| First Author | de Boer JF | Year | 2021 |
| Journal | Cell Mol Gastroenterol Hepatol | Volume | 11 |
| Issue | 4 | Pages | 1045-1069 |
| PubMed ID | 33309945 | Mgi Jnum | J:315746 |
| Mgi Id | MGI:6805597 | Doi | 10.1016/j.jcmgh.2020.12.004 |
| Citation | de Boer JF, et al. (2021) Cholangiopathy and Biliary Fibrosis in Cyp2c70-Deficient Mice Are Fully Reversed by Ursodeoxycholic Acid. Cell Mol Gastroenterol Hepatol 11(4):1045-1069 |
| abstractText | 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. |
