NASH-associated macrophages: regulation and role in disease pathogenesis

Project Summary/Abstract The obesity epidemic has increased the prevalence of non-alcoholic fatty liver disease, which ranges from clinically benign hepatic steatosis to non-alcoholic steatohepatitis (NASH). The latter represents a more severe disease state featured by the presence of chronic liver injury, inflammation, and liver fibrosis, which increases the risk for end-stage liver disease such as cirrhosis and hepatocellular carcinoma (HCC). Macrophages play an integral role in host defense, tissue homeostasis, and disease progression. Altered macrophage polarization, characterized by changes in its transcriptional and functional states, has been causally linked to the pathogenesis of metabolic disease including NASH. Despite this, the nature of macrophage heterogeneity, disease-associated reprogramming, and its contribution to NASH progression remains obscure. To address these challenges, we recently performed single-cell RNA sequencing analysis on liver cells isolated from healthy and diet-induced NASH mice. Our study uncovered a unique population of NASH-associated macrophages (NAMs) that exhibits strong association with mouse and human NASH. Several important questions emerge from these findings regarding the pathophysiological signals that trigger NAM induction, its role in NASH pathogenesis, and the underlying mechanisms. Based on a body of preliminary data, we hypothesize that intrahepatic pathogenic stimuli drive NAM induction during NASH, thereby reshaping the liver microenvironment and exacerbating disease progression. In this proposal, we plan to elucidate the signaling pathways that promote NAM induction and critically assess its role in disease pathogenesis. We plan to explore the mechanisms through which NAMs contribute to the reprogramming of the liver microenvironment.