Circulating FGF19 closely correlates with bile acid synthesis and cholestasis in patients with primary biliary cirrhosis.
Circulating FGF19 closely correlates with bile acid synthesis and cholestasis in patients with primary biliary cirrhosis.
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DOI：
10.1371/journal.pone.0178580
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Luo J
中科院分区：
文献类型：
--
作者：
Li Z;Lin B;Lin G;Wu Y;Jie Y;Li X;Ko B;Chong Y;Luo J
肝脏中胆汁酸（BA）的合成受回肠分泌的成纤维细胞生长因子19（FGF 19）的调节，这是一种肠肝反馈机制。虽然FGF 19 mRNA在正常肝脏中不存在，但据报道FGF 19基因表达在对肝外和肝内胆汁淤积的反应中增加。上调的FGF 19表达对BA合成的影响尚不清楚，胆汁淤积条件下循环FGF 19和BA合成的总体作用需要进一步研究。通过测定44例原发性胆汁性肝硬化（PBC）患者和10例健康受试者的血清7 α-羟基胆甾-4-烯-3-酮（C4）浓度、沿着血清FGF 19和其他参数，直接定量BA合成。与健康或非炎性PBC患者相比，炎性PBC患者的血清C4显著降低，而FGF 19则升高。对循环FGF 19、BA合成和胆汁淤积之间的关系的分析显示，循环FGF 19与BA合成（r =-0.735，p<0.0001）和胆汁淤积的严重程度（r = 0.590，p<0.001）强烈相关。此外，发现BA合成与胆汁淤积的程度强烈相关（r = 0.522，p = 0.0005）。这些发现表明，响应胆汁淤积的BA合成的调节主要由循环FGF 19控制，并且在胆汁淤积条件下，FGF 19-BA合成反馈机制保持完整。施用FGF 19或合适的模拟物作为药理学干预以增加FGF 19的循环水平并通过抑制CYP 7A 1基因表达来抑制BA合成可能为许多PBC患者提供治疗益处。
Bile acid (BA) synthesis in the liver is regulated by Fibroblast Growth Factor 19 (FGF19) secreted from the ileum as an enterohepatic feedback mechanism. Although FGF19 mRNA is absent in normal liver, FGF19 gene expression was reported to increase in response to both extrahepatic and intrahepatic cholestasis. The impact of upregulated FGF19 expression on BA synthesis is unclear and the overall role of circulating FGF19 and BA synthesis under cholestatic conditions needs to be further investigated. BA synthesis was directly quantified by measuring serum concentrations of 7alpha-hydroxycholest-4-en-3-one (C4), along with serum FGF19 and other parameters, in 44 patients with primary biliary cirrhosis (PBC) and 10 healthy subjects. Serum C4 were substantially lower, while those of FGF19 were higher, in cirrhotic PBC patients, as compared to those of either healthy or non-cirrhotic PBC patients. Analyses of the relationships between circulating FGF19, BA synthesis and cholestasis revealed that circulating FGF19 was strongly correlated with BA synthesis (r = -0.735, p<0.0001) and the severity of cholestasis (r = 0.590, p<0.001). Moreover, BA synthesis was found to be strongly correlated with the degree of cholestasis (r = 0.522, p = 0.0005). These findings demonstrate that the regulation of BA synthesis in response to cholestasis is primarily controlled by circulating FGF19 and that under cholestatic conditions, the FGF19-BA synthesis feedback mechanism remains intact. Administering FGF19, or suitable mimetic, as a pharmacological intervention to increase circulating levels of FGF19 and suppress BA synthesis by inhibiting CYP7A1 gene expression is likely to provide therapeutic benefits for many PBC patients.