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首页> 外文期刊>Journal of Lipid Research >Regulation of bile acid metabolism in mouse models with hydrophobic bile acid composition[S]
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Regulation of bile acid metabolism in mouse models with hydrophobic bile acid composition[S]

机译：用疏水胆汁酸组合物调节小鼠模型中的小鼠模型中的胆酸代谢[S]

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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.
机译：小鼠中的胆汁酸（BA）组合物与人类的胆汁酸（BA）组合物基本上不同于人体。赤二氧胆酸（CDCA）是人肝中的最终产品;然而，小鼠CYP2C70将CDCA代谢为亲水性杂体酸（MCA）。此外，在人类中，肠道微生物蛋白分别将初级碱，胆酸和CDCA转化为脱氧胆酸（DCA）和锂电酸（LCA）。相比之下，鼠标CYP2A12恢复此操作并将这些辅助基础转换为主BAS。这里，我们使用CRISPR-CAS9系统生成CYP2A12 KO，CYP2C70 KO和CYP2A12 / CYP2C70双KO（DKO）小鼠，以研究疏水性BA组合物在疏水性BA组合物下的BA代谢调节。 CYP2A12 KO小鼠显示DCA的积累，而CYP2C70 KO小鼠缺乏MCAS，并且表现出显着提高CDCA的肝胆比例。在DKO小鼠中，不仅是DCAS或CDCA，还包括DCAS，CDCAS和LCA都是升高的。在CYP2C70 KO和DKO小鼠中，根据肝脏未缀合的CDCA浓度观察到慢性肝脏炎症。 CYP2C70 KO和DKO小鼠的BA池显着降低，但FXR未激活。建议细胞因子/ C-JUM N-末端激酶信号传导途径和妊娠X受体介导的途径是主要机制，优选用于控制BA合成的FXR /小异二二二二二二二二二二二聚体伴侣和FXR /成纤维细胞生长因子15途径。在疏水性BA组合物下。从我们的结果中，我们假设这些KO小鼠可以是研究疏水性族在各种人类疾病中的作用的新颖和有用的模型。

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