Urinary metabolomics in Fxr-null mice reveals activated adaptive metabolic pathways upon bile acid challenge
Urinary metabolomics in Fxr-null mice reveals activated adaptive metabolic pathways upon bile acid challenge
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DOI：
10.1194/jlr.m002923
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发表时间：
2010-05-01
影响因子：
6.5
通讯作者：
Gonzalez, Frank J.
中科院分区：
文献类型：
--
作者：
Cho, Joo-Youn;Matsubara, Tsutomu;Gonzalez, Frank J.
法尼醇X受体(FXR)是一种核受体，调节胆汁酸的合成、代谢和转运相关基因，在维持胆汁酸动态平衡方面发挥重要作用。在这项研究中，用超高效液相色谱(UPLC)和电喷雾飞行时间质谱仪(TOFMS)联用，研究了FXR配体胆酸对野生型和FXR基因缺失小鼠尿液的代谢反应。对胆酸饮食的野生型和FXR缺失型小鼠之间的多变量数据分析显示，FXR缺失型小鼠中增加最多的离子是对甲酚(4-甲基苯酚)、皮质酮和胆酸的代谢物。通过化学合成和比较尿代谢物的保留时间(RT)和/或串联质量裂解模式与正品标准，证实了上述代谢物的结构一致性。牛磺酸-3α，6，7α，12α-四氢吡喃(3α，6，7α，12α-四羟基-5β-胆烷-26-甲酰牛磺酸)是服用CA饮食的FXR基因缺失小鼠体内增加最多的代谢物之一，它是有毒胆汁酸有效羟化的标志，可能是通过诱导Cyp3a11。石胆酸诱导的胆汁淤积模型显示，Cyp3a11的表达增强是FXR基因缺失小鼠解毒胆汁酸的主要防御机制。这些结果将有助于确定胆汁淤积的生物标志物和确定胆汁淤积的适应性分子机制。-Cho，J.Y.，T.Matsubara，D.W.Kang，S.H.Ahn，K.W.Krausz，J.R.Idle，H.Luecke，和F.J.Gonzalez。FXR基因缺失小鼠的尿液代谢组学揭示了胆汁酸攻击时激活的适应性代谢途径。J.Lipid Res.2010年。51：1063-1074。
Farnesoid X receptor (FXR) is a nuclear receptor that regulates genes involved in synthesis, metabolism, and transport of bile acids and thus plays a major role in maintaining bile acid homeostasis. In this study, metabolomic responses were investigated in urine of wild-type and Fxr-null mice fed cholic acid, an FXR ligand, using ultra-performance liquid chromatography (UPLC) coupled with electrospray time-of-flight mass spectrometry (TOFMS). Multivariate data analysis between wild-type and Fxr-null mice on a cholic acid diet revealed that the most increased ions were metabolites of p-cresol (4-methylphenol), corticosterone, and cholic acid in Fxr-null mice. The structural identities of the above metabolites were confirmed by chemical synthesis and by comparing retention time (RT) and/or tandem mass fragmentation patterns of the urinary metabolites with the authentic standards. Tauro-3 alpha,6,7 alpha,12 alpha-tetrol (3 alpha,6,7 alpha,12 alpha-tetrahydroxy-5 beta-cholestan-26-oyltaurine), one of the most increased metabolites in Fxr-null mice on a CA diet, is a marker for efficient hydroxylation of toxic bile acids possibly through induction of Cyp3a11. A cholestatic model induced by lithocholic acid revealed that enhanced expression of Cyp3a11 is the major defense mechanism to detoxify cholestatic bile acids in Fxr-null mice. These results will be useful for identification of biomarkers for cholestasis and for determination of adaptive molecular mechanisms in cholestasis.-Cho, J. Y., T. Matsubara, D. W. Kang, S. H. Ahn, K. W. Krausz, J. R. Idle, H. Luecke, and F. J. Gonzalez. Urinary metabolomics in Fxr-null mice reveals activated adaptive metabolic pathways upon bile acid challenge. J. Lipid Res. 2010. 51: 1063-1074.