Cholangiopathy and Biliary Fibrosis in Cyp2c70-Deficient Mice Are Fully Reversed by Ursodeoxycholic Acid,Cellular and Molecular Gastroenterology and Hepatology

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Cholangiopathy and Biliary Fibrosis in Cyp2c70-Deficient Mice Are Fully Reversed by Ursodeoxycholic Acid
Cellular and Molecular Gastroenterology and Hepatology ( IF 7.1 ) Pub Date : 2020-12-10 , DOI: 10.1016/j.jcmgh.2020.12.004
Jan Freark de Boer ₁ , Hilde D de Vries ₂ , Anna Palmiotti ₃ , Rumei Li ₃ , Marwah Doestzada ₄ , Joanne A Hoogerland ₅ , Jingyuan Fu ₄ , Anouk M La Rose ₃ , Marit Westerterp ₃ , Niels L Mulder ₃ , Milaine V Hovingh ₃ , Martijn Koehorst ₆ , Niels J Kloosterhuis ₃ , Justina C Wolters ₃ , Vincent W Bloks ₃ , Joel T Haas ₅ , David Dombrowicz ₅ , Bart Staels ₅ , Bart van de Sluis ₇ , Folkert Kuipers ₁

Affiliation

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.
Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; University of Groningen, Campus Fryslân, Leeuwarden, the Netherlands.
Department of Pediatrics, University of Groningen, University Medical Center Groningen, the Netherlands.
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.
Univ. Lille, Inserm, CHU Lille, Institut Pasteur Lille, U1011-EGID, F-59000 Lille, France.
Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
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.

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.

中文翻译：

熊去氧胆酸可完全逆转 Cyp2c70 缺陷小鼠的胆管病和胆道纤维化

背景和目标

胆汁酸 (BA) 有助于肠道脂肪吸收并通过受体介导的信号传导发挥全身作用。BA 受体已被确定为肝病的药物靶点。然而，人类和小鼠之间 BA 代谢的差异阻碍了临床前结果的转化。小鼠中的Cyp2c70消融可防止小鼠/大鼠特异性鼠胆酸 (MCA) 的合成，但它们缺失的潜在（病理）生理后果尚不清楚。因此，我们评估了Cyp2c70 缺陷对小鼠的年龄和性别依赖性影响。

方法

在不同年龄的雄性和雌性小鼠中评估了Cyp2c70 缺陷的后果。

结果

Cyp2c70 ^-/-小鼠缺乏 MCA，并显示出高丰度的鹅去氧胆酸和石胆酸。Cyp2c70 缺乏对微生物组组成产生了深远的影响。两种性别的Cyp2c70 ^-/-小鼠的胆汁流量和胆汁 BA 分泌均正常。然而，Cyp2c70 缺陷的病理生理学后果在两性之间存在很大差异。三周大的雄性Cyp2c70 ^-/-小鼠表现出高血浆 BA 和转氨酶，此后自发降低至接近正常水平。在 8 个月大的雄性Cyp2c70 ^-/-小鼠中仅观察到轻微的导管反应。在女性Cyp2c70 ^-/-小鼠、血浆 BA 和转氨酶随着年龄的增长而显着升高，肠道屏障功能受损，并且在高龄时观察到桥接纤维化。在饮食中添加 0.1% 熊去氧胆酸可使雌性Cyp2c70 ^-/-小鼠的肝和肠功能完全正常化。