Molecular Mechanisms of Altered Bile Acid Homeostasis in Organic Solute Transporter-Alpha Knockout Mice
Molecular Mechanisms of Altered Bile Acid Homeostasis in Organic Solute Transporter-Alpha Knockout Mice
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DOI：
10.1159/000324124
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发表时间：
2011-01-01
影响因子：
2.3
通讯作者：
Dawson, Paul A.
中科院分区：
文献类型：
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作者：
Lan, Tian;Haywood, Jamie;Dawson, Paul A.
背景/目标：顶端钠依赖性胆汁酸转运蛋白（SLC 10A 2）的突变阻断肠胆汁酸吸收，导致肝脏胆汁酸合成代偿性增加。基底外侧膜胆汁酸转运蛋白（OST α-OST β）的失活也会损害肠道胆汁酸吸收，但肝脏胆汁酸合成却受到抑制。我们假设胆汁酸稳态的改变是由回肠捕获胆汁酸引起的，胆汁酸通过法尼醇X受体（FXR）诱导FGF 15的过度表达。为了验证这一假设，我们研究了阻断FXR信号传导是否会逆转Ost α缺失小鼠的胆汁酸合成表型。方法：将Ost α Fxr基因敲除小鼠与相应的敲除小鼠杂交，建立Ost α Fxr双敲除小鼠模型。所有实验比较了野生型、Ost α、Fxr和Ost α Fxr无效同窝仔。体内表型分析包括胆汁酸粪便排泄、合并液大小和组成的测量。还检测了肝和肠的基因和蛋白表达。结果如下：与Ost α敲除小鼠相比，Ost α Fxr敲除小鼠显示胆汁酸粪便排泄量和合并液大小增加，胆汁酸合并液疏水性降低。FXR的失活逆转了回肠总FGF 15表达的增加，这与肝Cyp 7a 1表达的显著增加相关。结论：FXR的失活在很大程度上揭示了胆汁酸吸收不良表型，并纠正了Ost α缺失小鼠中的胆汁酸稳态缺陷，表明FXR-FGF 15-FGFR 4途径的不适当激活部分地构成了该表型的基础。在Ost alpha（-/-）Fxr（-/-）小鼠中维持了肠道形态学变化和顶端钠依赖性胆汁酸转运蛋白表达降低，表明FXR不是这些适应性反应所必需的。版权所有（C）2011 S. Karger AG，巴塞尔
Background/Aims: Mutations in the apical sodium-dependent bile acid transporter (SLC10A2) block intestinal bile acid absorption, resulting in a compensatory increase in hepatic bile acid synthesis. Inactivation of the basolateral membrane bile acid transporter (OST alpha-OST beta) also impairs intestinal bile acid absorption, but hepatic bile acid synthesis was paradoxically repressed. We hypothesized that the altered bile acid homeostasis resulted from ileal trapping of bile acids that act via the farnesoid X receptor (FXR) to induce overexpression of FGF15. To test this hypothesis, we investigated whether blocking FXR signaling would reverse the bile acid synthesis phenotype in Ost alpha null mice. Methods: The corresponding null mice were crossbred to generate Ost alpha Fxr double-null mice. All experiments compared wild-type, Ost alpha, Fxr and Ost alpha Fxr null littermates. Analysis of the in vivo phenotype included measurements of bile acid fecal excretion, pool size and composition. Hepatic and intestinal gene and protein expression were also examined. Results: Ost alpha Fxr null mice exhibited increased bile acid fecal excretion and pool size, and decreased bile acid pool hydrophobicity, as compared with Ost alpha null mice. Inactivation of FXR reversed the increase in ileal total FGF15 expression, which was associated with a significant increase in hepatic Cyp7a1 expression. Conclusions: Inactivation of FXR largely unmasked the bile acid malabsorption phenotype and corrected the bile acid homeostasis defect in Ost alpha null mice, suggesting that inappropriate activation of the FXR-FGF15-FGFR4 pathway partially underlies this phenotype. Intestinal morphological changes and reduced apical sodium-dependent bile acid transporter expression were maintained in Ost alpha(-/-)Fxr(-/-) mice, indicating that FXR is not required for these adaptive responses. Copyright (C) 2011 S. Karger AG, Basel