Repression of intestinal transporters and FXR-FGF15 signaling explains bile acids dysregulation in experimental colitis-associated colon cancer
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Lijuan Cao1,*, Yuan Che1,*, Tuo Meng1, Shanshan Deng1, Jun Zhang1, Min Zhao1, Wanfeng Xu1, Dandan Wang1, Zhichen Pu1, Guangji Wang1 and Haiping Hao1
1State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism & Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China
Haiping Hao, email: [email protected]
Lijuan Cao, email: [email protected]
Keywords: bile acids, malabsorption, FXR, UFLC-Triple-TOF/MS, colitis-associated colon cancer
Received: February 04, 2017 Accepted: June 02, 2017 Published: June 28, 2017
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.
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