Publication

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.

Research output: Contribution to journalArticleAcademicpeer-review

APA

de Boer, J. F., Verkade, E., Mulder, N. L., de Vries, H. D., Huijkman, N. C., Koehorst, M., ... Kuipers, F. (2019). A Human-like Bile Acid Pool Induced by Deletion of Cyp2c70 Modulates Effects of Farnesoid X Receptor Activation in Mice. Journal of Lipid Research. https://doi.org/10.1194/jlr.RA119000243

Author

de Boer, Jan Freark ; Verkade, Esther ; Mulder, Niels L ; de Vries, Hilde D ; Huijkman, Nicolette Ca ; Koehorst, Martijn ; Boer, Theo ; Wolters, Justina C ; Bloks, Vincent W ; van de Sluis, Bart ; Kuipers, Folkert. / A Human-like Bile Acid Pool Induced by Deletion of Cyp2c70 Modulates Effects of Farnesoid X Receptor Activation in Mice. In: Journal of Lipid Research. 2019.

Harvard

de Boer, JF, Verkade, E, Mulder, NL, de Vries, HD, Huijkman, NC, Koehorst, M, Boer, T, Wolters, JC, Bloks, VW, van de Sluis, B & Kuipers, F 2019, 'A Human-like Bile Acid Pool Induced by Deletion of Cyp2c70 Modulates Effects of Farnesoid X Receptor Activation in Mice', Journal of Lipid Research. https://doi.org/10.1194/jlr.RA119000243

Standard

A Human-like Bile Acid Pool Induced by Deletion of Cyp2c70 Modulates Effects of Farnesoid X Receptor Activation in Mice. / de Boer, Jan Freark; Verkade, Esther; Mulder, Niels L; de Vries, Hilde D; Huijkman, Nicolette Ca; Koehorst, Martijn; Boer, Theo; Wolters, Justina C; Bloks, Vincent W; van de Sluis, Bart; Kuipers, Folkert.

In: Journal of Lipid Research, 10.09.2019.

Research output: Contribution to journalArticleAcademicpeer-review

Vancouver

de Boer JF, Verkade E, Mulder NL, de Vries HD, Huijkman NC, Koehorst M et al. A Human-like Bile Acid Pool Induced by Deletion of Cyp2c70 Modulates Effects of Farnesoid X Receptor Activation in Mice. Journal of Lipid Research. 2019 Sep 10. https://doi.org/10.1194/jlr.RA119000243


BibTeX

@article{0d51dc0e1f7b4d17b20049054b281474,
title = "A Human-like Bile Acid Pool Induced by Deletion of Cyp2c70 Modulates Effects of Farnesoid X Receptor Activation in Mice",
abstract = "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.",
author = "{de Boer}, {Jan Freark} and Esther Verkade and Mulder, {Niels L} and {de Vries}, {Hilde D} and Huijkman, {Nicolette Ca} and Martijn Koehorst and Theo Boer and Wolters, {Justina C} and Bloks, {Vincent W} and {van de Sluis}, Bart and Folkert Kuipers",
note = "Published under license by The American Society for Biochemistry and Molecular Biology, Inc.",
year = "2019",
month = "9",
day = "10",
doi = "10.1194/jlr.RA119000243",
language = "English",
journal = "Journal of Lipid Research",
issn = "0022-2275",
publisher = "AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC",

}

RIS

TY - JOUR

T1 - A Human-like Bile Acid Pool Induced by Deletion of Cyp2c70 Modulates Effects of Farnesoid X Receptor Activation in Mice

AU - de Boer, Jan Freark

AU - Verkade, Esther

AU - Mulder, Niels L

AU - de Vries, Hilde D

AU - Huijkman, Nicolette Ca

AU - Koehorst, Martijn

AU - Boer, Theo

AU - Wolters, Justina C

AU - Bloks, Vincent W

AU - van de Sluis, Bart

AU - Kuipers, Folkert

N1 - Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

PY - 2019/9/10

Y1 - 2019/9/10

N2 - 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.

AB - 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.

U2 - 10.1194/jlr.RA119000243

DO - 10.1194/jlr.RA119000243

M3 - Article

JO - Journal of Lipid Research

JF - Journal of Lipid Research

SN - 0022-2275

ER -

ID: 96509772