Cyp3a11 is not essential for the formation of murine bile acids.
Cyp3a11 is not essential for the formation of murine bile acids.
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DOI：
10.1016/j.bbrep.2017.02.011
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发表时间：
2017-07
影响因子：
2.7
通讯作者：
Marschall HU
中科院分区：
文献类型：
--
作者：
Wahlström A;Al-Dury S;Ståhlman M;Bäckhed F;Marschall HU
人类和小鼠的胆汁酸谱存在很大差异，因为小鼠除了胆酸（CA）外，主要合成6β-羟基化胆酸（MCAs），而人类则产生鹅脱氧胆酸（CDCA）和CA作为初级胆汁酸。确定执行6β-羟基化的基因将有助于“人源化”小鼠胆汁酸谱，以研究胆汁酸、肠道微生物群和宿主代谢之间的相互作用。我们研究了原代小鼠肝细胞中MCAs的形成，发现αMCA由CDCA合成，βMCA由UDCA合成。通常认为p450酶CYP3A11催化胆汁酸的6β-羟基化，因此我们假设没有CYP3A11基因的小鼠缺乏MCAs。为了验证这一假设，我们分析了Cyp3a缺陷小鼠的胆汁酸谱，这些小鼠缺乏包括Cyp3a11在内的Cyp3a基因簇中的7个基因，并将其与野生型同伴对照进行了比较。用UPLC-MS/MS分析Cyp3a敲除小鼠和野生型同窝小鼠的肝脏、胆囊、盲肠和血清中的胆酸组成，发现胆酸组成无明显差异。我们得出结论，Cyp3a11不是6β-羟基化和MCAs形成所必需的。
Humans and mice differ substantially in their bile acid profiles as mice in addition to cholic acid (CA) predominantly synthesize 6β-hydroxylated muricholic acids (MCAs) whereas humans produces chenodeoxycholic acid (CDCA) and CA as primary bile acids. Identifying the gene performing 6β-hydroxylation would be useful for ‘humanizing’ the bile acid profile in mice for studies of the interaction between bile acids, gut microbiota, and host metabolism. We investigated the formation of MCAs in primary murine hepatocytes and found that αMCA is synthesized from CDCA and βMCA from UDCA. It is commonly assumed that the P450-enzyme CYP3A11 catalyzes 6β-hydroxylation of bile acids, thus we hypothesized that mice without the Cyp3a11 gene would lack MCAs. To test this hypothesis, we analyzed bile acid profiles in Cyp3a deficient mice, which lack 7 genes in the Cyp3a gene cluster including Cyp3a11, and compared them with wild-type littermate controls. Bile acid composition in liver, gallbladder, caecum and serum from Cyp3a knock out mice and wild-type littermate controls was analyzed with UPLC-MS/MS and revealed no major differences in bile acid composition. We conclude that Cyp3a11 is not necessary for 6β-hydroxylation and the formation of MCAs.