Cholangiopathy and Biliary Fibrosis in Cyp2c70-Deficient Mice Are Fully Reversed by Ursodeoxycholic Acid.

Autor:	de Boer JF; Department 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. Electronic address: j.f.de.boer@umcg.nl., de Vries HD; Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; University of Groningen, Campus Fryslân, Leeuwarden, the Netherlands., Palmiotti A; Department of Pediatrics, University of Groningen, University Medical Center Groningen, the Netherlands., Li R; Department of Pediatrics, University of Groningen, University Medical Center Groningen, the Netherlands., Doestzada M; Department of Pediatrics, University of Groningen, University Medical Center Groningen, the Netherlands; Department of Genetics University of Groningen, University Medical Center Groningen, Groningen, the Netherlands., Hoogerland JA; Univ. Lille, Inserm, CHU Lille, Institut Pasteur Lille, U1011-EGID, F-59000 Lille, France., Fu J; Department of Pediatrics, University of Groningen, University Medical Center Groningen, the Netherlands; Department of Genetics University of Groningen, University Medical Center Groningen, Groningen, the Netherlands., La Rose AM; Department of Pediatrics, University of Groningen, University Medical Center Groningen, the Netherlands., Westerterp M; Department of Pediatrics, University of Groningen, University Medical Center Groningen, the Netherlands., Mulder NL; Department of Pediatrics, University of Groningen, University Medical Center Groningen, the Netherlands., Hovingh MV; Department of Pediatrics, University of Groningen, University Medical Center Groningen, the Netherlands., Koehorst M; Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands., Kloosterhuis NJ; Department of Pediatrics, University of Groningen, University Medical Center Groningen, the Netherlands., Wolters JC; Department of Pediatrics, University of Groningen, University Medical Center Groningen, the Netherlands., Bloks VW; Department of Pediatrics, University of Groningen, University Medical Center Groningen, the Netherlands., Haas JT; Univ. Lille, Inserm, CHU Lille, Institut Pasteur Lille, U1011-EGID, F-59000 Lille, France., Dombrowicz D; Univ. Lille, Inserm, CHU Lille, Institut Pasteur Lille, U1011-EGID, F-59000 Lille, France., Staels B; Univ. Lille, Inserm, CHU Lille, Institut Pasteur Lille, U1011-EGID, F-59000 Lille, France., van de Sluis B; Department of Pediatrics, University of Groningen, University Medical Center Groningen, the Netherlands; iPSC/CRISPR Center Groningen, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands., Kuipers F; Department 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.
Jazyk:	angličtina
Zdroj:	Cellular and molecular gastroenterology and hepatology [Cell Mol Gastroenterol Hepatol] 2021; Vol. 11 (4), pp. 1045-1069. Date of Electronic Publication: 2020 Dec 10.
DOI:	10.1016/j.jcmgh.2020.12.004
Abstrakt:	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. (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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