Cao Lijuan, Che Yuan, Meng Tuo, Deng Shanshan, Zhang Jun, Zhao Min, Xu Wanfeng, Wang Dandan, Pu Zhichen, Wang Guangji, Hao Haiping
State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism & Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
Oncotarget. 2017 Jun 28;8(38):63665-63679. doi: 10.18632/oncotarget.18885. eCollection 2017 Sep 8.
Bile acids (BAs) are important endogenous signaling molecules that play vital roles in the pathological development of various diseases including colitis-associated cancer (CAC). BAs were previously found dysregulated under conditions of CAC; however, the exact patterns and underlying molecular mechanisms remain largely elusive. Based on the development of a method for comprehensive analysis of BAs, this study aims to elucidate the dysregulation patterns and involved mechanisms in a typical CAC model induced by azoxymethane (AOM)/dextran sodium sulfate (DSS). CAC mice showed decreased BAs transformation in gut and glucuronidation in colon, leading to accumulation of primary BAs but reduction of secondary BAs in colon. CAC mice were characterized by an accumulation of BAs in various compartments except ileum, which is in line with repressed ileal FXR-FGF15 feedback signaling and the increased expression of hepatic CYP7A1. The compromised ileal FXR-FGF15 signaling was caused in part by the reduced absorption of FXR ligands including free and tauro-conjungated BAs due to the downregulation of various transporters of BAs in the ileum of CAC mice.
胆汁酸（BAs）是重要的内源性信号分子，在包括结肠炎相关癌（CAC）在内的各种疾病的病理发展中起着至关重要的作用。此前发现，在CAC情况下胆汁酸失调；然而，确切模式和潜在分子机制在很大程度上仍不清楚。基于一种用于胆汁酸综合分析方法的开发，本研究旨在阐明由氧化偶氮甲烷（AOM）/葡聚糖硫酸钠（DSS）诱导的典型CAC模型中的失调模式及相关机制。CAC小鼠肠道中胆汁酸转化减少，结肠中葡萄糖醛酸化减少，导致结肠中初级胆汁酸积累而次级胆汁酸减少。CAC小鼠的特征是除回肠外各部位胆汁酸均有积累，这与回肠FXR-FGF15反馈信号受抑制以及肝脏CYP7A1表达增加一致。回肠FXR-FGF15信号受损部分是由于CAC小鼠回肠中各种胆汁酸转运体下调，导致包括游离和牛磺结合胆汁酸在内的FXR配体吸收减少。
