FXR agonists and FGF15 reduce fecal bile acid excretion in a mouse model of bile acid malabsorption
FXR agonists and FGF15 reduce fecal bile acid excretion in a mouse model of bile acid malabsorption
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DOI：
10.1194/jlr.m700351-jlr200
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发表时间：
2007-12-01
影响因子：
6.5
通讯作者：
Moschetta, Antonio
中科院分区：
文献类型：
--
作者：
Jung, Diana;Inagaki, Takeshi;Moschetta, Antonio
胆汁酸吸收不良会导致患者粪便胆汁酸排泄过多和腹泻，其特点是恶性循环，其中胆汁酸合成的反馈调节被中断，导致额外的胆汁酸产生。胆汁酸合成的反馈调节受到内分泌途径的控制，其中核胆汁酸受体法尼醇 X 受体 (FXR) 的激活诱导激素成纤维细胞生长因子 15 (FGF15) 的肠道表达。在肝脏中，FGF15 与 FXR 介导的小异二聚体伴侣的表达一起作用，抑制胆汁酸合成。在这里，我们发现缺乏顶端回肠胆汁酸转运蛋白的小鼠（胆汁酸吸收不良的模型）中 FXR-FGF15 通路被破坏。用合成 FXR 激动剂或 FGF15 治疗 Asbt(-/-) 小鼠可下调肝脏胆固醇 7 α-羟化酶 mRNA 水平，减少胆汁酸池大小，并减少粪便胆汁酸排泄。这些发现表明，FXR 激动剂或 FGF15 可用于治疗性中断胆汁酸吸收不良患者过度产生胆汁酸的循环。
Bile acid malabsorption, which in patients leads to excessive fecal bile acid excretion and diarrhea, is characterized by a vicious cycle in which the feedback regulation of bile acid synthesis is interrupted, resulting in additional bile acid production. Feedback regulation of bile acid synthesis is under the control of an endocrine pathway wherein activation of the nuclear bile acid receptor, farnesoid X receptor (FXR), induces enteric expression of the hormone, fibroblast growth factor 15 (FGF15). In liver, FGF15 acts together with FXR-mediated expression of small heterodimer partner to repress bile acid synthesis. Here, we show that the FXR-FGF15 pathway is disrupted in mice lacking apical ileal bile acid transporter, a model of bile acid malabsorption. Treatment of Asbt(-/-) mice with either a synthetic FXR agonist or FGF15 downregulates hepatic cholesterol 7 alpha-hydroxylase mRNA levels, decreases bile acid pool size, and reduces fecal bile acid excretion. These findings suggest that FXR agonists or FGF15 could be used therapeutically to interrupt the cycle of excessive bile acid production in patients with bile acid malabsorption.