YAP Activation and Implications in Patients and a Mouse Model of Biliary Atresia

Overview

Journal Front Pediatr

Specialty Pediatrics

Date 2021 Feb 8

PMID 33553074

Citations 4

Authors

Chao Zheng

Jiaqian Luo

Yifan Yang

Rui Dong

Fa-Xing Yu

Shan Zheng

Affiliations

Soon will be listed here.

Abstract

Biliary atresia (BA), an inflammatory destruction of the bile ducts, leads to liver fibrosis in infants and accounts for half of cases undergoing pediatric liver transplantation. Yes-associated protein (YAP), an effector of the Hippo signaling pathway, is critical in maintaining identities of bile ductal cells. Here, we evaluated the expression of YAP and YAP target genes in BA livers and a rhesus rotavirus (RRV)-induced BA mice model. Liver specimens collected from 200 BA patients were compared with those of 30 non-BA patients. Model mice liver tissues were also collected. The expression of YAP and YAP target genes were measured by transfection, RNA-seq, immunohistochemistry, immunoblot, and quantitative PCR. Masson's trichrome staining and the Biliary Atresia Research Consortium (BARC) system were utilized to score liver fibrosis status. The expression of YAP is elevated and positively correlated with fibrosis in BA livers. Moreover, , which is identified as the target gene of YAP, is also highly expressed in BA livers. Consistent with clinical data, YAP and ANKRD1 are significantly upregulated in RRV-induced BA mouse model. YAP expression is closely correlated with the bile duct hyperplasia and liver fibrosis, and may serve as an indicator for liver fibrosis and BA progression. This study indicates an involvement of the Hippo signaling pathway in the development of BA, and the YAP induced ANKRD1 expression may also be related to bile duct hyperplasia in BA. This provides a new direction for more in-depth exploration of the etiology and pathogenesis of biliary atresia.

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References

Yu H, Yao Y, Bu F, Chen Y, Wu Y, Yang Y . Blockade of YAP alleviates hepatic fibrosis through accelerating apoptosis and reversion of activated hepatic stellate cells. Mol Immunol. 2019; 107:29-40. DOI: 10.1016/j.molimm.2019.01.004. View

Gurda G, Zhu Q, Bai H, Pan D, Schwarz K, Anders R . The use of Yes-associated protein expression in the diagnosis of persistent neonatal cholestatic liver disease. Hum Pathol. 2014; 45(5):1057-64. PMC: 4151519. DOI: 10.1016/j.humpath.2014.01.002. View

Konishi T, Schuster R, Lentsch A . Proliferation of hepatic stellate cells, mediated by YAP and TAZ, contributes to liver repair and regeneration after liver ischemia-reperfusion injury. Am J Physiol Gastrointest Liver Physiol. 2018; 314(4):G471-G482. PMC: 5966748. DOI: 10.1152/ajpgi.00153.2017. View

Sokol R, Mack C, Narkewicz M, Karrer F . Pathogenesis and outcome of biliary atresia: current concepts. J Pediatr Gastroenterol Nutr. 2003; 37(1):4-21. DOI: 10.1097/00005176-200307000-00003. View

Dupont S, Morsut L, Aragona M, Enzo E, Giulitti S, Cordenonsi M . Role of YAP/TAZ in mechanotransduction. Nature. 2011; 474(7350):179-83. DOI: 10.1038/nature10137. View

Nio M, Wada M, Sasaki H, Tanaka H . Effects of age at Kasai portoenterostomy on the surgical outcome: a review of the literature. Surg Today. 2014; 45(7):813-8. DOI: 10.1007/s00595-014-1024-z. View

Dong J, Feldmann G, Huang J, Wu S, Zhang N, Comerford S . Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell. 2007; 130(6):1120-33. PMC: 2666353. DOI: 10.1016/j.cell.2007.07.019. View

Kobayashi H, Hayashi N, Hayashi K, Yamataka A, Lane G, Miyano T . Connective tissue growth factor and progressive fibrosis in biliary atresia. Pediatr Surg Int. 2004; 21(1):12-6. DOI: 10.1007/s00383-004-1254-z. View

Wu N, Nguyen Q, Wan Y, Zhou T, Venter J, Frampton G . The Hippo signaling functions through the Notch signaling to regulate intrahepatic bile duct development in mammals. Lab Invest. 2017; 97(7):843-853. PMC: 5901959. DOI: 10.1038/labinvest.2017.29. View

10.

Chiu C, Chen P, Chan C, Chang M, Wu T . Biliary atresia in preterm infants in Taiwan: a nationwide survey. J Pediatr. 2013; 163(1):100-3.e1. DOI: 10.1016/j.jpeds.2012.12.085. View

11.

Than T, Tran G, Son K, Park E, Kim S, Lim Y . Ankyrin Repeat Domain 1 is Up-regulated During Hepatitis C Virus Infection and Regulates Hepatitis C Virus Entry. Sci Rep. 2016; 6:20819. PMC: 4748412. DOI: 10.1038/srep20819. View

12.

Zhang N, Bai H, David K, Dong J, Zheng Y, Cai J . The Merlin/NF2 tumor suppressor functions through the YAP oncoprotein to regulate tissue homeostasis in mammals. Dev Cell. 2010; 19(1):27-38. PMC: 2925178. DOI: 10.1016/j.devcel.2010.06.015. View

13.

Petersen C . Biliary atresia: the animal models. Semin Pediatr Surg. 2012; 21(3):185-91. DOI: 10.1053/j.sempedsurg.2012.05.002. View

14.

Weerasooriya V, White F, Shepherd R . Hepatic fibrosis and survival in biliary atresia. J Pediatr. 2004; 144(1):123-5. DOI: 10.1016/j.jpeds.2003.09.042. View

15.

Chardot C, Buet C, Serinet M, Golmard J, Lachaux A, Roquelaure B . Improving outcomes of biliary atresia: French national series 1986-2009. J Hepatol. 2013; 58(6):1209-17. DOI: 10.1016/j.jhep.2013.01.040. View

16.

Schreiber R, Barker C, Roberts E, Martin S, Alvarez F, Smith L . Biliary atresia: the Canadian experience. J Pediatr. 2007; 151(6):659-65, 665.e1. DOI: 10.1016/j.jpeds.2007.05.051. View

17.

Li C, Srivastava R, Elmets C, Afaq F, Athar M . Arsenic-induced cutaneous hyperplastic lesions are associated with the dysregulation of Yap, a Hippo signaling-related protein. Biochem Biophys Res Commun. 2013; 438(4):607-12. DOI: 10.1016/j.bbrc.2013.08.008. View

18.

Mannaerts I, Batista Leite S, Verhulst S, Claerhout S, Eysackers N, Thoen L . The Hippo pathway effector YAP controls mouse hepatic stellate cell activation. J Hepatol. 2015; 63(3):679-88. DOI: 10.1016/j.jhep.2015.04.011. View

19.

Wada H, Muraji T, Yokoi A, Okamoto T, Sato S, Takamizawa S . Insignificant seasonal and geographical variation in incidence of biliary atresia in Japan: a regional survey of over 20 years. J Pediatr Surg. 2007; 42(12):2090-2. DOI: 10.1016/j.jpedsurg.2007.08.035. View

20.

Mack C, Feldman A, Sokol R . Clues to the etiology of bile duct injury in biliary atresia. Semin Liver Dis. 2013; 32(4):307-16. PMC: 3827890. DOI: 10.1055/s-0032-1329899. View