Cholangiopathy and Biliary Fibrosis in Cyp2c70-Deficient Mice Are Fully Reversed by Ursodeoxycholic Acid.
Cell Mol Gastroenterol Hepatol
; 11(4): 1045-1069, 2021.
Article
em En
| MEDLINE
| ID: mdl-33309945
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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ácido Ursodesoxicólico
/
Doenças Biliares
/
Fibrose
/
Ácidos e Sais Biliares
/
Colangite
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Ácidos Cólicos
/
Sistema Enzimático do Citocromo P-450
Tipo de estudo:
Etiology_studies
Limite:
Animals
Idioma:
En
Revista:
Cell Mol Gastroenterol Hepatol
Ano de publicação:
2021
Tipo de documento:
Article