Yes-associated protein 1 (YAP1) plays a significant role in the regulation of liver health and disease, such as Alagille syndrome. As a link in the chain of important liver signaling pathways, it regulates processes in the liver, such as proliferation, differentiation, and survival.

YAP1 is largely expressed in biliary epithelial cells during development and in healthy adult livers. Molina and colleagues wrote, “Generally, YAP1 regulates gene expression to promote cell proliferation and survival, enhance metabolic activity, and alter extracellular matrix composition.”

In addition, YAP1 plays a significant role in determining baseline liver size, its regenerative response to injury, and liver tumorigenesis. Interestingly, YAP1 promotes biliary differentiation in some contexts and cell dedifferentiation in others. In other words, YAP1 in some ways remains an enigma to medical researchers. But to understand how biliary development and repair work, a proper understanding of YAP1 is indispensable.


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Read more about Alagille syndrome etiology 

Clincal Study Shows Multifaceted Function

Scientists sought to learn more about the role of YAP1 in liver development by deleting it from the hepatoblasts in mouse models during early liver development. More specifically, the purpose of the study was to investigate the role of YAP1 during the very earliest development stages of the embryonic liver, as well as to define its importance in bile duct morphogenesis. 

The YAP1 knockout (KO) mice survived for more than 8 months before being euthanized due to increasing morbidity. The researchers discovered that YAP1 appeared to be necessary for the differentiation of the second layer of biliary epithelial cells; its absence resulted in ductal morphogenetic failure and the lack of an intrahepatic biliary tree. 

In addition, scientists deduced that YAP1 may play a crucial role in turning off a hepatoblast/hepatocyte genetic program while promoting a Notch-driven biliary program. Previous studies have indicated that YAP1 upregulates NOTCH2 and JAG1 gene expression, as well as activates Notch signaling in mature hepatocytes and in a number of liver carcinomas. 

The researchers also discovered that, in the absence of YAP1, the formation of primary cilia was impaired in the development of biliary epithelial cells. This strengthens previous suggestions that a positive feedback loop exists between YAP1 activity and the development of primary cilia in biliary epithelial cells. 

“Overall, YAP1 KO mice exhibited significant failure to thrive and cholestatic injury, associated with persistent lack of intrahepatic bile ducts in the postnatal liver, resembling an Alagille syndrome-like phenotype,” the authors of the study reported. 

YAP1 signaling may also play a role in regulating liver cancer stem cells. In another study, Zhu and colleagues wrote, “YAP1 signaling is required for the self-renewal maintenance of liver cancer stem cells.” Two complementary observations were made: YAP1 overexpression in nonsphere cells enhanced their self-renewal potential, while verteporfin, a YAP-1-specific inhibitor, impaired self-renewal capacity. 

YAP1 has also been implicated in chronic ductular reaction, which can worsen cholestatic liver injury. The theory here is that the chronic activation of YAP1 in biliary epithelial cells promotes inflammation and fibrosis via the production of cytokines from biliary epithelial cells and hepatocytes. 

A Disease Modifier in Alagille Syndrome? 

We will now turn our attention to a rare liver pathology, Alagille syndrome, and the role of YAP1 in its pathogenesis. Alagille syndrome is an autosomal dominant disorder that results in multisystem malformations, including the aberrant development of bile ducts. 

Children with Alagille syndrome can present with a number of health problems, including congenital cardiovascular disease, renal disease, skeletal abnormalities, and growth deficiencies. Growth deficiency, in particular, is often the first clear symptom of Alagille syndrome, since a reduced secretion of bile into the gut results in chronic fat malabsorption. Cholestasis is diagnosed overwhelmingly in children with Alagille syndrome. 

Read more about Alagille syndrome epidemiology 

Molina et al’s murine study reported that the mouse models developed mild-to-severe bile duct paucity, which is of interest because it resembles the clinical phenotype of Alagille syndrome.

“Altered YAP1 regulation and/or decreased YAP1 function whether by genetic mutation in the YAP1 gene or associated signaling partners could compound the effect of decreased Notch signaling resulting in worsened overall phenotype,” Molina and colleagues wrote. 

This opens the door for future researchers to investigate the role of YAP1 activity status in causing pathologies similar to those seen in Alagille syndrome. If the deletion of YAP1 in mouse models produces a similar phenotype, does this mean that YAP1 may also play an underrecognized role in driving Alagille syndrome pathophysiology?

The YAP1 KO mice study demonstrated that the chronic elevation of serum total and conjugated bilirubin levels decreased the likelihood of spontaneous recovery over time, similar to the findings of studies conducted on children with Alagille syndrome. This suggests that YAP1 activation may be an important disease modifier in Alagille syndrome patients and those with other biliary disorders. 

Molina and colleagues concluded, “Further studies are needed to determine if perturbations in YAP1 can contribute to the pathogenesis of Alagille syndrome and biliary atresia as well as as-of-yet uncharacterized biliary defects in pediatric and even adult patients.” 

References

Molina L, Nejak-Bowen K, Monga SP. Role of YAP1 signaling in biliary development, repair, and disease. Semin Liver Dis. 2022;10.1055/s-0041-1742277. doi:10.1055/s-0041-1742277

Zhu P, Wang Y, Wu J, et al. LncBRM initiates YAP1 signalling activation to drive self-renewal of liver cancer stem cellsNat Commun. Published online December 1, 2016. doi:10.1038/ncomms13608

Molina LM, Zhu J, Li Q, et al. Compensatory hepatic adaptation accompanies permanent absence of intrahepatic biliary network due to YAP1 loss in liver progenitorsCell Rep. 2021;36(1):109310. doi:10.1016/j.celrep.2021.109310