Characterization of Novel Low Bile Acid Mouse Model

Bile acids (BAs) are signaling molecules synthesized in the liver initiated by CYP7A1 and CYP27A1 in the classical and alternative pathways, respectively. BAs are essential for cholesterol clearance, intestinal absorption of lipids, and endogenous modulators of farnesoid x receptor (FXR). FXR is critical in maintaining BA homeostasis and gut-liver crosstalk. Complex reactions in vivo and the lack of suitable animal models impede on our understanding of the functions of individual BAs. In the study, we characterized the low in vivo BA mouse model comparing naive WT and DKO (Cyp7a1-/-/Cyp27a1-/-, DKO) mice. In the same study we also investigated the effects of three-day feeding of cholic acid (CA), deoxycholic acid (DCA), or ursodeoxycholic acid (UDCA) in a novel low BA mouse model. The current study is the first to mechanistically investigate to what degree that CA, DCA and UDCA signal individually in a low-BA mouse model at physiological/non-hepatotoxic concentrations. We determined BA signaling by the FXR-fibroblast growth factor 15 axis, liver injury, and BA levels and composition. Low BAs in DKO mice was associated with higher basal inflammation and altered lipid metabolism compared to WT mice. Dietary CA/DCA altered tissue BA profiles similarly. UDCA did not offer any overt protective effects and altered tissue BA profile compared to baseline. Our data demonstrate that CA, DCA and UDCA feeding activates FXR with tissue specificity. UDCA promoted a more hydrophobic tissue BA pool with the profiles shifted towards non-12-alpha-OH BAs and secondary BAs. These findings allow us to determine more precisely the individual effect of BAs in vivo on BA-FXR signaling and overall BA homeostasis, which may help to better understand the mechanisms by which BAs signal in liver physiology and pathologies.

胆汁酸（Bile acids, BAs）是在肝脏中合成的信号分子，其经典合成途径由CYP7A1启动，替代合成途径则由CYP27A1介导。胆汁酸对于胆固醇清除、肠道脂质吸收至关重要，同时也是法尼醇X受体（Farnesoid X receptor, FXR）的内源性调节剂。法尼醇X受体在维持胆汁酸稳态与肝肠串扰中发挥关键作用。体内复杂的代谢反应以及合适动物模型的匮乏，阻碍了我们对单一胆汁酸功能的解析。本研究构建了低体内胆汁酸水平的小鼠模型，对比了野生型（WT）与双基因敲除小鼠（DKO，Cyp7a1-/-/Cyp27a1-/-）的表型。与此同时，本研究还利用该新型低胆汁酸小鼠模型，探究了连续3天饲喂胆酸（cholic acid, CA）、脱氧胆酸（deoxycholic acid, DCA）或熊去氧胆酸（ursodeoxycholic acid, UDCA）的生物学效应。本研究首次在低胆汁酸小鼠模型中，以生理浓度及非肝毒性浓度，从机制层面探究了CA、DCA与UDCA各自的信号调控作用。我们通过检测法尼醇X受体-成纤维细胞生长因子15（fibroblast growth factor 15）信号轴、肝脏损伤情况以及胆汁酸的水平与组成，来表征胆汁酸的信号通路活性。与野生型小鼠相比，双基因敲除小鼠体内胆汁酸水平低下，伴随更高的基础炎症水平与脂质代谢紊乱。饲喂CA或DCA可相似地改变组织胆汁酸谱。与基线水平相比，UDCA未表现出明显的保护作用，且会改变组织胆汁酸谱。我们的研究数据表明，饲喂CA、DCA与UDCA均可通过组织特异性方式激活法尼醇X受体。UDCA可促进形成更具疏水性的组织胆汁酸池，其谱型向非12α-羟基胆汁酸与次级胆汁酸偏移。上述发现使我们能够更精准地明确单一胆汁酸在体内对胆汁酸-FXR信号通路及整体胆汁酸稳态的调控作用，这将有助于进一步阐明胆汁酸在肝脏生理与病理过程中的信号调控机制。