Activation of the Unfolded Protein Response (UPR) Is Associated with Cholangiocellular Injury, Fibrosis and Carcinogenesis in an Experimental Model of Fibropolycystic Liver Disease

Fibropolycystic liver disease is characterized by hyperproliferation of the biliary epithelium and the formation of multiple dilated cysts, a process associated with unfolded protein response (UPR). In the present study, we aimed to understand the mechanisms of cyst formation and UPR activation in h...

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Authors: Chen, Chaobo, Wu, Hanghang, Ye, Hui, Tortajada, Agustín, Rodríguez Perales, Sandra, Torres Ruiz, Raúl, Vidal, August, Peligros, Maria Isabel, Reissing, Johanna, Bruns, Tony, Ramadan Mohamed, Mohamed, Zheng, Kang, Lujambio, Amaia, Iraburu, Maria J., Colyn, Leticia, Ujue Latasa, Maria, Arechederra, María, Fernández Barrena, Maite G., Berasain, Carmen, Vaquero, Javier, Bañares, Rafael, Nelson, Leonard J., Trautwein, Christian, Davis, Roger J., Martinez Naves, Eduardo, Nevzorova, Yulia A., Villanueva Garatachea, Alberto, Avila, Matías A., Cubero, Francisco Javier
Format: article
Status:Published version
Publication Date:2021
Country:España
Institution:Universidad de Barcelona
Repository:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/182754
Online Access:https://hdl.handle.net/2445/182754
Access Level:Open access
Keyword:Malalties del fetge
Carcinogènesi
Liver diseases
Carcinogenesis
Description
Summary:Fibropolycystic liver disease is characterized by hyperproliferation of the biliary epithelium and the formation of multiple dilated cysts, a process associated with unfolded protein response (UPR). In the present study, we aimed to understand the mechanisms of cyst formation and UPR activation in hepatocytic c-Jun N-terminal kinase 1/2 (Jnk1/2) knockout mice. Floxed JNK1/2 (Jnkf/f) and Jnk∆hepa animals were sacrificed at different time points during progression of liver disease. Histological examination of specimens evidenced the presence of collagen fiber deposition, increased α-smooth muscle actin (αSMA), infiltration of CD45, CD11b and F4/80 cells and proinflammatory cytokines (Tnf, Tgfβ1) and liver injury (e.g., ALT, apoptosis and Ki67-positive cells) in Jnk∆hepa compared with Jnkf/f livers from 32 weeks of age. This was associated with activation of effectors of the UPR, including BiP/GRP78, CHOP and spliced XBP1. Tunicamycin (TM) challenge strongly induced ER stress and fibrosis in Jnk∆hepa animals compared with Jnkf/f littermates. Finally, thioacetamide (TAA) administration to Jnk∆hepa mice induced UPR activation, peribiliary fibrosis, liver injury and markers of biliary proliferation and cholangiocarcinoma (CCA). Orthoallografts of DEN/CCl4-treated Jnk∆hepa liver tissue triggered malignant CCA. Altogether, these results suggest that activation of the UPR in conjunction with fibrogenesis might trigger hepatic cystogenesis and early stages of CCA.

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