基于代谢组学与FXR/NLRP3通路的分析探讨糖尿病大鼠肝脏代谢紊乱的机制OA

Objective By establishing a streptozotocin(STZ)-induced diabetic rat model combined with a high-fat diet,this study aimed to compare the biochemical indicators,pathological features,differential metabolites,and key protein expressions in the liver between the model group and the normal group.The goal was to screen for diabetes-associated liver-specific metabolic biomarkers and elucidate the mechanisms underlying hepatic metabolic dysfunction,thereby providing a basis for the identification of therapeutic targets.Methods Ten SPF male wistar rats were randomly divided into a blank(Control)group and a model(Model)group,with five rats in each group.The Model group was given STZ injection combined with a high-fat diet to establish the model.After 6 weeks of feeding,the following parameters were measured in both groups following an 8-hour fasting period:fasting blood glucose(FBG),liver alanine aminotransferase(ALT),aspar-tate aminotransferase(AST),total cholesterol(TC),triglycerides(TG),superoxide dismutase(SOD),malondialdehyde(MDA),and glu-tathione(GSH).Hematoxylin-eosin(HE)staining was used to observe the pathological changes in liver tissues.Non-targeted metabolomics was employed to screen for differential metabolites in the liver and identify enriched metabolic pathways.Finally,Western blotting was used to detect the protein expression levels of farnesoid X receptor(FXR),NOD-like receptor pyrin domain-containing protein 3(NLRP3),nu-clear factor κB(NF-κB),interleukin-6(IL-6),tumor necrosis factor-α(TNF-α),and caspase-1.Results Compared with the Control group,the FBG value in the Model group was significantly increased(P＜0.01).The Model group rats exhibited pathological liver injury,with significantly increased ALT,AST,TC,and TG(P＜0.01),and significantly decreased GSH and SOD and increased MDA(P＜0.01).The expression of FXR protein was significantly decreased,accompanied by a significant upregulation of inflammatory-related factor proteins.These differences were statistically significant.Liver metabolomics analysis identified 22 differential metabolites(with taurine and glutamic acid being particularly representative).The core metabolic pathways involved included taurine and hypotaurine metabolism,alanine,aspar-tate,and glutamate metabolism,starch and sucrose metabolism,and glycerophospholipid metabolism.The Model group showed a significant reduction in hypotaurine metabolites and a significant increase in glutamic acid(P＜0.05).Conclusion Distinct differences were observed between the livers of diabetic model rats and normal rats.The FXR/NLRP3 pathway may influence endocrine homeostasis—and thereby par-ticipate in the pathogenesis and progression of diabetes—by regulating taurine-hypotaurine and alanine-aspartate-glutamate metabolism.These findings provide an experimental basis for elucidating the mechanisms underlying hepatic metabolic dysfunction in diabetes,identifying specific metabolic biomarkers,and discovering potential therapeutic targets.