Abstract
Liver fibrosis is characterized by the excessive deposition of extracellular matrix proteins including collagen that occurs in most types of chronic liver disease. Even though our knowledge of the cellular and molecular mechanisms of liver fibrosis has deeply improved in the last years, therapeutic approaches for liver fibrosis remain limited. Profiling and characterization of the post-translational modifications (PTMs) of proteins, and more specifically NEDDylation and SUMOylation ubiquitin-like (Ubls) modifications, can provide a better understanding of the liver fibrosis pathology as well as novel and more effective therapeutic approaches. On this basis, in the last years, several studies have described how changes in the intermediates of the Ubl cascades are altered during liver fibrosis and how specific targeting of particular enzymes mediating these ubiquitin-like modifications can improve liver fibrosis, mainly in in vitro models of hepatic stellate cells, the main fibrogenic cell type, and in pre-clinical mouse models of liver fibrosis. The development of novel inhibitors of the Ubl modifications as well as novel strategies to assess the modified proteome can provide new insights into the overall role of Ubl modifications in liver fibrosis.
Highlights
Liver fibrosis is characterized by the excessive deposition of extracellular matrix proteins including collagen that occurs in most types of chronic liver disease
A big effort has been made on the study of the role of post-translational modifications (PTMs) mediated by ubiquitin-like proteins (Ubls) in liver fibrosis (Figure 1)
In spite of the improved knowledge obtained on this highly dynamic and pan-cellular process of liver fibrosis and its regulation by Ubl PTMs, it is clear that novel tools need to be developed
Summary
Liver damage leads to death of hepatocytes and cholangiocytes, which induces the release of pro-inflammatory mediators and stimulates phagocytosis of dead cell bodies by liver macrophages, mainly Kupffer cells and bone marrow-derived recruited monocytes [10]. When liver fibrosis is developed in an onset of ALD or NAFLD, the excessive deposition of ECM proteins is principally observed around the sinusoids (peri-sinusoidal fibrosis) and around groups of hepatocytes (peri-cellular fibrosis), and is mainly due to hepatic stellate cells (HSC) [4,12]. In chronic diseases of the biliary tract, the excessive deposition of ECM proteins is principally observed around the injured bile ducts (biliary fibrosis pattern) and is mainly characterized by the proliferation of reactive ductular cells and myofibroblasts originated from portal fibroblast and HSC [4,15,16]. Fibrotic human livers showed co-localization of synoviolin and the main fibrotic marker, α-SMA [38] This compelling evidence implicating ubiquitination in liver fibrosis led several authors to evaluate the impact of ubiquitin-like proteins (Ubls)-mediated PTMs in liver fibrosis, the topic of this Review.
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