Abstract
Neddylation inhibition reduces fibrosis, suggesting neddylation as a potential and attractive therapeutic target in liver fibrosis. (Hepatology 2017;65:694-709).
Highlights
Hepatic fibrosis is a global health problem currently without effective therapeutic approaches
Direct cellular toxicity of ethanol affects hepatocytes attributed to the fact that alcohol-detoxifying enzymes are mainly expressed in these cells.[5]. Hepatocyte death leads to the release of cellular contents and reactive oxygen species that activate the liver-resident macrophages, the Kupffer cells (KCs), to release proinflammatory factors like tumor necrosis factor alpha (TNFa), interleukins (ILs; IL-1b and IL-6), and profibrogenic factors, especially transforming growth factor beta (TGFb).(6,7) TGFb further drives the transdifferentiation of hepatic stellate cells (HSCs) to fibrogenic myofibroblast-like cells,(8) the main source of extracellular matrix proteins leading to fibrosis.[9]
Neddylation was measured in experimental models recapitulating the key steps of fibrosis clinical progression, such as bile duct ligation (BDL), the most frequently used macrosurgical extrahepatic cholestasis experimental model,(24) and in the well-established toxic model of CCl4-induced liver fibrosis.[25]. Both global protein neddylation and neural precursor cell expressed developmentally down-regulated 8 (Nedd8)-activating enzyme E1 subunit 1 (NAE1) expression levels measured by IHC (Fig. 1C,D), as well as neddylated cullins measured by western blotting were increased at 21 days after BDL and after 6 weeks of CCl4 (Fig. 1E,F)
Summary
Hepatic fibrosis is a global health problem currently without effective therapeutic approaches. As a result of the complexity of the multicellular pathophysiology of LF, alternative pharmacological therapies that can reverse this disease or even halt progression to decompensated cirrhosis and HCC are still in an early developmental stage.[10] Understanding the molecular mechanisms underlying LF can provide clues on new treatments and drug development On this basis, neddylation is a ubiquitin-like reversible posttranslational modification characterized by conjugation of Nedd (neural precursor cell expressed developmentally down-regulated 8) to its target proteins. Several neddylation targets were found to be disrupted in liver tumors from HCC patients.[17,18,19] In spite of this, the relevance of neddylation modifications in LF, especially focusing on HSCs, the major fibrogenic cell type and highly refractive to current therapies, remained rather unexplored
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