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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >β‐Catenin regulation of farnesoid X receptor signaling and bile acid metabolism during murine cholestasis
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β‐Catenin regulation of farnesoid X receptor signaling and bile acid metabolism during murine cholestasis

机译：法腹X受体信号传导和胆汁酸代谢的β-catenin调节鼠胆汁淤积

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Cholestatic liver diseases result from impaired bile flow and are characterized by inflammation, atypical ductular proliferation, and fibrosis. The Wnt/β‐catenin pathway plays a role in bile duct development, yet its role in cholestatic injury remains indeterminate. Liver‐specific β‐catenin knockout mice and wild‐type littermates were subjected to cholestatic injury through bile duct ligation or short‐term exposure to 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine diet. Intriguingly, knockout mice exhibit a dramatic protection from liver injury, fibrosis, and atypical ductular proliferation, which coincides with significantly decreased total hepatic bile acids (BAs). This led to the discovery of a role for β‐catenin in regulating BA synthesis and transport through regulation of farnesoid X receptor (FXR) activation. We show that β‐catenin functions as both an inhibitor of nuclear translocation and a nuclear corepressor through formation of a physical complex with FXR. Loss of β‐catenin expedited FXR nuclear localization and FXR/retinoic X receptor alpha association, culminating in small heterodimer protein promoter occupancy and activation in response to BA or FXR agonist. Conversely, accumulation of β‐catenin sequesters FXR, thus inhibiting its activation. Finally, exogenous suppression of β‐catenin expression during cholestatic injury reduces β‐catenin/FXR complex activation of FXR to decrease total BA and alleviate hepatic injury. Conclusion: We have identified an FXR/β‐catenin interaction whose modulation through β‐catenin suppression promotes FXR activation and decreases hepatic BAs, which may provide unique therapeutic opportunities in cholestatic liver diseases. (H epatology 2018;67:955–971)
机译：胆汁淤积性肝脏疾病因胆汁流量受损，其特征在于炎症，非典型导管和纤维化。 Wnt /β-catenin途径在胆管开发中起作用，但其在胆管损伤中的作用仍然不确定。通过胆管结扎或短期暴露于3,5-二乙氧基羰基-1,4-二氢钴胶鸡饮食，对肝脏特异性β-catenin敲除小鼠和野生型凋落物进行胆汁损伤。有趣的是，敲除小鼠表现出从肝损伤，纤维化和非典型导管增殖的显着保护，这与总肝胆汁（BAS）的总含量显着降低。这导致了发现β-catenin在调节BA合成和运输方面的作用，通过法呢X受体（FXR）激活。我们展示β-连环蛋白通过形成与FXR的物理复合物形成核易位和核心压制者的抑制剂。 β-连环蛋白的丧失加速了FXR核定位和FXR / RETINICIC X受体α关联，响应于BA或FXR激动剂的小异二聚体蛋白促进剂占用和活化。相反，β-连环蛋白螯合FXR的积累，从而抑制其活化。最后，在胆管损伤期间的β-连环蛋白表达的外源抑制可降低FXR的β-catenin / fxr复合物激活，降低总Ba并减轻肝损伤。结论：我们鉴定了一种FXR /β-连环蛋白相互作用，其调节通过β-连环蛋白抑制促进FXR活化并降低肝病，这可能在胆汁淤积肝病中提供独特的治疗机会。 （H Popatology 2018; 67：955-971）

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