Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD
Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD
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DOI：
10.1136/gutjnl-2017-314307
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发表时间：
2018-10-01
期刊：
影响因子：
24.5
通讯作者：
Zhu, Lixin
中科院分区：
文献类型：
--
作者：
Jiao, Na;Baker, Susan S.;Zhu, Lixin
目的胆汁酸是糖、脂代谢的调节剂，对肝脏等组织的炎症反应具有调节作用。初级胆汁酸如胆酸和鹅去氧胆酸（CDCA）在肝脏中产生，并通过肠道微生物群转化为次级胆汁酸如脱氧胆酸（DCA）和石胆酸。在这里，我们研究了胆汁酸在非酒精性脂肪性肝病（NAFLD）发病机制中的可能作用以及肠道微生物组对NAFLD中胆汁酸信号传导的影响。设计在NAFLD患者中测定血清胆汁酸水平和成纤维细胞生长因子19（FGF 19）、肝脏基因表达谱和肠道微生物组组成，结果NAFLD患者血清中初级胆汁酸和次级胆汁酸浓度升高。在NAFLD中，法尼醇X受体（FXR）拮抗性DCA增加，而激动性CDCA减少。细胞色素P450 7A 1、Na+-牛磺胆酸盐共转运多肽和对氧磷酶1的mRNA表达增加，小异源二聚体伴侣和胆盐输出泵的mRNA表达无变化，血清FGF 19降低，这些都是NAFLD中FXR和成纤维细胞生长因子受体4（FGFR 4）介导的信号传导受损的证据。NAFLD患者肠道中牛磺酸和甘氨酸代谢细菌增加，反映次级胆汁酸产生增加。在高脂饮食喂养的大鼠中观察到肝脏基因表达和肠道微生物组的类似变化。结论血清胆汁酸谱、肝脏基因表达模式和肠道微生物组组成一致支持NAFLD中胆汁酸产生升高。FXR拮抗性胆汁酸的比例增加至少部分解释了肝脏FXR介导和FGFR 4介导的信号传导的抑制。我们的研究表明，未来的NAFLD干预可能针对FXR信号传导的组分，包括胆汁酸转化肠道微生物组。
Objective Bile acids are regulators of lipid and glucose metabolism, and modulate inflammation in the liver and other tissues. Primary bile acids such as cholic acid and chenodeoxycholic acid (CDCA) are produced in the liver, and converted into secondary bile acids such as deoxycholic acid (DCA) and lithocholic acid by gut microbiota. Here we investigated the possible roles of bile acids in non-alcoholic fatty liver disease (NAFLD) pathogenesis and the impact of the gut microbiome on bile acid signalling in NAFLD.Design Serum bile acid levels and fibroblast growth factor 19 (FGF19), liver gene expression profiles and gut microbiome compositions were determined in patients with NAFLD, high-fat diet-fed rats and their controls.Results Serum concentrations of primary and secondary bile acids were increased in patients with NAFLD. In per cent, the farnesoid X receptor (FXR) antagonistic DCA was increased, while the agonistic CDCA was decreased in NAFLD. Increased mRNA expression for cytochrome P450 7A1, Na+-taurocholate cotransporting polypeptide and paraoxonase 1, no change in mRNA expression for small heterodimer partner and bile salt export pump, and reduced serum FGF19 were evidence of impaired FXR and fibroblast growth factor receptor 4 (FGFR4)-mediated signalling in NAFLD. Taurine and glycine metabolising bacteria were increased in the gut of patients with NAFLD, reflecting increased secondary bile acid production. Similar changes in liver gene expression and the gut microbiome were observed in high-fat diet-fed rats.Conclusions The serum bile acid profile, the hepatic gene expression pattern and the gut microbiome composition consistently support an elevated bile acid production in NAFLD. The increased proportion of FXR antagonistic bile acid explains, at least in part, the suppression of hepatic FXR-mediated and FGFR4-mediated signalling. Our study suggests that future NAFLD intervention may target the components of FXR signalling, including the bile acid converting gut microbiome.