Activation of the unfolded protein response (UPR) and fibrosis is associated withcholangiocellular injury in an experimental model of fibropolycystic liver disease

Background&Aim Fibropolycistic liver disease is characterized by hyperproliferation of the biliary epithelium and the formation of multiple dilated cysts, a process recently associated with unfolded protein response (UPR). In the present study, we aimed to understand the mechanisms of cyst formation and UPR activation of hepatocyte-specific c-Jun N-terminal kinase 1/2 (Jnk1/2) knockout mice.

Methods&Results 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 pro-inflammatory cytokines (Tnf, Tgfβ1), and liver injury (eg: 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 8 week-old Jnk∆hepa animals compared with Jnkf/f littermates. Finally, thioacetamide (TAA) supplementation to Jnk∆hepa induced UPR activation, peribiliary fibrosis, liver injury and markers of biliary proliferation and cholangiocarcinoma (CCA) in Jnk∆hepa animals.

Conclusions These results suggest that activation of the UPR in conjuction with fibrogenesis might trigger hepatic cystogenesis and early stages of CCA.

Publikationsverlauf

Artikel online veröffentlicht:
26. Januar 2022