title: Deregulated neddylation in liver fibrosis.
abstract: Hepatic fibrosis is a global health problem currently without effective therapeutic approaches. Even though the ubiquitin-like posttranslational modification of neddylation, that conjugates Nedd8 (neural precursor cell expressed developmentally downregulated) to specific targets, is aberrant in many pathologies, its relevance in liver fibrosis (LF) remained unexplored. Our results show deregulated neddylation in clinical fibrosis and both in mouse bileductligation- and CCl4-induced fibrosis. Importantly, neddylation inhibition, by using the pharmacological inhibitor, MLN4924, reduced liver injury, apoptosis, inflammation, and fibrosis by targeting different hepatic cell types. On one hand, increased neddylation was associated with augmented caspase 3 activity in bile-acid-induced apoptosis in mouse hepatocytes whereas neddylation inhibition ameliorated apoptosis through reduction of expression of the Cxcl1 and Ccl2 chemokines. On the other hand, chemokine receptors and cytokines, usually induced in activated macrophages, were reduced after neddylation inhibition in mouse Kupffer cells. Under these circumstances, decreased hepatocyte cell death and inflammation after neddylation inhibition could partly account for reduction of hepatic stellate cell (HSC) activation. We provide evidence that augmented neddylation characterizes activated HSCs, suggesting that neddylation inhibition could be important for resolving LF by directly targeting these fibrogenic cells. Indeed, neddylation inhibition in activated HSCs induces apoptosis in a process partly mediated by accumulation of c-Jun, whose cullin-mediated degradation is impaired under these circumstances.
  
  
  
  Neddylation inhibition reduces fibrosis, suggesting neddylation as a potential and attractive therapeutic target in liver fibrosis. (Hepatology 2017;65:694-709).
authors.affiliation: Center for Cooperative Research in Bioscience (CIC bioGUNE), CIBERehd, Derio, Bizkaia, Spain.
authors.forename: Imanol
authors.initials: I
authors.lastname: Zubiete-Franco
authors.affiliation: Center for Cooperative Research in Bioscience (CIC bioGUNE), CIBERehd, Derio, Bizkaia, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Fernández-Tussy
authors.affiliation: Center for Cooperative Research in Bioscience (CIC bioGUNE), CIBERehd, Derio, Bizkaia, Spain.
authors.forename: Lucía
authors.initials: L
authors.lastname: Barbier-Torres
authors.affiliation: Center for Cooperative Research in Bioscience (CIC bioGUNE), CIBERehd, Derio, Bizkaia, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Simon
authors.affiliation: Center for Cooperative Research in Bioscience (CIC bioGUNE), CIBERehd, Derio, Bizkaia, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Fernández-Ramos
authors.affiliation: Center for Cooperative Research in Bioscience (CIC bioGUNE), CIBERehd, Derio, Bizkaia, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Lopitz-Otsoa
authors.affiliation: Center for Cooperative Research in Bioscience (CIC bioGUNE), CIBERehd, Derio, Bizkaia, Spain.
authors.forename: Virginia
authors.initials: V
authors.lastname: Gutiérrez-de Juan
authors.affiliation: Center for Cooperative Research in Bioscience (CIC bioGUNE), CIBERehd, Derio, Bizkaia, Spain.
authors.forename: Sergio López
authors.initials: SL
authors.lastname: de Davalillo
authors.affiliation: Nursery Department, University of Alcalá, Madrid, Spain.
authors.forename: Antonio Martín
authors.initials: AM
authors.lastname: Duce
authors.affiliation: Gastroenterology and Hepatology Department, Marqués de Valdecilla University Hospital, Santander, Spain.|Infection, Immunity and Digestive Pathology Group, Research Institute Marqués de Valdecilla (IDIVAL), Santander, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: Iruzubieta
authors.affiliation: Center for Cooperative Research in Bioscience (CIC bioGUNE), CIBERehd, Derio, Bizkaia, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Taibo
authors.affiliation: Gastroenterology and Hepatology Department, Marqués de Valdecilla University Hospital, Santander, Spain.|Infection, Immunity and Digestive Pathology Group, Research Institute Marqués de Valdecilla (IDIVAL), Santander, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Crespo
authors.affiliation: Liver Unit, Hospital Clínic, CIBERehd, IDIBAPS, Barcelona, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Caballeria
authors.affiliation: Department of Gastroenterology, University Hospital of Modena & University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Erica
authors.initials: E
authors.lastname: Villa
authors.affiliation: Department of Physiology, University of the Basque Country UPV/EHU, Faculty of Medicine and Dentistry, Leioa, Spain, and Biocruces Health Research Institute, Barakaldo, Spain.
authors.forename: Igor
authors.initials: I
authors.lastname: Aurrekoetxea
authors.affiliation: Department of Physiology, University of the Basque Country UPV/EHU, Faculty of Medicine and Dentistry, Leioa, Spain, and Biocruces Health Research Institute, Barakaldo, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Aspichueta
authors.affiliation: Center for Cooperative Research in Bioscience (CIC bioGUNE), CIBERehd, Derio, Bizkaia, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Varela-Rey
authors.affiliation: Division of Digestive Liver Disease, Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Shelly C
authors.initials: SC
authors.lastname: Lu
authors.affiliation: Center for Cooperative Research in Bioscience (CIC bioGUNE), CIBERehd, Derio, Bizkaia, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Mato
authors.affiliation: Center for Cooperative Research in Bioscience (CIC bioGUNE), CIBERehd, Derio, Bizkaia, Spain.
authors.forename: Naiara
authors.initials: N
authors.lastname: Beraza
authors.affiliation: Center for Cooperative Research in Bioscience (CIC bioGUNE), CIBERehd, Derio, Bizkaia, Spain.
authors.forename: Teresa C
authors.initials: TC
authors.lastname: Delgado
authors.affiliation: Center for Cooperative Research in Bioscience (CIC bioGUNE), CIBERehd, Derio, Bizkaia, Spain.
authors.forename: María L
authors.initials: ML
authors.lastname: Martínez-Chantar
mesh_terms: D000375:Aging / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001707:Biopsy, Needle; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D054407:Chemokine CCL4 / Q000494:pharmacology; D018925:Chemokines / Q000187:drug effects / Q000378:metabolism*; D003517:Cyclopentanes / Q000494:pharmacology*; D004195:Disease Models, Animal; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008103:Liver Cirrhosis / Q000235:genetics* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000075687:NEDD8 Protein; D011743:Pyrimidines / Q000494:pharmacology*; D011897:Random Allocation; D015398:Signal Transduction; D014452:Ubiquitins / Q000235:genetics*
chemical_list: D054407:Chemokine CCL4; D018925:Chemokines; D003517:Cyclopentanes; D000075687:NEDD8 Protein; C513172:Nedd8 protein, mouse; D011743:Pyrimidines; D014452:Ubiquitins; C539933:pevonedistat