Abstract：
The prevalence of different metabolic syndromes has grown globally, and the farnesoid X receptor (FXR), a metabolic homeostat for glucose, lipid, and bile acid metabolisms, may serve an important role in the progression of metabolic disorders. Glucose intolerance by FXR deficiency was previously reported and observed in our study, but the underlying biology remained unclear. To investigate the ambiguity, we collected the nontargeted profiles of the fecal metaproteome, serum metabolome, and liver proteome in Fxr-null (Fxr-/-) and wild-type (WT) mice with LC-HRMS. FXR deficiency showed a global impact on the different molecular levels we monitored, suggesting its serious disruption in the gut microbiota, hepatic metabolism, and circulating biomolecules. The network and enrichment analyses of the dysregulated metabolites and proteins suggested the perturbation of carbohydrate and lipid metabolism by FXR deficiency. Fxr-/- mice presented lower levels of hepatic proteins involved in glycogenesis. The impairment of glycogenesis by an FXR deficiency may leave glucose to accumulate in the circulation, which may deteriorate glucose tolerance. Lipid metabolism was dysregulated by FXR deficiency in a structural-dependent manner. Fatty acid β-oxidations were alleviated, but cholesterol metabolism was promoted by an FXR deficiency. Together, we explored the molecular events associated with glucose intolerance by impaired FXR with integrated novel multiomic data.
摘要：
不同代谢综合征的患病率在全球范围内增长，和法尼醇X受体（FXR），葡萄糖的代谢稳态仪，脂质，和胆汁酸代谢，可能在代谢紊乱的进展中起重要作用。以前在我们的研究中报道并观察到FXR缺乏引起的葡萄糖耐受不良，但潜在的生物学仍不清楚。为了调查歧义，我们收集了粪便代谢蛋白质组的非靶向概况，血清代谢组，和具有LC-HRMS的Fxr-null(Fxr-/-)和野生型(WT)小鼠中的肝脏蛋白质组。FXR缺乏对我们监测的不同分子水平产生了全球影响，这表明它对肠道微生物群的严重破坏，肝代谢，和循环的生物分子。对失调的代谢物和蛋白质的网络和富集分析表明，FXR缺乏会干扰碳水化合物和脂质代谢。Fxr-/-小鼠呈现较低水平的参与糖原生成的肝蛋白。FXR缺乏对糖原的损害可能会使葡萄糖在循环中积累，这可能会降低葡萄糖耐量。FXR缺乏以结构依赖性方式调节脂质代谢异常。脂肪酸β-氧化得到缓解，但是FXR缺乏促进了胆固醇代谢。一起,我们利用整合的新的多组数据探索了FXR受损与葡萄糖耐受不良相关的分子事件.
