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

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.

SUBMITTER: Cao L

PROVIDER: S-EPMC5609951 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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

Cao Lijuan L Che Yuan Y Meng Tuo T Deng Shanshan S Zhang Jun J Zhao Min M Xu Wanfeng W Wang Dandan D Pu Zhichen Z Wang Guangji G Hao Haiping H

Oncotarget 20170628 38

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 ...[more]

PMID: 28969019

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Project description:Hepatic bile acid synthesis is subject to complex modes of transcriptional control, in which the bile acid-activated nuclear receptor farnesoid X receptor (FXR) in liver and intestine-derived, FXR-controlled fibroblast growth factor 15 (Fgf15) are involved. The Fgf15 pathway is assumed to contribute significantly to control of hepatic bile acid synthesis. However, scientific evidence supporting this assumption is primarily based on gene expression data. Using intestine-selective FXR knockout mice (iFXR-KO), we show that contribution of intestinal FXR-Fgf15 signalling in regulation of hepatic cholesterol 7?-hydroxylase (Cyp7A1) expression depends on time of the day with increased hepatic Cyp7A1 expression in iFXR-KO mice compared with controls exclusively during the dark phase. To assess the physiological relevance hereof, we determined effects of intestine-selective deletion of FXR on physiological parameters such as bile formation and kinetics of the enterohepatic circulation of bile acids. It appeared that intestinal FXR deficiency leads to a modest but significant increase in cholic acid pool size, without changes in fractional turnover rate. As a consequence, bile flow and biliary bile acid secretion rates were increased in iFXR-KO mice compared with controls. Feeding a bile acid-containing diet or treatment with a bile acid sequestrant similarly affected bile formation in iFXR-KO and control mice and induced similar changes in Cyp7A1 and Cyp8B1 expression patterns. In conclusion, this study is the first to demonstrate the physiological relevance of the contribution of the intestinal FXR-Fgf15 signalling pathway in control of hepatic bile acid synthesis. Fgf15 contributes to the regulation of hepatic bile acid synthesis in mice mainly during the dark phase. Expansion of the circulating bile acid pool as well as bile acid sequestration diminishes the contribution of intestinal FXR-Fgf15 signalling in control of hepatic bile acid synthesis and bile formation.

Project description:It is a common practice to provide fast-growing broilers with high-fat diets in the context of integrated farms in Northeast China. Therefore, fat digestion, absorption, and utilization efficiency are critical for broiler meat production. Bile acids (BA) promote fat digestion and absorption, but whether and how BA affects muscle growth in broilers remains unclear. In this study, 1-day-old broilers were fed diets containing varying levels of crude fat (low, medium, and high) with or without BA supplementation for 42 d. Chickens fed a high-fat diet supplemented with BA exhibited significantly (P < 0.05) higher body weight (BW) at 21 d and average daily gain (ADG) during the first 21 d compared to the other groups. Throughout the entire experiment, feed conversion rate (FCR) was significantly (P < 0.05) lower in the high-fat group without the addition of BA, which was further decreased (P < 0.05) with BA supplementation. The improved growth performance in the BA-supplemented high-fat group was associated with significantly (P < 0.05) higher lipase activity in the small intestine chyme, a decreased trend (P = 0.06) in abdominal fat ratio, and significantly (P < 0.05) higher breast muscle mass. Histological analysis revealed significant (P < 0.05) increases in myofiber diameter, cross-sectional area, and RNA and DNA concentrations in the breast muscle of BA-supplemented broilers on the high-fat diet. Additional histological analysis further revealed significant (P < 0.05) enhancements in myofiber diameter, cross-sectional area, and RNA and DNA concentrations within the breast muscles of broilers supplemented with BA and a high-fat diet. The increased insulin-like growth factor 2 (IGF2) in the breast muscle of broilers fed a BA-supplemented high-fat diet correlated with significantly (P < 0.05) increased farnesoid X factor (FXR) protein expression and binding to the IGF2 promoter. These results suggest that dietary BA supplementation improves FCR and breast muscle growth in broilers fed a high-fat diet, potentially through the FXR-mediated IGF2 pathway.

Project description:Background & aimsThe degree of cholestasis is an important disease driver in alcoholic hepatitis, a severe clinical condition that needs new biomarkers and targeted therapies. We aimed to identify the largely unknown mechanisms and biomarkers linked to cholestasis in alcoholic hepatitis.MethodsHerein, we analyzed a well characterized cohort of patients with alcoholic hepatitis and correlated clinical and histological parameters and outcomes with serum bile acids and fibroblast growth factor 19 (FGF19), a major regulator of bile acid synthesis.ResultsWe found that total and conjugated bile acids were significantly increased in patients with alcoholic hepatitis compared with controls. Serum FGF19 levels were strongly increased and gene expression of FGF19 was induced in biliary epithelial cells and ductular cells of patients with alcoholic hepatitis. De novo bile acid synthesis (CYP7A1 gene expression and C4 serum levels) was significantly decreased in patients with alcoholic hepatitis. Importantly, total and conjugated bile acids correlated positively with FGF19 and with disease severity (model for end-stage liver disease score). FGF19 correlated best with conjugated cholic acid, and model for end-stage liver disease score best with taurine-conjugated chenodeoxycholic acid. Univariate analysis demonstrated significant associations between FGF19 and bilirubin as well as gamma glutamyl transferase, and negative correlations between FGF19 and fibrosis stage as well as polymorphonuclear leukocyte infiltration, in all patients with alcoholic hepatitis.ConclusionSerum FGF19 and bile acids are significantly increased in patients with alcoholic hepatitis, while de novo bile acid synthesis is suppressed. Modulation of bile acid metabolism or signaling could represent a promising target for treatment of alcoholic hepatitis in humans.Lay summaryUnderstanding the underlying mechanisms that drive alcoholic hepatitis is important for the development of new biomarkers and targeted therapies. Herein, we describe a molecule that is increased in patients with alcoholic hepatitis. Modulating the molecular pathway of this molecule might lead to promising targets for the treatment of alcoholic hepatitis.

Dataset Information

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

Publications

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

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