法尼甾体X受体
胆汁淤积
内科学
胆汁酸
小异二聚体伴侣
内分泌学
肝肠循环
G蛋白偶联胆汁酸受体
FGF19型
化学
小肠
核受体
进行性家族性肝内胆汁淤积症
孕烷X受体
生物
受体
CYP8B1
胆固醇7α羟化酶
成纤维细胞生长因子
转录因子
生物化学
医学
肝移植
移植
基因
作者
Salvatore Modica,Michele Petruzzelli,Elena Bellafante,Stefania Murzilli,Lorena Salvatore,Nicola Celli,Giuseppe Di Tullio,Giuseppe Palasciano,Tarek Moustafa,Emina Halilbasic,Michael Trauner,Antonio Moschetta
标识
DOI:10.1053/j.gastro.2011.10.028
摘要
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 7α-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.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.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 α-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.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.
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