1. Deregulated neddylation in liver fibrosis
- Author
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Zubiete‐Franco, Imanol, Fernández‐Tussy, Pablo, Barbier‐Torres, Lucía, Simon, Jorge, Fernández‐Ramos, David, Lopitz‐Otsoa, Fernando, Juan, Virginia Gutiérrez‐de, 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, and Martínez‐Chantar, María L
- Subjects
Digestive Diseases ,Chronic Liver Disease and Cirrhosis ,Liver Disease ,2.1 Biological and endogenous factors ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Aetiology ,Oral and gastrointestinal ,Good Health and Well Being ,Aging ,Analysis of Variance ,Animals ,Apoptosis ,Biopsy ,Needle ,Cell Proliferation ,Cell Survival ,Cells ,Cultured ,Chemokine CCL4 ,Chemokines ,Cyclopentanes ,Disease Models ,Animal ,Hepatic Stellate Cells ,Humans ,Immunohistochemistry ,Liver Cirrhosis ,Male ,Mice ,Mice ,Inbred C57BL ,NEDD8 Protein ,Pyrimidines ,Random Allocation ,Signal Transduction ,Ubiquitins ,Medical Biochemistry and Metabolomics ,Clinical Sciences ,Immunology ,Gastroenterology & Hepatology - 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.ConclusionNeddylation inhibition reduces fibrosis, suggesting neddylation as a potential and attractive therapeutic target in liver fibrosis. (Hepatology 2017;65:694-709).
- Published
- 2017