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SHR Neuro Krebs Kardio Lipid Stoffw Microb

Liu, K; Wehling, L; Wan, S; Weiler, SME; Tóth, M; Ibberson, D; Marhenke, S; Ali, A; Lam, M; Guo, T; Pinna, F; Pedrini, F; Damle-Vartak, A; Dropmann, A; Rose, F; Colucci, S; Cheng, W; Bissinger, M; Schmitt, J; Birner, P; Poth, T; Angel, P; Dooley, S; Muckenthaler, MU; Longerich, T; Vogel, A; Heikenwälder, M; Schirmacher, P; Breuhahn, K.
Dynamic YAP expression in the non-parenchymal liver cell compartment controls heterologous cell communication.
Cell Mol Life Sci. 2024; 81(1): 115 Doi: 10.1007/s00018-024-05126-1 [OPEN ACCESS]
Web of Science PubMed PUBMED Central FullText FullText_MUG

 

Co-Autor*innen der Med Uni Graz
Toth Marcell
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Abstract:
INTRODUCTION: The Hippo pathway and its transcriptional effectors yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are targets for cancer therapy. It is important to determine if the activation of one factor compensates for the inhibition of the other. Moreover, it is unknown if YAP/TAZ-directed perturbation affects cell-cell communication of non-malignant liver cells. MATERIALS AND METHODS: To investigate liver-specific phenotypes caused by YAP and TAZ inactivation, we generated mice with hepatocyte (HC) and biliary epithelial cell (BEC)-specific deletions for both factors (YAPKO, TAZKO and double knock-out (DKO)). Immunohistochemistry, single-cell sequencing, and proteomics were used to analyze liver tissues and serum. RESULTS: The loss of BECs, liver fibrosis, and necrosis characterized livers from YAPKO and DKO mice. This phenotype was weakened in DKO tissues compared to specimens from YAPKO animals. After depletion of YAP in HCs and BECs, YAP expression was induced in non-parenchymal cells (NPCs) in a cholestasis-independent manner. YAP positivity was detected in subgroups of Kupffer cells (KCs) and endothelial cells (ECs). The secretion of pro-inflammatory chemokines and cytokines such as C-X-C motif chemokine ligand 11 (CXCL11), fms-related receptor tyrosine kinase 3 ligand (FLT3L), and soluble intercellular adhesion molecule-1 (ICAM1) was increased in the serum of YAPKO animals. YAP activation in NPCs could contribute to inflammation via TEA domain transcription factor (TEAD)-dependent transcriptional regulation of secreted factors. CONCLUSION: YAP inactivation in HCs and BECs causes liver damage, and concomitant TAZ deletion does not enhance but reduces this phenotype. Additionally, we present a new mechanism by which YAP contributes to cell-cell communication originating from NPCs.
Find related publications in this database (using NLM MeSH Indexing)
Animals - administration & dosage
Mice - administration & dosage
Cell Communication - genetics
Endothelial Cells - administration & dosage
Hepatocytes - administration & dosage
Ligands - administration & dosage
Liver - metabolism
YAP-Signaling Proteins - genetics, metabolism

Find related publications in this database (Keywords)
Hippo pathway
TAZ
Liver damage
Kupffer cell
Endothelial cell
Hepatocyte
Cholangiocyte
Proteomics
Single-cell analysis
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