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Semin Liver Dis 2022; 42(01): 017-033
DOI: 10.1055/s-0041-1742277
Review Article

Role of YAP1 Signaling in Biliary Development, Repair, and Disease

Laura Molina
1   Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine
,
Kari Nejak-Bowen
1   Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine
2   Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
,
Satdarshan P. Monga
1   Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine
2   Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
3   Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh and UPMC, Pittsburgh, Pennsylvania
› Author Affiliations Funding Funding was provided by 2T32EB001026-16A1 (S.P.M and L.M.); 1F30DK121393 to L.M., and 1R01DK62277, 1R01DK100287, 1R01DK116993, R01CA204586, 1R01CA251155 and Endowed Chair for Experimental Pathology to S.P.M., and by National Institutes of Health grant 1P30DK120531–01 to Pittsburgh Liver Research Center (S.P.M.).
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Abstract

Yes-associated protein 1 (YAP1) is a transcriptional coactivator that activates transcriptional enhanced associate domain transcription factors upon inactivation of the Hippo signaling pathway, to regulate biological processes like proliferation, survival, and differentiation. YAP1 is most prominently expressed in biliary epithelial cells (BECs) in normal adult livers and during development. In the current review, we will discuss the multiple roles of YAP1 in the development and morphogenesis of bile ducts inside and outside the liver, as well as in orchestrating the cholangiocyte repair response to biliary injury. We will review how biliary repair can occur through the process of hepatocyte-to-BEC transdifferentiation and how YAP1 is pertinent to this process. We will also discuss the liver's capacity for metabolic reprogramming as an adaptive mechanism in extreme cholestasis, such as when intrahepatic bile ducts are absent due to YAP1 loss from hepatic progenitors. Finally, we will discuss the roles of YAP1 in the context of pediatric pathologies afflicting bile ducts, such as Alagille syndrome and biliary atresia. In conclusion, we will comprehensively discuss the spatiotemporal roles of YAP1 in biliary development and repair after biliary injury while describing key interactions with other well-known developmental pathways.

Keywords

Hippo signaling - bile duct development - cholestasis - transdifferentiation - ductular reaction


Publication History

Article published online:
24 January 2022

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