Regulation of bile acid metabolism in mouse models with hydrophobic bile acid composition

• Published in: Journal of lipid research Vol. 61; no. 1; pp. 54 - 69
• Main Authors: Honda, Akira, Miyazaki, Teruo, Iwamoto, Junichi, Hirayama, Takeshi, Morishita, Yukio, Monma, Tadakuni, Ueda, Hajime, Mizuno, Seiya, Sugiyama, Fumihiro, Takahashi, Satoru, Ikegami, Tadashi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2020; The American Society for Biochemistry and Molecular Biology; Elsevier
• Subjects: 7α-hydroxy-4-cholesten-3-one 12α-hydroxylase; Animals; Aryl Hydrocarbon Hydroxylases - deficiency; Aryl Hydrocarbon Hydroxylases - genetics; Aryl Hydrocarbon Hydroxylases - metabolism; Bile Acids and Salts - chemistry; Bile Acids and Salts - metabolism; Chenodeoxycholic Acid - chemistry; Chenodeoxycholic Acid - metabolism; cholesterol 7α-hydroxylase; CRISPR-Cas9; CYP2A12; CYP2C70; Cytochrome P-450 Enzyme System - deficiency; Cytochrome P-450 Enzyme System - genetics; Cytochrome P-450 Enzyme System - metabolism; cytochrome P450; cytokines; Disease Models, Animal; farnesoid X receptor; Female; Hydrophobic and Hydrophilic Interactions; knockout mouse; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Structure; pregnane X receptor; Rats; Rats, Sprague-Dawley; Steroid Hydroxylases - deficiency; Steroid Hydroxylases - genetics; Steroid Hydroxylases - metabolism; CYP2A12; farnesoid X receptor; CRISPR-Cas9; cholesterol 7α-hydroxylase; cytokines; pregnane X receptor; cytochrome P450; CYP2C70; knockout mouse; 7α-hydroxy-4-cholesten-3-one 12α-hydroxylase
• ISSN: 0022-2275; 1539-7262; 1539-7262
• DOI: 10.1194/jlr.RA119000395

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.