Intestinal FXR-mediated FGF15 production contributes to diurnal control of hepatic bile acid synthesis in mice.
Intestinal FXR-mediated FGF15 production contributes to diurnal control of hepatic bile acid synthesis in mice.
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DOI：
10.1038/labinvest.2010.107
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发表时间：
2010-10
期刊：
影响因子：
--
通讯作者：
Kuipers F
中科院分区：
文献类型：
--
作者：
Stroeve JH;Brufau G;Stellaard F;Gonzalez FJ;Staels B;Kuipers F
肝脏胆汁酸合成受复杂的转录调控模式的影响，其中涉及肝脏中胆汁酸激活的核受体法尼醇X受体（FXR）和精氨酸衍生的、FXR控制的成纤维细胞生长因子15（Fgf 15）。假定Fgf 15途径对控制肝胆汁酸合成有显著贡献。然而，支持这一假设的科学证据主要基于基因表达数据。使用精氨酸选择性FXR敲除小鼠（iFXR-KO），我们发现肠道FXR-Fgf 15信号传导在调节肝脏胆固醇7 α-羟化酶（Cyp 7A 1）表达中的作用取决于一天中的时间，与对照组相比，iFXR-KO小鼠中肝脏Cyp 7A 1表达仅在黑暗期增加。为了评估其生理相关性，我们确定了FXR的精氨酸选择性缺失对胆汁形成和胆汁酸肠肝循环动力学等生理参数的影响。似乎肠道FXR缺乏导致胆酸池大小适度但显著增加，而部分周转率无变化。因此，与对照组相比，iFXR-KO小鼠的胆汁流量和胆汁胆汁酸分泌率增加。喂食含胆汁酸的饮食或用胆汁酸螯合剂处理类似地影响iFXR-KO和对照小鼠中的胆汁形成，并诱导Cyp 7A 1和Cyp 8B 1表达模式的类似变化。总之，本研究首次证明了肠道FXR-Fgf 15信号通路在控制肝胆汁酸合成中的生理相关性。fgf 15主要在黑暗期参与调节小鼠肝脏胆汁酸的合成。循环胆汁酸库的扩大以及胆汁酸螯合减少了肠FXR-Fgf 15信号传导在控制肝胆汁酸合成和胆汁形成中的贡献。
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 7a-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.
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作者：
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