A human-like bile acid pool induced by deletion of hepatic Cyp2c70 modulates effects of FXR activation in mice[S]
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...
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| Format: | Article |
| Language: | English |
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Elsevier
2020-03-01
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| Series: | Journal of Lipid Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S002222752043514X |
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doaj-1b56e3171b514bbe9f8130fcfd347f64 |
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Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Jan Freark de Boer Esther Verkade Niels L. Mulder Hilde D. de Vries Nicolette Huijkman Martijn Koehorst Theo Boer Justina C. Wolters Vincent W. Bloks Bart van de Sluis Folkert Kuipers |
| spellingShingle |
Jan Freark de Boer Esther Verkade Niels L. Mulder Hilde D. de Vries Nicolette Huijkman Martijn Koehorst Theo Boer Justina C. Wolters Vincent W. Bloks Bart van de Sluis Folkert Kuipers A human-like bile acid pool induced by deletion of hepatic Cyp2c70 modulates effects of FXR activation in mice[S] Journal of Lipid Research liver humanized mouse model cholesterol transintestinal cholesterol excretion cytochrome P450 family 2 subfamily c polypeptide 70 |
| author_facet |
Jan Freark de Boer Esther Verkade Niels L. Mulder Hilde D. de Vries Nicolette Huijkman Martijn Koehorst Theo Boer Justina C. Wolters Vincent W. Bloks Bart van de Sluis Folkert Kuipers |
| author_sort |
Jan Freark de Boer |
| title |
A human-like bile acid pool induced by deletion of hepatic Cyp2c70 modulates effects of FXR activation in mice[S] |
| title_short |
A human-like bile acid pool induced by deletion of hepatic Cyp2c70 modulates effects of FXR activation in mice[S] |
| title_full |
A human-like bile acid pool induced by deletion of hepatic Cyp2c70 modulates effects of FXR activation in mice[S] |
| title_fullStr |
A human-like bile acid pool induced by deletion of hepatic Cyp2c70 modulates effects of FXR activation in mice[S] |
| title_full_unstemmed |
A human-like bile acid pool induced by deletion of hepatic Cyp2c70 modulates effects of FXR activation in mice[S] |
| title_sort |
human-like bile acid pool induced by deletion of hepatic cyp2c70 modulates effects of fxr activation in mice[s] |
| publisher |
Elsevier |
| series |
Journal of Lipid Research |
| issn |
0022-2275 |
| publishDate |
2020-03-01 |
| description |
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. Cytochrome P450 family 2 subfamily c polypeptide 70 (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 knockout 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 WT 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. |
| topic |
liver humanized mouse model cholesterol transintestinal cholesterol excretion cytochrome P450 family 2 subfamily c polypeptide 70 |
| url |
http://www.sciencedirect.com/science/article/pii/S002222752043514X |
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doaj-1b56e3171b514bbe9f8130fcfd347f642021-04-29T04:38:51ZengElsevierJournal of Lipid Research0022-22752020-03-01613291305A human-like bile acid pool induced by deletion of hepatic Cyp2c70 modulates effects of FXR activation in mice[S]Jan Freark de Boer0Esther Verkade1Niels L. Mulder2Hilde D. de Vries3Nicolette Huijkman4Martijn Koehorst5Theo Boer6Justina C. Wolters7Vincent W. Bloks8Bart van de Sluis9Folkert Kuipers10To whom correspondence should be addressed j.f.de.boer@umcg.nl; Departments of Laboratory Medicine University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; To whom correspondence should be addressed j.f.de.boer@umcg.nlPediatrics, University Medical Center Groningen, University of Groningen, Groningen, The NetherlandsPediatrics, University Medical Center Groningen, University of Groningen, Groningen, The NetherlandsDepartments of Laboratory Medicine University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; iPSC/CRISPR Center Groningen, University Medical Center Groningen, University of Groningen, Groningen, The NetherlandsPediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; University of Groningen, Campus Fryslân, Leeuwarden, The NetherlandsDepartments of Laboratory Medicine University Medical Center Groningen, University of Groningen, Groningen, The NetherlandsDepartments of Laboratory Medicine University Medical Center Groningen, University of Groningen, Groningen, The NetherlandsPediatrics, University Medical Center Groningen, University of Groningen, Groningen, The NetherlandsPediatrics, University Medical Center Groningen, University of Groningen, Groningen, The NetherlandsPediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; University of Groningen, Campus Fryslân, Leeuwarden, The NetherlandsDepartments of Laboratory Medicine University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The NetherlandsBile 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. Cytochrome P450 family 2 subfamily c polypeptide 70 (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 knockout 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 WT 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.http://www.sciencedirect.com/science/article/pii/S002222752043514Xliverhumanized mouse modelcholesteroltransintestinal cholesterol excretioncytochrome P450 family 2 subfamily c polypeptide 70 |