Proteostasis disturbances and endoplasmic reticulum stress contribute to polycystic liver disease: New therapeutic targets

Background & Aims Polycystic liver diseases (PLDs) are genetic disorders characterized by progressive development of multiple biliary cysts. Recently, novel PLD‐causative genes, encoding for endoplasmic reticulum (ER)‐resident proteins involved in protein biogenesis and transport, were identifie...

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Bibliographic Details
Published in:Liver international 2020-07, Vol.40 (7), p.1670-1685
Main Authors: Santos‐Laso, Alvaro, Izquierdo‐Sanchez, Laura, Rodrigues, Pedro M., Huang, Bing Q., Azkargorta, Mikel, Lapitz, Ainhoa, Munoz‐Garrido, Patricia, Arbelaiz, Ander, Caballero-Camino, Francisco J., Fernández‐Barrena, Maite G., Jimenez‐Agüero, Raul, Argemi, Josepmaria, Aragon, Tomas, Elortza, Felix, Marzioni, Marco, Drenth, Joost P. H., LaRusso, Nicholas F., Bujanda, Luis, Perugorria, Maria J., Banales, Jesus M., Andersson, Emma
Format: Article
Language:English
Subjects:
Apoptosis
cholangiocyte
Cysts
Degradation
Endoplasmic reticulum
endoplasmic reticulum stress
Enlargement
Folding
Gene expression
Genetic disorders
hepatic cystogenesis
Hyperactivity
Liver
Liver diseases
Mass spectrometry
Mass spectroscopy
Pathogenesis
Phenylbutyric acid
Proteasomes
Protein biosynthesis
Protein folding
Protein synthesis
Protein transport
Proteins
Proteomics
proteostasis
Restoration
Stress
Therapeutic applications
Transcription
Transmission electron microscopy
Tunicamycin
unfolded protein response
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Summary:Background & Aims Polycystic liver diseases (PLDs) are genetic disorders characterized by progressive development of multiple biliary cysts. Recently, novel PLD‐causative genes, encoding for endoplasmic reticulum (ER)‐resident proteins involved in protein biogenesis and transport, were identified. We hypothesized that aberrant proteostasis contributes to PLD pathogenesis, representing a potential therapeutic target. Methods ER stress was analysed at transcriptional (qPCR), proteomic (mass spectrometry), morphological (transmission electron microscopy, TEM) and functional (proteasome activity) levels in different PLD models. The effect of ER stress inhibitors [4‐phenylbutyric acid (4‐PBA)] and/or activators [tunicamycin (TM)] was tested in polycystic (PCK) rats and cystic cholangiocytes in vitro. Results The expression levels of unfolded protein response (UPR) components were upregulated in liver tissue from PLD patients and PCK rats, as well as in primary cultures of human and rat cystic cholangiocytes, compared to normal controls. Cystic cholangiocytes showed altered proteomic profiles, mainly related to proteostasis (ie synthesis, folding, trafficking and degradation of proteins), marked enlargement of the ER lumen (by TEM) and hyperactivation of the proteasome. Notably, chronic treatment of PCK rats with 4‐PBA decreased liver weight, as well as both liver and cystic volumes, of animals under baseline conditions or after TM administration compared to controls. In vitro, 4‐PBA downregulated the expression (mRNA) of UPR effectors, normalized proteomic profiles related to protein synthesis, folding, trafficking and degradation and reduced the proteasome hyperactivity in cystic cholangiocytes, reducing their hyperproliferation and apoptosis. Conclusions Restoration of proteostasis in cystic cholangiocytes with 4‐PBA halts hepatic cystogenesis, emerging as a novel therapeutic strategy.
ISSN:1478-3223
1478-3231
DOI:10.1111/liv.14485