Li Zhanyi, Lin Bingliang, Lin Guoli, Wu Yuankai, Jie Yusheng, Li Xiangyong, Ko Brian, Chong Yutian, Luo Jian
Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
NGM Biopharmaceuticals, Inc., South San Francisco, California, United States of America.
PLoS One. 2017 Jun 1;12(6):e0178580. doi: 10.1371/journal.pone.0178580. eCollection 2017.
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.
肝脏中的胆汁酸（BA）合成受回肠分泌的成纤维细胞生长因子19（FGF19）调节，作为一种肠肝反馈机制。虽然正常肝脏中不存在FGF19 mRNA，但据报道，肝外和肝内胆汁淤积均可导致FGF19基因表达增加。FGF19表达上调对BA合成的影响尚不清楚，胆汁淤积条件下循环FGF19和BA合成的整体作用有待进一步研究。
通过测量44例原发性胆汁性肝硬化（PBC）患者和10名健康受试者的血清7α-羟基胆甾-4-烯-3-酮（C4）浓度、血清FGF19及其他参数，直接定量BA合成。
与健康或非肝硬化PBC患者相比，肝硬化PBC患者的血清C4显著降低，而FGF19则较高。对循环FGF19、BA合成与胆汁淤积之间关系的分析表明，循环FGF19与BA合成密切相关（r = -0.735，p<0.0001），与胆汁淤积严重程度密切相关（r = 0.590，p<0.001）。此外，发现BA合成与胆汁淤积程度密切相关（r = 0.522，p = 0.0005）。
这些发现表明，胆汁淤积时BA合成的调节主要受循环FGF19控制，在胆汁淤积条件下，FGF19-BA合成反馈机制保持完整。给予FGF19或合适的模拟物作为药物干预，以提高循环FGF19水平并通过抑制CYP7A1基因表达来抑制BA合成，可能会为许多PBC患者带来治疗益处。
