RT Journal Article
T1 Activation of the Unfolded Protein Response (UPR) Is Associated with Cholangiocellular Injury, Fibrosis and Carcinogenesis in an Experimental Model of Fibropolycystic Liver Disease
A1 Chaobo, Chen
A1 Hanghang, Wu
A1 Hui, Ye
A1 Tortajada Alonso, Agustín
A1 Peligros Gómez, María Isabel
A1 Kang, Zheng
A1 Vaquero Martín, Francisco Javier
A1 Bañares Cañizares, Rafael
A1 Martínez Naves, Eduardo
A1 Nevzorova, Yulia
A1 Cubero Palero, Francisco Javier
AB 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.
PB MDPI
SN 2072-6694
YR 2021
FD 2021
LK https://hdl.handle.net/20.500.14352/91998
UL https://hdl.handle.net/20.500.14352/91998
LA eng
NO Ministerio de Economía, Comercio y Empresa (España)
NO German Research Foundation
DS Docta Complutense
RD 21 ago 2024