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A Human-like Bile Acid Pool Induced by Deletion of Cyp2c70 Modulates Effects of Farnesoid X Receptor Activation in Mice

de Boer, J. F., Verkade, E., Mulder, N. L., de Vries, H. D., Huijkman, N. C., Koehorst, M., Boer, T., Wolters, J. C., Bloks, V. W., van de Sluis, B. & Kuipers, F., 10-Sep-2019, In : Journal of Lipid Research.

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  • A Human-like Bile Acid Pool Induced by Deletion of Cyp2c70 Modulates Effects of Farnesoid X Receptor Activation in Mice

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DOI

Bile acids (BAs) facilitate intestinal absorption of lipid-soluble nutrients and modulate various metabolic pathways through the farnesoid X receptor (FXR) and Takeda G-protein-coupled receptor 5. These receptors are targets for therapy in cholestatic and metabolic diseases. However, dissimilarities in BA metabolism between humans and mice complicate translation of preclinical data. CYP2C70 was recently proposed to catalyze the formation of rodent-specific muricholic acids (MCAs). With CRISPR/Cas9-mediated somatic genome editing, we generated an acute hepatic Cyp2c70 knock-out mouse model (Cyp2c70ako) to clarify the role of CYP2C70 in BA metabolism in vivo and evaluate whether its activity modulates effects of pharmacologic FXR activation on cholesterol homeostasis. In Cyp2c70ako mice, chenodeoxycholic acid (CDCA) increased at the expense of βMCA, resulting in a more hydrophobic, human-like BA pool. Tracer studies demonstrated that, in vivo, CYP2C70 catalyzes the formation of βMCA primarily by sequential 6β- hydroxylation and C7-epimerization of CDCA, generating αMCA as an intermediate metabolite. Physiologically, the humanized BA composition in Cyp2c70ako mice blunted the stimulation of fecal cholesterol disposal in response to FXR activation compared with wild-type mice, predominantly due to reduced stimulation of transintestinal cholesterol excretion. Thus, deletion of hepatic Cyp2c70 in adult mice translates into a human-like BA pool composition and impacts the response to pharmacologic FXR activation. This Cyp2c70ako mouse model may be a useful tool for future studies of BA signaling and metabolism that informs human disease development and treatment.

Original languageEnglish
JournalJournal of Lipid Research
Publication statusE-pub ahead of print - 10-Sep-2019

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