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Cholangiopathy and biliary fibrosis in Cyp2c70-deficient mice are fully reversed by ursodeoxycholic acid

Abstract : 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.
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https://www.hal.inserm.fr/inserm-03177441
Contributor : Marie-Hélène Derudas <>
Submitted on : Tuesday, March 23, 2021 - 10:47:07 AM
Last modification on : Monday, June 21, 2021 - 9:30:17 AM

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Jan de Boer, Hilde de Vries, Anna Palmiotti, Rumei Li, Marwah Doestzada, et al.. Cholangiopathy and biliary fibrosis in Cyp2c70-deficient mice are fully reversed by ursodeoxycholic acid. Cellular and Molecular Gastroenterology and Hepatology, Philadelphia, PA : American Gastroenterological Association, [2015]-, 2021, 11 (4), pp.1045-1069. ⟨10.1016/j.jcmgh.2020.12.004⟩. ⟨inserm-03177441⟩

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