Cholangiopathy and Biliary Fibrosis in Cyp2c70-Deficient Mice Are Fully Reversed by Ursodeoxycholic AcidSummary
Background and Aims: Bile acids (BAs) aid intestinal fat absorption and exert systemic actions by receptor-mediated signaling. BA receptors have been identified as drug targets for liver diseases. Yet, differences in BA metabolism between humans and mice hamper translation of pre-clinical outcomes....
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| Format: | Article |
| Language: | English |
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Elsevier
2021-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X20302034 |
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doaj-7532521445514e72b3e86eded4106a3d |
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Article |
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DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Jan Freark de Boer Hilde D. de Vries Anna Palmiotti Rumei Li Marwah Doestzada Joanne A. Hoogerland Jingyuan Fu Anouk M. La Rose Marit Westerterp Niels L. Mulder Milaine V. Hovingh Martijn Koehorst Niels J. Kloosterhuis Justina C. Wolters Vincent W. Bloks Joel T. Haas David Dombrowicz Bart Staels Bart van de Sluis Folkert Kuipers |
| spellingShingle |
Jan Freark de Boer Hilde D. de Vries Anna Palmiotti Rumei Li Marwah Doestzada Joanne A. Hoogerland Jingyuan Fu Anouk M. La Rose Marit Westerterp Niels L. Mulder Milaine V. Hovingh Martijn Koehorst Niels J. Kloosterhuis Justina C. Wolters Vincent W. Bloks Joel T. Haas David Dombrowicz Bart Staels Bart van de Sluis Folkert Kuipers Cholangiopathy and Biliary Fibrosis in Cyp2c70-Deficient Mice Are Fully Reversed by Ursodeoxycholic AcidSummary Cellular and Molecular Gastroenterology and Hepatology Bile Acids Liver Humanized Mouse Model Primary Biliary Cholangitis |
| author_facet |
Jan Freark de Boer Hilde D. de Vries Anna Palmiotti Rumei Li Marwah Doestzada Joanne A. Hoogerland Jingyuan Fu Anouk M. La Rose Marit Westerterp Niels L. Mulder Milaine V. Hovingh Martijn Koehorst Niels J. Kloosterhuis Justina C. Wolters Vincent W. Bloks Joel T. Haas David Dombrowicz Bart Staels Bart van de Sluis Folkert Kuipers |
| author_sort |
Jan Freark de Boer |
| title |
Cholangiopathy and Biliary Fibrosis in Cyp2c70-Deficient Mice Are Fully Reversed by Ursodeoxycholic AcidSummary |
| title_short |
Cholangiopathy and Biliary Fibrosis in Cyp2c70-Deficient Mice Are Fully Reversed by Ursodeoxycholic AcidSummary |
| title_full |
Cholangiopathy and Biliary Fibrosis in Cyp2c70-Deficient Mice Are Fully Reversed by Ursodeoxycholic AcidSummary |
| title_fullStr |
Cholangiopathy and Biliary Fibrosis in Cyp2c70-Deficient Mice Are Fully Reversed by Ursodeoxycholic AcidSummary |
| title_full_unstemmed |
Cholangiopathy and Biliary Fibrosis in Cyp2c70-Deficient Mice Are Fully Reversed by Ursodeoxycholic AcidSummary |
| title_sort |
cholangiopathy and biliary fibrosis in cyp2c70-deficient mice are fully reversed by ursodeoxycholic acidsummary |
| publisher |
Elsevier |
| series |
Cellular and Molecular Gastroenterology and Hepatology |
| issn |
2352-345X |
| publishDate |
2021-01-01 |
| description |
Background and Aims: Bile acids (BAs) aid intestinal fat absorption and exert systemic actions by receptor-mediated signaling. BA receptors have been identified as drug targets for liver diseases. Yet, differences in BA metabolism between humans and mice hamper translation of pre-clinical outcomes. Cyp2c70-ablation in mice prevents synthesis of mouse/rat-specific muricholic acids (MCAs), but potential (patho)physiological consequences of their absence are unknown. We therefore assessed age- and gender-dependent effects of Cyp2c70-deficiency in mice. Methods: The consequences of Cyp2c70-deficiency were assessed in male and female mice at different ages. Results: Cyp2c70-/- mice were devoid of MCAs and showed high abundances of chenodeoxycholic and lithocholic acids. Cyp2c70-deficiency profoundly impacted microbiome composition. Bile flow and biliary BA secretion were normal in Cyp2c70-/- mice of both sexes. Yet, the pathophysiological consequences of Cyp2c70-deficiency differed considerably between sexes. Three-week old male Cyp2c70-/- mice showed high plasma BAs and transaminases, which spontaneously decreased thereafter to near-normal levels. Only mild ductular reactions were observed in male Cyp2c70-/- mice up to 8 months of age. In female Cyp2c70-/- mice, plasma BAs and transaminases remained substantially elevated with age, gut barrier function was impaired and bridging fibrosis was observed at advanced age. Addition of 0.1% ursodeoxycholic acid to the diet fully normalized hepatic and intestinal functions in female Cyp2c70-/- mice. Conclusion: Cyp2c70-/- mice show transient neonatal cholestasis and develop cholangiopathic features that progress to bridging fibrosis in females only. These consequences of Cyp2c70-deficiency are restored by treatment with UDCA, indicating a role of BA hydrophobicity in disease development. |
| topic |
Bile Acids Liver Humanized Mouse Model Primary Biliary Cholangitis |
| url |
http://www.sciencedirect.com/science/article/pii/S2352345X20302034 |
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doaj-7532521445514e72b3e86eded4106a3d2021-03-25T04:30:23ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2021-01-0111410451069Cholangiopathy and Biliary Fibrosis in Cyp2c70-Deficient Mice Are Fully Reversed by Ursodeoxycholic AcidSummaryJan Freark de Boer0Hilde D. de Vries1Anna Palmiotti2Rumei Li3Marwah Doestzada4Joanne A. Hoogerland5Jingyuan Fu6Anouk M. La Rose7Marit Westerterp8Niels L. Mulder9Milaine V. Hovingh10Martijn Koehorst11Niels J. Kloosterhuis12Justina C. Wolters13Vincent W. Bloks14Joel T. Haas15David Dombrowicz16Bart Staels17Bart van de Sluis18Folkert Kuipers19Department of Pediatrics, University of Groningen, University Medical Center Groningen, the Netherlands; Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Correspondence Address correspondence to: Jan Freark de Boer, PhD, University Medical Center Groningen, Department of Pediatrics, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands. fax: +31(0)503611746.Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; University of Groningen, Campus Fryslân, Leeuwarden, the NetherlandsDepartment of Pediatrics, University of Groningen, University Medical Center Groningen, the NetherlandsDepartment of Pediatrics, University of Groningen, University Medical Center Groningen, the NetherlandsDepartment of Pediatrics, University of Groningen, University Medical Center Groningen, the Netherlands; Department of Genetics University of Groningen, University Medical Center Groningen, Groningen, the NetherlandsUniv. Lille, Inserm, CHU Lille, Institut Pasteur Lille, U1011-EGID, F-59000 Lille, FranceDepartment of Pediatrics, University of Groningen, University Medical Center Groningen, the Netherlands; Department of Genetics University of Groningen, University Medical Center Groningen, Groningen, the NetherlandsDepartment of Pediatrics, University of Groningen, University Medical Center Groningen, the NetherlandsDepartment of Pediatrics, University of Groningen, University Medical Center Groningen, the NetherlandsDepartment of Pediatrics, University of Groningen, University Medical Center Groningen, the NetherlandsDepartment of Pediatrics, University of Groningen, University Medical Center Groningen, the NetherlandsDepartment of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, the NetherlandsDepartment of Pediatrics, University of Groningen, University Medical Center Groningen, the NetherlandsDepartment of Pediatrics, University of Groningen, University Medical Center Groningen, the NetherlandsDepartment of Pediatrics, University of Groningen, University Medical Center Groningen, the NetherlandsUniv. Lille, Inserm, CHU Lille, Institut Pasteur Lille, U1011-EGID, F-59000 Lille, FranceUniv. Lille, Inserm, CHU Lille, Institut Pasteur Lille, U1011-EGID, F-59000 Lille, FranceUniv. Lille, Inserm, CHU Lille, Institut Pasteur Lille, U1011-EGID, F-59000 Lille, FranceDepartment of Pediatrics, University of Groningen, University Medical Center Groningen, the Netherlands; iPSC/CRISPR Center Groningen, University of Groningen, University Medical Center Groningen, Groningen, the NetherlandsDepartment of Pediatrics, University of Groningen, University Medical Center Groningen, the Netherlands; Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, the NetherlandsBackground and Aims: Bile acids (BAs) aid intestinal fat absorption and exert systemic actions by receptor-mediated signaling. BA receptors have been identified as drug targets for liver diseases. Yet, differences in BA metabolism between humans and mice hamper translation of pre-clinical outcomes. Cyp2c70-ablation in mice prevents synthesis of mouse/rat-specific muricholic acids (MCAs), but potential (patho)physiological consequences of their absence are unknown. We therefore assessed age- and gender-dependent effects of Cyp2c70-deficiency in mice. Methods: The consequences of Cyp2c70-deficiency were assessed in male and female mice at different ages. Results: Cyp2c70-/- mice were devoid of MCAs and showed high abundances of chenodeoxycholic and lithocholic acids. Cyp2c70-deficiency profoundly impacted microbiome composition. Bile flow and biliary BA secretion were normal in Cyp2c70-/- mice of both sexes. Yet, the pathophysiological consequences of Cyp2c70-deficiency differed considerably between sexes. Three-week old male Cyp2c70-/- mice showed high plasma BAs and transaminases, which spontaneously decreased thereafter to near-normal levels. Only mild ductular reactions were observed in male Cyp2c70-/- mice up to 8 months of age. In female Cyp2c70-/- mice, plasma BAs and transaminases remained substantially elevated with age, gut barrier function was impaired and bridging fibrosis was observed at advanced age. Addition of 0.1% ursodeoxycholic acid to the diet fully normalized hepatic and intestinal functions in female Cyp2c70-/- mice. Conclusion: Cyp2c70-/- mice show transient neonatal cholestasis and develop cholangiopathic features that progress to bridging fibrosis in females only. These consequences of Cyp2c70-deficiency are restored by treatment with UDCA, indicating a role of BA hydrophobicity in disease development.http://www.sciencedirect.com/science/article/pii/S2352345X20302034Bile AcidsLiverHumanized Mouse ModelPrimary Biliary Cholangitis |