An FXR Agonist Reduces Bile Acid Synthesis Independently of Increases in FGF19 in Healthy Volunteers
An FXR Agonist Reduces Bile Acid Synthesis Independently of Increases in FGF19 in Healthy Volunteers
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DOI：
10.1053/j.gastro.2018.06.038
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发表时间：
2018-10-01
期刊：
影响因子：
29.4
通讯作者：
Angelin, Bo
中科院分区：
文献类型：
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作者：
Al-Khaifi, Amani;Rudling, Mats;Angelin, Bo
胆汁酸（BA）的合成是通过肝细胞和/或肠细胞中法尼醇X受体（FXR）活化抑制肝胆固醇7 α-羟化酶来调节的;在肠细胞中，该过程需要FGF 19信号传导。为了研究这些途径，我们量化了BA合成的标记物（7 α-羟基-4-异戊烯-3-酮[C4]）和胆固醇生成来自给予1次口服剂量的非甾体FXR激动剂Px-102的健康男性志愿者的血清中的纤维母细胞生长因子（FGF）19和BA（0.15 mg/kg、0.3 mg/kg、0.6 mg/kg、1.12 mg/kg、2.25 mg/kg、3.38 mg/kg或4.5 mg/kg）。8小时后，在给予0.15 mg/kg的志愿者中，C4的血清水平降低了80%，而FGF 19的血清水平没有变化。在给予> 0.3mg/kg Px-102的志愿者中，FGF 19的血清水平以剂量依赖性方式显著增加，高达1600%，而C4水平保持显著降低（>80%）。对于所有剂量，在给予Px-102后24小时，FGF 19水平恢复正常。C4的血清水平在FGF 19水平增加之前降低，并且在最高剂量（4.5mg/kg）的Px-102后24小时仍降低95%，即使FGF 19水平已恢复至基线。我们的研究结果表明，肝FXR的激活能够抑制BA的合成，独立于FGF 19。
Bile acid (BA) synthesis is regulated through suppression of hepatic cholesterol 7 alpha-hydroxylase via farnesoid X receptor (FXR) activation in hepatocytes and/or enterocytes; in enterocytes, this process requires FGF19 signaling. To study these pathways, we quantified markers of BA synthesis (7 alpha-hydroxy-4-cholesten-3-one [C4]) and cholesterol production (lathosterol), fibroblast growth factor (FGF)19, and BAs in serum from healthy male volunteers given 1 oral dose of the nonsteroidal FXR agonist Px-102 (0.15 mg/kg, 0.3 mg/kg, 0.6 mg/kg, 1.12 mg/kg, 2.25 mg/kg, 3.38 mg/kg, or 4.5 mg/kg). After 8 hours, serum levels of C4 decreased by 80% in volunteers given 0.15 mg/kg, whereas serum levels of FGF19 were unchanged. Serum levels of FGF19 increased significantly, in a dose-dependent manner, in volunteers given >0.3 mg/kg Px-102, up to as much as 1600%, whereas C4 levels remained significantly reduced (by >80%). For all doses, FGF19 levels returned to normal 24 hours after administration of Px-102. Serum levels of C4 decreased before levels of FGF19 levels increased, and were still reduced by 95% 24 hours after the highest dose (4.5 mg/kg) of Px-102, even though levels of FGF19 had returned to baseline. Our findings indicate that activation of hepatic FXR is able to suppress BA synthesis, independent of FGF19.