Mechanisms of Fibrosis Development in NASH

Abstract Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disease world-wide, affecting 20-25% of the adult population. In 25% of patients, NAFLD progresses to non-alcoholic steatohepatitis (NASH), which increases the risk for the development of cirrhosis, liver failure and hepatocellular carcinoma. In patients with NASH, liver fibrosis is the main determinant of mortality. Here, we review how interactions between different liver cells culminate in fibrosis development in NASH, focusing on triggers and consequences of hepatocyte-macrophage-hepatic stellate cell (HSC) crosstalk. We will discuss pathways through which stressed and dead hepatocytes instigate the profibrogenic crosstalk with HSC and macrophages including the reactivation of developmental pathways such as TAZ, Notch and hedgehog; how clearance of dead cells in NASH via efferocytosis may affect inflammation and fibrogenesis; and insights into HSC and macrophage heterogeneity revealed by single cell RNA-sequencing. Finally, we will summarize options to therapeutically interrupt this profibrogenic hepatocyte-macrophage-HSC network in NASH.