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

Alvaro Santos-Laso, Laura Izquierdo-Sanchez, Pedro M. Rodrigues, Bing Q. Huang, Mikel Azkargorta, Ainhoa Lapitz, Patricia Munoz-Garrido, Ander Arbelaiz, Francisco J. Caballero-Camino, Maite G. Fernández-Barrena, Raul Jimenez-Agüero, Josepmaria Argemi, Tomas Aragon, Felix Elortza, Marco Marzioni, Joost P.H. Drenth, Nicholas F. LaRusso, Luis Bujanda, Maria J. Perugorria, Jesus M. Banales

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1670-1685
Number of pages16
JournalLiver International
Issue number7
StatePublished - Jul 1 2020


  • cholangiocyte
  • endoplasmic reticulum stress
  • hepatic cystogenesis
  • pathogenesis
  • proteostasis
  • unfolded protein response

ASJC Scopus subject areas

  • Hepatology


Dive into the research topics of 'Proteostasis disturbances and endoplasmic reticulum stress contribute to polycystic liver disease: New therapeutic targets'. Together they form a unique fingerprint.

Cite this