Lipid metabolism and inflammation in the pathogenesis of chronic liver diseases 480 views

Chronic liver diseases are a rising global health burden that include chronic viral hepatitis C and nonalcoholic steatohepatitis (NASH). Despite differences in their etiologies, both hepatitis C and NASH are marked by alterations in systemic lipid metabolism that are accompanied by chronic hepatic inflammation. In order to dissect how lipid metabolism and the immune response contribute to liver pathology, we investigated the role of de novo lipid synthesis in hepatitis C virus (HCV) infection and established novel in vitro systems to study the role of a newly described immune population, the innate lymphoid cells (ILCs), in NASH. We demonstrate that HCV replication, assembly, and infectious virion production are decreased upon inhibition of de novo lipogenesis. Suboptimal propagation of the virus is in part due to changes in the lipid composition of hepatocytes and alterations in post-translational modifications of proteins under conditions of limited de novo lipid synthesis. Conversely, treatment of hepatoma cells with an excess of lipids transforms them into steatotic hepatocytes characteristic of fatty liver disease. These in vitro equivalents of NASH hepatocytes upregulate expression of profibrogenic markers such as TGF-β, which in turn triggers expression of collagen I in hepatic stellate cells, thus initiating the fibrotic cascade seen in NASH livers. Importantly, a subtype of ILCs secretes IL-22, which facilitates tissue repair through inhibition of fibrogenesis, potentially inhibiting the transformation of hepatic lipid accumulation to chronic liver disease. Indeed, given that fibrogenesis, inflammation, and dysregulation hepatic lipid metabolism are common signatures of all chronic liver diseases, the findings from our studies collectively identify metabolic and immunological targets that can be modulated for increased understanding of homeostatic and pathological liver biology.

PHD (Doctor of Philosophy)

English

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2016-06-06