Selective Activation of Nuclear Bile Acid Receptor FXR in the Intestine Protects Mice Against Cholestasis
Selective Activation of Nuclear Bile Acid Receptor FXR in the Intestine Protects Mice Against Cholestasis
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DOI：
10.1053/j.gastro.2011.10.028
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发表时间：
2012-02-01
期刊：
影响因子：
29.4
通讯作者：
Moschetta, Antonio
中科院分区：
文献类型：
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作者：
Modica, Salvatore;Petruzzelli, Michele;Moschetta, Antonio
背景与目的：胆汁淤积是一种肝脏疾病，其特征在于胆汁流动受损，肠道中胆汁酸（BA）减少，以及肝脏中BA滞留。法尼醇X受体（FXR）是BA稳态的转录调节因子。BA激活FXR可通过反馈机制降低循环BA水平，抑制肝胆固醇7 α-羟化酶（Cyp 7a 1），胆固醇转化为BA的限速酶。该机制涉及肝核受体小异源二聚体伴侣和肠成纤维细胞生长因子（FGF）19和15。我们研究了激活精氨酸特异性FXR在降低小鼠肝脏BA水平和保护肝脏免于胆汁淤积中的作用。方法：我们产生了在肠道中表达组成型活性FXR的转基因小鼠。利用FXR功能获得和丧失模型，我们研究了肠道FXR在肝内和肝外胆汁淤积小鼠中的作用。研究结果：选择性激活肠道FXR诱导FGF 15和抑制肝Cyp 7a 1，减少池大小的BA和改变BA池组成。肠道FXR的激活可保护胆管结扎或给予α-萘异硫氰酸酯后的小鼠免受阻塞性肝外胆汁淤积。在Mdr 2（-/-）小鼠中，肠中活化FXR的转基因表达可保护肝脏免受损伤，而FXR的缺失则促进肝脏疾病的进展。结论：肠道中FXR转录的激活通过诱导FGF 15表达和减少BA的肝池来保护小鼠肝脏免受胆汁淤积;这种方法可能被开发用于逆转患者的胆汁淤积。
BACKGROUND & AIMS: Cholestasis is a liver disorder characterized by impaired bile flow, reduction of bile acids (BAs) in the intestine, and retention of BAs in the liver. The farnesoid X receptor (FXR) is the transcriptional regulator of BA homeostasis. Activation of FXR by BAs reduces circulating BA levels in a feedback mechanism, repressing hepatic cholesterol 7 alpha-hydroxylase (Cyp7a1), the rate-limiting enzyme for the conversion of cholesterol to BAs. This mechanism involves the hepatic nuclear receptor small heterodimer partner and the intestinal fibroblast growth factor (FGF) 19 and 15. We investigated the role of activation of intestine-specific FXR in reducing hepatic levels of BAs and protecting the liver from cholestasis in mice. METHODS: We generated transgenic mice that express a constitutively active FXR in the intestine. Using FXR gain-and loss-of-function models, we studied the roles of intestinal FXR in mice with intrahepatic and extrahepatic cholestasis. RESULTS: Selective activation of intestinal FXR induced FGF15 and repressed hepatic Cyp7a1, reducing the pool size of BAs and changing the BA pool composition. Activation of intestinal FXR protected mice from obstructive extrahepatic cholestasis after bile duct ligation or administration of alpha-naphthylisothiocyanate. In Mdr2(-/-) mice, transgenic expression of activated FXR in the intestine protected against liver damage, whereas absence of FXR promoted progression of liver disease. CONCLUSIONS: Activation of FXR transcription in the intestine protects the liver from cholestasis in mice by inducing FGF15 expression and reducing the hepatic pool of BA; this approach might be developed to reverse cholestasis in patients.