Jung Diana, Inagaki Takeshi, Gerard Robert D, Dawson Paul A, Kliewer Steven A, Mangelsdorf David J, Moschetta Antonio
Howard Hughes Medical Institute and Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9050, USA.
J Lipid Res. 2007 Dec;48(12):2693-700. doi: 10.1194/jlr.M700351-JLR200. Epub 2007 Sep 6.
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 7alpha-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.
胆汁酸吸收不良在患者中会导致粪便胆汁酸排泄过多和腹泻，其特征是一个恶性循环，即胆汁酸合成的反馈调节被中断，从而导致额外的胆汁酸生成。胆汁酸合成的反馈调节受一条内分泌途径控制，其中核胆汁酸受体法尼酯X受体（FXR）的激活会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介导的小异源二聚体伴侣的表达共同作用，抑制胆汁酸合成。在此，我们表明，在缺乏顶端回肠胆汁酸转运蛋白的小鼠（一种胆汁酸吸收不良模型）中，FXR-FGF15途径被破坏。用合成FXR激动剂或FGF15治疗Asbt-/-小鼠可下调肝脏胆固醇7α-羟化酶mRNA水平，减小胆汁酸池大小，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，以中断胆汁酸吸收不良患者中胆汁酸过度生成的循环。
