Urinary metabolomics in Fxr-null mice reveals activated adaptive metabolic pathways upon bile acid challenge.
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-3alpha,6,7alpha,12alpha-tetrol (3alpha,6,7alpha,12alpha-tetrahydroxy-5beta-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
Joo-Youn
JY
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
Matsubara
Tsutomu
T
Kang
Dong Wook
DW
Ahn
Sung-Hoon
SH
Krausz
Kristopher W
KW
Idle
Jeffrey R
JR
Luecke
Hans
H
Gonzalez
Frank J
FJ
D000222:Adaptation, Physiological; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism / Q000494:pharmacology*; D002793:Cholic Acids / Q000378:metabolism / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D003408:Cresols / Q000378:metabolism / Q000652:urine; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000378:metabolism / Q000652:urine; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D053858:Metabolic Networks and Pathways; D055432:Metabolomics; D051379:Mice; D015999:Multivariate Analysis; D010641:Phenotype; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency* / Q000235:genetics; D016482:Urinalysis; D000099150:Receptor, Farnesoid X-Activated
D001647:Bile Acids and Salts; D002793:Cholic Acids; D003408:Cresols; D005938:Glucocorticoids; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C032538:4-cresol