Metabolism Unit, Endocrinology, Metabolism and Diabetes, Department of Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden.
Department of Medicine, Karolinska Institutet/AstraZeneca Integrated CardioMetabolic Center (KI/AZ ICMC), Novum, Stockholm, Sweden.
J Intern Med. 2018 Nov;284(5):546-559. doi: 10.1111/joim.12811. Epub 2018 Jul 31.
Bile acids (BAs) traversing the enterohepatic circulation (EHC) influence important metabolic pathways. By determining individual serum BAs in relation to markers of metabolic activity, we explored how diurnal variations in their EHC relate to hepatic metabolism in normal humans.
Serum BAs, fibroblast growth factor 19 (FGF19), lipoproteins, glucose/insulin and markers of cholesterol and BA syntheses were monitored for 32 h in 8 healthy males. Studies were conducted at basal state and during initiation of cholestyramine treatment, with and without atorvastatin pretreatment. Time series cross-correlation analysis, Bayesian structural model and Granger causality test were applied.
Bile acids synthesis dominated daytime, and cholesterol production at night. Conjugated BAs peaked after food intake, with subsequent FGF19 elevations. BA synthesis was reduced following conjugated BA and FGF19 peaks. Cholestyramine reduced conjugated BAs and FGF19, and increased BA and cholesterol production; the latter effects attenuated by atorvastatin. The relative importance of FGF19 vs. conjugated BAs in this feedback inhibition could not be discriminated. Unconjugated BAs displayed one major peak late at night/early morning that was unrelated to FGF19 and BA synthesis, and abolished by cholestyramine. The normal suppression of serum triglycerides, glucose and insulin observed at night was attenuated by cholestyramine.
Conjugated and unconjugated BAs have asynchronous rhythms of EHC in humans. Postprandial transintestinal flux of conjugated BAs increases circulating FGF19 levels and suppresses BA synthesis. Unconjugated BAs peak late at night, indicating a non-postprandial diurnal change in human gut microflora, the physiological implications of which warrants further study.
胆汁酸（BAs）在肠肝循环（EHC）中转运，影响重要的代谢途径。通过确定与代谢活性标志物相关的个体血清 BAs，我们探索了它们在 EHC 中的昼夜变化如何与正常人的肝代谢相关。
在 8 名健康男性中，监测血清 BAs、成纤维细胞生长因子 19（FGF19）、脂蛋白、葡萄糖/胰岛素以及胆固醇和 BA 合成标志物 32 小时。在基础状态下以及开始用考来烯胺治疗时，以及在阿托伐他汀预处理前后进行研究。应用时间序列交叉相关分析、贝叶斯结构模型和格兰杰因果检验。
胆汁酸合成在白天占主导地位，胆固醇生成在夜间。结合型 BAs 在进食后达到峰值，随后 FGF19 升高。BA 合成在结合型 BA 和 FGF19 峰值后减少。考来烯胺降低了结合型 BAs 和 FGF19，并增加了 BA 和胆固醇的产生；阿托伐他汀减弱了后者的作用。在这种反馈抑制中，FGF19 与结合型 BAs 的相对重要性无法区分。未结合型 BAs 在深夜/清晨出现一个主要峰值，与 FGF19 和 BA 合成无关，并用考来烯胺消除。夜间观察到的血清甘油三酯、葡萄糖和胰岛素的正常抑制作用被考来烯胺减弱。
人类 EHC 中的结合型和未结合型 BAs 具有不同步的节律。结合型 BAs 的餐后跨肠通量增加循环 FGF19 水平并抑制 BA 合成。未结合型 BAs 在深夜达到峰值，表明人类肠道微生物群发生了非餐后昼夜变化，其生理意义值得进一步研究。
