title: Repair-associated inflammation in nonalcoholic fatty liver disease.
abstract: The mechanisms that drive non-alcoholic fatty liver disease (NAFLD) progression from simple steatosis to non-alcoholic steatohepatitis (NASH) and NASH-fibrosis and/or cirrhosis are complex. Recent studies suggest that the liver progenitor cell (ie liver stem cell) population expands during chronic liver injury, and is an essential component of the repair process. Hedgehog (Hh) is a developmental morphogen that has an important role in the adult tissue repair (and progenitor) response. Accumulating data in mice and human show that resurrection of the Hh pathway occurs during progressive NAFLD, and that activity of this pathway correlates with NASH-fibrosis stage. Importantly, Hh ligands secreted by dying (or stressed) hepatocytes, hepatic stellate cells (i.e. myofibroblasts), cholangiocytes and recruited immune cells can act on neighbouring cells to perpetuate the fibrogenic response. Intriguingly, Hh ligands can also stimulate cholangiocytes to secrete chemokines that recruit immune cell subsets (such as natural killer T cells), which could explain why fibrosis generally occurs in the context of chronic inflammation (i.e. fibrosis-associated inflammatory response). Finally, the administration of Hh inhibitors led to reduced fibrosis in a model of NASH. Future studies are needed to evaluate the utility of these inhibitors in other models of chronic liver disease. If successful, this could pave the way for the development of new therapy for patients with NASH, because Hh pathway inhibitors have now been licensed for use in patients with advanced basal cell carcinoma.
authors.affiliation: The Institute of Hepatology, Foundation for Liver Research, London UK.
authors.forename: Wing-Kin
authors.initials: WK
authors.lastname: Syn
mesh_terms: D000818:Animals; D005234:Fatty Liver; D053823:Hedgehog Proteins; D006801:Humans; D007249:Inflammation; D008103:Liver Cirrhosis; D065626:Non-alcoholic Fatty Liver Disease
chemical_list: D053823:Hedgehog Proteins
keywords: Fibrosis; hedgehog; immune; liver progenitors; osteopontin