The bile acid (BA) composition in mice is substantially different from that in humans. Chenodeoxycholic acid (CDCA) is an end product in the human liver; however, mouse Cyp2c70 metabolizes CDCA to hydrophilic muricholic acids (MCAs). Moreover, in humans, the gut microbiota converts the primary BAs, cholic acid and CDCA, into deoxycholic acid (DCA) and lithocholic acid (LCA), respectively. In contrast, the mouse Cyp2a12 reverts this action and converts these secondary BAs to primary BAs. Here, we generated Cyp2a12 KO, Cyp2c70 KO, and Cyp2a12/Cyp2c70 double KO (DKO) mice using the CRISPR-Cas9 system to study the regulation of BA metabolism under hydrophobic BA composition. Cyp2a12 KO mice showed the accumulation of DCAs, whereas Cyp2c70 KO mice lacked MCAs and exhibited markedly increased hepatobiliary proportions of CDCA. In DKO mice, not only DCAs or CDCAs but also DCAs, CDCAs, and LCAs were all elevated. In Cyp2c70 KO and DKO mice, chronic liver inflammation was observed depending on the hepatic unconjugated CDCA concentrations. The BA pool was markedly reduced in Cyp2c70 KO and DKO mice, but the FXR was not activated. It was suggested that the cytokine/c-Jun N-terminal kinase signaling pathway and the pregnane X receptor-mediated pathway are the predominant mechanisms, preferred over the FXR/small heterodimer partner and FXR/fibroblast growth factor 15 pathways, for controlling BA synthesis under hydrophobic BA composition. From our results, we hypothesize that these KO mice can be novel and useful models for investigating the roles of hydrophobic BAs in various human diseases.

中文翻译：

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疏水性胆汁酸成分对小鼠模型中胆汁酸代谢的调节。

小鼠中的胆汁酸（BA）组成与人类中的胆汁酸（BA）组成基本不同。鹅去氧胆酸（CDCA）是人类肝脏中的终产物。但是，小鼠Cyp2c70将CDCA代谢为亲水性muricholic酸（MCA）。此外，在人体中，肠道菌群分别将主要的BA，胆酸和CDCA分别转化为脱氧胆酸（DCA）和石胆酸（LCA）。相比之下，鼠标Cyp2a12还原此动作并将这些辅助BA转换为主要BA。在这里，我们使用CRISPR-Cas9系统生成了Cyp2a12 KO，Cyp2c70 KO和Cyp2a12 / Cyp2c70双KO（DKO）小鼠，以研究疏水性BA组成下BA代谢的调控。Cyp2a12 KO小鼠显示出DCA的积累，而Cyp2c70 KO小鼠缺乏MCA，并且显示CDCA肝胆比例明显增加。在DKO小鼠中，不仅DCA或CDCA，而且DCA，CDCA和LCA均升高。在Cyp2c70 KO和DKO小鼠中，根据肝脏未结合的CDCA浓度观察到慢性肝炎。Cyp2c70中BA库显着减少KO和DKO小鼠，但FXR未激活。提示控制BA合成的主要机制是细胞因子/ c-Jun N末端激酶信号传导途径和孕烷X受体介导的途径，优于FXR /小的异二聚体伴侣和FXR /成纤维细胞生长因子15途径。在疏水BA组成下。从我们的结果，我们假设这些KO小鼠可以是新颖和有用的模型，用于研究疏水性BA在各种人类疾病中的作用。