Cholecystectomy inhibits fasting hepatic fatty acid oxidation in mice

Cholecystectomy is associated with an increased risk of metabolic syndrome (MetS); however, the underlying mechanism remains unknown. The gallbladder acts as a storage organ for hepatic bile and regulates the feeding/fasting cycles of bile acid (BA) flow in the enterohepatic circulation (EHC). In this study, we aimed to use C57BL/6 mice to investigate the effects of cholecystectomy in the regulation of glucose homeostasis and bile acid metabolism with metabolomics and quantitative RT-PCR. The results show that cholecystectomy increases fasting hepatic BA levels by enhancing EHC. Livers from cholecystectomized (XGB) mice displayed suppression of genes involved in fatty acid oxidation (FAO), abnormal lipid accumulation, and marked remodeling of their metabolomic profiles, particularly a reduction in FAO intermediate acylcarnitines. Many FAO genes were transcriptional targets of the peroxisome proliferator-activated receptor α (PPARα), and BA inhibited PPARα, resulting in impeded FAO. Consistent with this, blocking intestinal BA uptake using an apical sodium-BA transporter inhibitor enhanced fasting hepatic FAO levels and ameliorated metabolic disorders in XGB mice. Analysis of patient peripheral blood revealed directional trends in bile acid and fatty acid metabolites that were consistent with the metabolic disruptions observed in mice. Nevertheless, these findings suggest that cholecystectomy could inhibit fasting hepatic FAO by disturbing the EHC of BA, and reveal the role of the gallbladder in coordinating PPARα-regulated FAO in the liver.

胆囊切除术（Cholecystectomy）与代谢综合征（MetS）风险升高相关，但其潜在作用机制仍未明确。胆囊作为肝脏胆汁的储存器官，可调控肠肝循环（EHC）内胆汁酸（BA）流动的进食-禁食周期。本研究采用C57BL/6小鼠，借助代谢组学与定量逆转录PCR（quantitative RT-PCR）技术，探究胆囊切除术对葡萄糖稳态及胆汁酸代谢的调控作用。研究结果显示，胆囊切除术可通过增强肠肝循环，升高禁食状态下小鼠肝脏的胆汁酸水平。胆囊切除术组（XGB）小鼠的肝脏呈现出脂肪酸氧化（FAO）相关基因表达受抑制、脂质异常蓄积，以及代谢组谱显著重塑的特征，尤以脂肪酸氧化中间产物酰基肉碱的减少最为明显。诸多脂肪酸氧化相关基因均为过氧化物酶体增殖物激活受体α（PPARα）的转录靶标，而胆汁酸可抑制PPARα活性，进而阻碍脂肪酸氧化进程。与此一致，使用顶端钠依赖性胆汁酸转运体抑制剂阻断肠道胆汁酸摄取后，胆囊切除术组小鼠禁食状态下肝脏的脂肪酸氧化水平得以提升，代谢紊乱症状也得到改善。对患者外周血的分析显示，其胆汁酸与脂肪酸代谢物的变化趋势与小鼠体内观察到的代谢紊乱特征相符。综上，本研究结果表明，胆囊切除术可通过扰乱胆汁酸的肠肝循环，抑制禁食状态下肝脏的脂肪酸氧化，同时揭示了胆囊在协调肝脏过氧化物酶体增殖物激活受体α调控的脂肪酸氧化过程中的重要作用。