA-induced β-cell apoptosis, insulin secretion disorders, and increase Ass1 expression. While, overexpression of Ass1 in β-cell inhibited PA or LPS-induced β-cell damage. CONCLUSIONS: Our study confirmed that TLR4KO could improve dysfunction of β-cell, and the underlying mechanism might be involved in ebalancing proteomics disorders in pancreas, affecting the expression of Ass1.
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