Diminished gallbladder filling, increased fecal bile acids, and promotion of colon epithelial cell proliferation and neoplasia in fibroblast growth factor 15-deficient mice.
Diminished gallbladder filling, increased fecal bile acids, and promotion of colon epithelial cell proliferation and neoplasia in fibroblast growth factor 15-deficient mice.
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DOI：
10.18632/oncotarget.25385
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发表时间：
2018-05-22
期刊：
影响因子：
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通讯作者：
Raufman JP
中科院分区：
文献类型：
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作者：
Cheng K;Metry M;Felton J;Shang AC;Drachenberg CB;Xu S;Zhan M;Schumacher J;Guo GL;Polli JE;Raufman JP
成纤维细胞生长因子-19（人FGF 19;鼠FGF 15）抑制胆汁酸合成。在FGF 19缺乏症中，胆汁酸溢出进入结肠导致的腹泻类似于肠易激综合征。为了寻找FGF 19/15缺乏的其他后果，我们使用FGF 15-/-和野生型（WT）小鼠来评估胆囊充盈、胆汁酸池、粪便胆汁酸水平和结肠肿瘤。在通过磁共振成像（MRI）评估胆囊大小之前，我们将小鼠禁食6小时。我们通过酶法测定不同隔室中的胆汁酸水平，并用氧化偶氮甲烷（AOM）/葡聚糖硫酸钠（DSS）诱导结肠肿瘤形成，并在20周后定量上皮Ki 67免疫染色和结肠肿瘤。体内MRI证实了与WT小鼠相比，FGF 15缺陷小鼠中管状胆囊的大体发现，但空腹胆囊体积重叠。用胆汁酸类似物灌胃后，离体MRI显示FGF 15缺陷小鼠的胆囊充盈减少（P = 0.0399）。在FGF 15缺陷小鼠中，总胆汁酸池扩大45%（P <0.05），粪便胆汁酸水平增加2.26倍（P <0.001）。在AOM/DSS处理后，来自FGF 15缺陷型小鼠的结肠具有更多上皮细胞Ki 67染色和肿瘤（7.33 ± 1.32对4.57 ± 0.72肿瘤/小鼠;与WT小鼠相比P = 0.003）;癌在FGF 15缺陷型小鼠中更常见（P = 0.01）。这些发现证实了FGF 15，FGF 19的鼠同系物，在调节胆囊充盈和胆汁酸稳态中起关键作用。在一个充分表征的结肠癌动物模型中，FGF 15缺陷小鼠粪便胆汁酸水平的增加促进了上皮细胞增殖和晚期肿瘤形成。
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.