Repression of intestinal transporters and FXR-FGF15 signaling explains bile acids dysregulation in experimental colitis-associated colon cancer

Lijuan Cao,Dandan Wang,Guangji Wang,Min Zhao,Wanfeng Xu,Zhichen Pu,Tuo Meng,Yuan Che,Shanshan Deng,Jun Zhang,Haiping Hao

doi:10.18632/oncotarget.18885

Lijuan Cao, Dandan Wang + Show 9 more

Open Access

https://doi.org/10.18632/oncotarget.18885

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Journal: Oncotarget	Publication Date: Jun 28, 2017
Citations: 18	License type: cc-by

Affiliation: China Pharmaceutical University

Abstract

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.

Highlights

Bile acids (BAs) are a class of important endogenous bioactive substances that play pivotal roles in lipid digestion and absorption, but more importantly, serving as signaling molecules with systemic endocrine functions in a panel of important physiological and pathological processes [1,2,3,4]
Based on developing a powerful method for the simultaneous quantification of major BAs and their glucuronides, this study contributes to a comprehensive understanding of BAs dysregulations and the mechanisms involved in CAC
Our previous findings indicated that the intestinal transporters of BAs remained largely unchanged in colitis; in contrast, we found that the system involved in the ileal uptake of BAs, including various transporters and their upstream nuclear receptors (NRs), is markedly repressed

Summary

Introduction

Bile acids (BAs) are a class of important endogenous bioactive substances that play pivotal roles in lipid digestion and absorption, but more importantly, serving as signaling molecules with systemic endocrine functions in a panel of important physiological and pathological processes [1,2,3,4]. Primary BAs are synthesized in the liver and conjugated with glycine or taurine before secretion to intestinal tract where they are deconjugated and transformed to secondary BAs and reabsorbed in terminal ileum. Such an enterohepatic cycle leads to the production of more than 30 kinds of BA species. Increased levels of deoxycholic acid (DCA) was reported to facilitate tumorigenesis of hepatocellular carcinoma [8] and CAC [9], despite that DCA has been repeatedly shown to be able to inhibit proinflammatory cytokines in monocytes/ macrophages [10]. It has been well known that patients with colon cancer are characterized with increased levels of BAs in feces [11, 12]

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