Mechanism of tissue-specific farnesoid X receptor in suppressing the expression of genes in bile-acid synthesis in mice
Mechanism of tissue-specific farnesoid X receptor in suppressing the expression of genes in bile-acid synthesis in mice
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DOI：
10.1002/hep.25740
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发表时间：
2012-09-01
期刊：
影响因子：
13.5
通讯作者：
Guo, Grace L.
中科院分区：
文献类型：
--
作者：
Kong, Bo;Wang, Li;Guo, Grace L.
法尼醇X受体（Fxr，Nr 1h 4）的激活是通过降低编码关键胆汁酸合成酶（例如，细胞色素P450 [C] 7A 1/Cyp 7a 1和CYP 8B 1/Cyp 8b 1）。FXR介导的肝小异源二聚体伴侣（SHP/Shp，Nr 0 b2）和肠成纤维细胞生长因子15（Fgf 15;人中的FGF 19）的诱导已被证明是这种抑制的原因。然而，Shp/Fgf 15对这种抑制的确切贡献以及相关的细胞信号传导途径尚不清楚。通过使用新的转基因小鼠，目前的研究表明，肠道Fxr/Fgf 15途径是抑制Cyp 7a 1和Cyp 8b 1基因表达的关键，但肝脏Fxr/Shp途径是抑制Cyp 8b 1基因表达的重要途径，在抑制Cyp 7a 1基因表达中起次要作用。此外，在体内管理的Fgf 15蛋白的小鼠导致了强烈的激活细胞外信号相关激酶（ERK），并在较小程度上，Jun N-末端激酶（JNK）在肝脏。此外，缺乏ERK或JNK途径在小鼠肝脏减少的基础，但不是Fgf 15介导的，Cyp 7a 1和Cyp 8b 1基因表达的抑制。然而，ERK和JNK途径的缺陷阻止了Fgf 15介导的Cyp 7a 1和Cyp 8b 1基因表达的抑制。结论：目前的研究清楚地阐明了肝脏与肠道Fxr在调节肝脏中胆汁酸合成和疏水性关键基因表达方面的潜在分子机制。（肝脏学2012;56：10341043）
Activation of farnesoid X receptor (Fxr, Nr1h4) is a major mechanism in suppressing bile-acid synthesis by reducing the expression levels of genes encoding key bile-acid synthetic enzymes (e.g., cytochrome P450 [CYP]7A1/Cyp7a1 and CYP8B1/Cyp8b1). FXR-mediated induction of hepatic small heterodimer partner (SHP/Shp, Nr0b2) and intestinal fibroblast growth factor 15 (Fgf15; FGF19 in humans) has been shown to be responsible for this suppression. However, the exact contribution of Shp/Fgf15 to this suppression, and the associated cell-signaling pathway, is unclear. By using novel genetically modified mice, the current study showed that the intestinal Fxr/Fgf15 pathway was critical for suppressing both Cyp7a1 and Cyp8b1 gene expression, but the liver Fxr/Shp pathway was important for suppressing Cyp8b1 gene expression and had a minor role in suppressing Cyp7a1 gene expression. Furthermore, in vivo administration of Fgf15 protein to mice led to a strong activation of extracellular signal-related kinase (ERK) and, to a smaller degree, Jun N-terminal kinase (JNK) in the liver. In addition, deficiency of either the ERK or JNK pathway in mouse livers reduced the basal, but not the Fgf15-mediated, suppression of Cyp7a1 and Cyp8b1 gene expression. However, deficiency of both ERK and JNK pathways prevented Fgf15-mediated suppression of Cyp7a1 and Cyp8b1 gene expression. Conclusion: The current study clearly elucidates the underlying molecular mechanism of hepatic versus intestinal Fxr in regulating the expression of genes critical for bile-acid synthesis and hydrophobicity in the liver. (HEPATOLOGY 2012;56:10341043)