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 bileductligationâ 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-acidâ 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. Conclusion: Neddylation inhibition reduces fibrosis, suggesting neddylation as a potential and attractive therapeutic target in liver fibrosis. (Hepatology 2017;65:694-709).

Deregulated neddylation in liver fibrosis / Zubiete-Franco, Imanol; Fernández-Tussy, Pablo; Barbier-Torres, Lucía; Simon, Jorge; Fernández-Ramos, David; Lopitz-Otsoa, Fernando; Gutiérrez-de Juan, Virginia; de Davalillo, Sergio López; Duce, Antonio Martín; Iruzubieta, Paula; Taibo, Daniel; Crespo, Javier; Caballeria, Juan; Villa, Erica; Aurrekoetxea, Igor; Aspichueta, Patricia; Varela-Rey, Marta; Lu, Shelly C; Mato, José M.; Beraza, Naiara; Delgado, Teresa C.; Martínez-Chantar, María L. - In: HEPATOLOGY. - ISSN 0270-9139. - 65:2(2017), pp. 694-709. [10.1002/hep.28933]

Deregulated neddylation in liver fibrosis

Villa, Erica;
2017

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 bileductligationâ 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-acidâ 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. Conclusion: Neddylation inhibition reduces fibrosis, suggesting neddylation as a potential and attractive therapeutic target in liver fibrosis. (Hepatology 2017;65:694-709).
2017
30-dic-2016
65
2
694
709
Deregulated neddylation in liver fibrosis / Zubiete-Franco, Imanol; Fernández-Tussy, Pablo; Barbier-Torres, Lucía; Simon, Jorge; Fernández-Ramos, David; Lopitz-Otsoa, Fernando; Gutiérrez-de Juan, Virginia; de Davalillo, Sergio López; Duce, Antonio Martín; Iruzubieta, Paula; Taibo, Daniel; Crespo, Javier; Caballeria, Juan; Villa, Erica; Aurrekoetxea, Igor; Aspichueta, Patricia; Varela-Rey, Marta; Lu, Shelly C; Mato, José M.; Beraza, Naiara; Delgado, Teresa C.; Martínez-Chantar, María L. - In: HEPATOLOGY. - ISSN 0270-9139. - 65:2(2017), pp. 694-709. [10.1002/hep.28933]
Zubiete-Franco, Imanol; Fernández-Tussy, Pablo; Barbier-Torres, Lucía; Simon, Jorge; Fernández-Ramos, David; Lopitz-Otsoa, Fernando; Gutiérrez-de Juan...espandi
File in questo prodotto:
File Dimensione Formato  
hep.28933.pdf

Accesso riservato

Tipologia: Versione pubblicata dall'editore
Dimensione 1.52 MB
Formato Adobe PDF
1.52 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

Licenza Creative Commons
I metadati presenti in IRIS UNIMORE sono rilasciati con licenza Creative Commons CC0 1.0 Universal, mentre i file delle pubblicazioni sono rilasciati con licenza Attribuzione 4.0 Internazionale (CC BY 4.0), salvo diversa indicazione.
In caso di violazione di copyright, contattare Supporto Iris

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1154123
Citazioni
  • ???jsp.display-item.citation.pmc??? 36
  • Scopus 55
  • ???jsp.display-item.citation.isi??? 55
social impact