In:
Hepatology Communications, Ovid Technologies (Wolters Kluwer Health), Vol. 7, No. 9 ( 2023-08-9)
Abstract:
We previously showed that loss of yes-associated protein 1 (YAP) in early liver development (YAP KO ) leads to an Alagille syndrome-like phenotype, with failure of intrahepatic bile duct development, severe cholestasis, and chronic hepatocyte adaptations to reduce liver injury. TAZ, a paralog of YAP, was significantly upregulated in YAP KO hepatocytes and interacted with TEA domain family member (TEAD) transcription factors, suggesting possible compensatory activity. Methods: We deleted both Yap1 and Wwtr1 (which encodes TAZ) during early liver development using the Foxa3 promoter to drive Cre expression, similar to YAP KO mice, resulting in YAP/TAZ double knockout (DKO) and YAP KO with TAZ heterozygosity (YAP KO TAZ HET ). We evaluated these mice using immunohistochemistry, serum biochemistry, bile acid profiling, and RNA sequencing. Results: DKO mice were embryonic lethal, but their livers were similar to YAP KO , suggesting an extrahepatic cause of death. Male YAP KO TAZ HET mice were also embryonic lethal, with insufficient samples to determine the cause. However, YAP KO TAZ HET females survived and were phenotypically similar to YAP KO mice, with increased bile acid hydrophilicity and similar global gene expression adaptations but worsened the hepatocellular injury. TAZ heterozygosity in YAP KO impacted the expression of canonical YAP targets Ctgf and Cyr61 , and we found changes in pathways regulating cell division and inflammatory signaling correlating with an increase in hepatocyte cell death, cell cycling, and macrophage recruitment. Conclusions: YAP loss (with or without TAZ loss) aborts biliary development. YAP and TAZ play a codependent critical role in foregut endoderm development outside the liver, but they are not essential for hepatocyte development. TAZ heterozygosity in YAP KO livers increased cell cycling and inflammatory signaling in the setting of chronic injury, highlighting genes that are especially sensitive to TAZ regulation.
Type of Medium:
Online Resource
ISSN:
2471-254X
DOI:
10.1097/HC9.0000000000000220
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2023
detail.hit.zdb_id:
2881134-3
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