Dual β-Catenin and γ-Catenin Loss in Hepatocytes Impacts Their Polarity through Altered Transforming Growth Factor-β and Hepatocyte Nuclear Factor 4α Signaling.
Dual β-Catenin and γ-Catenin Loss in Hepatocytes Impacts Their Polarity through Altered Transforming Growth Factor-β and Hepatocyte Nuclear Factor 4α Signaling.
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肝细胞中双 β-连环蛋白和 γ-连环蛋白丢失通过改变转化生长因子-β 和肝细胞核因子 4α 信号传导影响其极性。
DOI：
10.1016/j.ajpath.2021.02.008
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Monga,SatdarshanP
中科院分区：
文献类型：
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作者：
Pradhan-Sundd,Tirthadipa;Liu,Silvia;Singh,Sucha;Poddar,Minakshi;Ko,Sungjin;Bell,Aaron;Franks,Jonathan;Huck,Ian;Stolz,Donna;Apte,Udayan;Ranganathan,Sarangarajan;Nejak-Bowen,Kari;Monga,SatdarshanP
肝细胞是高度极化的上皮。肝细胞极性的丧失与多种肝脏疾病有关，包括胆汁淤积。然而，肝细胞极化的分子基础仍然知之甚少。粘附连接处β-连环蛋白的丢失由γ-连环蛋白补偿，小鼠肝脏双敲除（dko）中两种连环蛋白的双重丢失导致进行性肝内胆汁淤积。然而，这一观察的临床相关性，以及进一步的表型表征是重要的。本研究发现，在进行性家族性肝内胆汁潴积和原发性硬化性胆管炎患者的肝脏样本亚组中，β-catenin和γ-catenin同时缺失。DKO小鼠的肝细胞表现出极性蛋白顶端-基底外侧定位缺陷，胆管形成受损，微绒毛缺失。DKO肝极性丧失表现为上皮-间质转化、肝细胞增殖增加、肝细胞分化抑制，与转化生长因子-β信号上调、肝细胞核因子4α表达和活性抑制有关。总之，肝脏中这两种连环蛋白的同时缺失可能在胆管病亚群中起致病作用。这些发现也支持了β-catenin和γ-catenin在维持肝细胞极性中的作用。进一步了解β-catenin和γ-catenin对肝细胞极化过程的调节可能有助于开发新的胆汁淤滞症治疗方法。
Hepatocytes are highly polarized epithelia. Loss of hepatocyte polarity is associated with various liver diseases, including cholestasis. However, the molecular underpinnings of hepatocyte polarization remain poorly understood. Loss of β-catenin at adherens junctions is compensated by γ-catenin and dual loss of both catenins in double knockouts (DKOs) in mice liver leads to progressive intrahepatic cholestasis. However, the clinical relevance of this observation, and further phenotypic characterization of the phenotype, is important. Herein, simultaneous loss of β-catenin and γ-catenin was identified in a subset of liver samples from patients of progressive familial intrahepatic cholestasis and primary sclerosing cholangitis. Hepatocytes in DKO mice exhibited defects in apical-basolateral localization of polarity proteins, impaired bile canaliculi formation, and loss of microvilli. Loss of polarity in DKO livers manifested as epithelial-mesenchymal transition, increased hepatocyte proliferation, and suppression of hepatocyte differentiation, which was associated with up-regulation of transforming growth factor-β signaling and repression of hepatocyte nuclear factor 4α expression and activity. In conclusion, concomitant loss of the two catenins in the liver may play a pathogenic role in subsets of cholangiopathies. The findings also support a previously unknown role of β-catenin and γ-catenin in the maintenance of hepatocyte polarity. Improved understanding of the regulation of hepatocyte polarization processes by β-catenin and γ-catenin may potentially benefit development of new therapies for cholestasis.