Regulation of bile acid metabolism in mouse models with hydrophobic bile acid composition
| Autor: | Teruo Miyazaki, Tadashi Ikegami, Satoru Takahashi, Junichi Iwamoto, Tadakuni Monma, Fumihiro Sugiyama, Akira Honda, Yukio Morishita, Seiya Mizuno, Takeshi Hirayama, Hajime Ueda |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Lithocholic acid cytochrome P450 medicine.drug_class QD415-436 030204 cardiovascular system & hematology Chenodeoxycholic Acid Biochemistry Bile Acids and Salts Rats Sprague-Dawley CYP2A12 Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Endocrinology Cytochrome P-450 Enzyme System Chenodeoxycholic acid 7α-hydroxy-4-cholesten-3-one 12α-hydroxylase medicine Animals Research Articles Mice Knockout Molecular Structure cholesterol 7α-hydroxylase Bile acid Deoxycholic acid Cholic acid CYP2C70 Cell Biology Molecular biology Rats Mice Inbred C57BL Disease Models Animal 030104 developmental biology chemistry Steroid Hydroxylases Knockout mouse Small heterodimer partner Female Farnesoid X receptor Aryl Hydrocarbon Hydroxylases CRISPR-Cas9 Hydrophobic and Hydrophilic Interactions |
| Zdroj: | Journal of Lipid Research, Vol 61, Iss 1, Pp 54-69 (2020) J Lipid Res |
| ISSN: | 0022-2275 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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