TLR4 knockout can improve dysfunction of β-cell by rebalancing proteomics disorders in pancreas of obese rats
Sunjie Yan1,2, Zhen Jiang1, Ling Cheng1
1From Endocrinology Department, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, China.
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.
Insights
Toll-like receptor 4 knockout (TLR4KO) improves pancreatic islet function in obese rats by rebalancing pancreatic proteomics and increasing Ass1 expression, mitigating high-fat diet-induced insulin resistance.
Area of Science:
- Metabolomics and Proteomics
- Endocrinology
- Immunology
Background:
- High-fat diets induce obesity and insulin resistance, impacting pancreatic islet function.
- Toll-like receptor 4 (TLR4) plays a role in metabolic disorders.
- Previous studies indicated TLR4 knockout (TLR4KO) mitigates diet-induced obesity and insulin resistance.
Purpose of the Study:
- To investigate the effects of TLR4KO on islet function and pancreatic proteomics in high-fat diet-induced obese rats.
- To elucidate the molecular mechanisms underlying TLR4KO-mediated protection of pancreatic beta cells.
Main Methods:
- Utilized TLR4 knockout (TLR4KO) and diet-induced obese rat models.
- Employed iTRAQ proteomics, Western blotting, and TUNEL assays.
- Conducted in vitro experiments to assess beta-cell apoptosis and insulin secretion.
Main Results:
- TLR4KO improved beta-cell function and regulated body composition in obese rats.
- Proteomic analysis revealed TLR4KO rebalanced pancreatic proteomic disorders, affecting metabolic pathways and signaling cascades.
- Silencing TLR4 inhibited palmitic acid (PA)-induced beta-cell apoptosis and increased Ass1 expression, while Ass1 overexpression protected beta cells.
Conclusions:
- TLR4KO ameliorates beta-cell dysfunction in obese rats.
- The protective mechanism involves rebalancing pancreatic proteomics and modulating Ass1 expression.
- Targeting TLR4 and Ass1 presents a potential therapeutic strategy for metabolic diseases.
