Oncotarget

Research Papers:

Diminished gallbladder filling, increased fecal bile acids, and promotion of colon epithelial cell proliferation and neoplasia in fibroblast growth factor 15-deficient mice

Kunrong Cheng, Melissa Metry, Jessica Felton, Aaron C. Shang, Cinthia B. Drachenberg, Su Xu, Min Zhan, Justin Schumacher, Grace L. Guo, James E. Polli and Jean-Pierre Raufman _

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Oncotarget. 2018; 9:25572-25585. https://doi.org/10.18632/oncotarget.25385

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Abstract

Kunrong Cheng1,2,*, Melissa Metry3,*, Jessica Felton4,*, Aaron C. Shang2, Cinthia B. Drachenberg5, Su Xu6, Min Zhan7, Justin Schumacher8, Grace L. Guo8, James E. Polli3 and Jean-Pierre Raufman1,2,9,*

1VA Maryland Healthcare System, Baltimore, Maryland, 21201, USA

2Department of Medicine, Division of Gastroenterology & Hepatology, University of Maryland School of Medicine, Baltimore, Maryland, 21201, USA

3Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland, 21201, USA

4Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, 21201, USA

5Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, 21201, USA

6Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, Maryland, 21201, USA

7Department of Epidemiology & Public Health, University of Maryland School of Medicine, Baltimore, Maryland, 21201, USA

8Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey, 08854, USA

9Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland, 21201, USA

*These authors have contributed equally to this work

Correspondence to:

Jean-Pierre Raufman, email: jraufman@som.umaryland.edu

Keywords: colon neoplasia; bile acids; cell proliferation; gallbladder; enterohepatic circulation

Received: January 19, 2018     Accepted: April 26, 2018     Published: May 22, 2018

ABSTRACT

Fibroblast growth factor-19 (human FGF19; murine FGF15) suppresses bile acid synthesis. In FGF19 deficiency, diarrhea resulting from bile acid spillage into the colon mimics irritable bowel syndrome. To seek other consequences of FGF19/15 deficiency, we used Fgf15-/- and wild-type (WT) mice to assess gallbladder filling, the bile acid pool, fecal bile acid levels, and colon neoplasia. We fasted mice for six hours before assessing gallbladder size by magnetic resonance imaging (MRI). We measured bile acid levels in different compartments by enzymatic assay, and induced colon neoplasia with azoxymethane (AOM)/dextran sodium sulfate (DSS) and quantified epithelial Ki67 immunostaining and colon tumors 20 weeks later. In vivo MRI confirmed the gross finding of tubular gallbladders in FGF15-deficient compared to WT mice, but fasting gallbladder volumes overlapped. After gavage with a bile acid analogue, ex vivo MRI revealed diminished gallbladder filling in FGF15-deficient mice (P = 0.0399). In FGF15-deficient mice, the total bile acid pool was expanded 45% (P <0.05) and fecal bile acid levels were increased 2.26-fold (P <0.001). After AOM/DSS treatment, colons from FGF15-deficient mice had more epithelial cell Ki67 staining and tumors (7.33 ± 1.32 vs. 4.57 ± 0.72 tumors/mouse; P = 0.003 compared to WT mice); carcinomas were more common in FGF15-deficient mice (P = 0.01). These findings confirm FGF15, the murine homolog of FGF19, plays a key role in modulating gallbladder filling and bile acid homeostasis. In a well-characterized animal model of colon cancer, increased fecal bile acid levels in FGF15-deficient mice promoted epithelial proliferation and advanced neoplasia.


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