Nonalcoholic steatohepatitis (NASH) is rapidly emerging as a prevalent liver disease that is associated with metabolic syndrome. NASH increases the risk for end-stage liver diseases such as cirrhosis and liver cancer and currently has no effective treatments. Despite this, the pathophysiological mechanisms underlying NASH initiation and progression remain poorly understood. We and others have previously established a diet-induced NASH model in mice that recapitulates key aspects of human NASH pathologies, including hepatic steatosis, liver injury, inflammation, and liver fibrosis in the context of obesity and insulin resistance. Here we performed single-cell RNA sequencing (sc-RNAseq) analysis on liver cells isolated from healthy and diet-induced NASH mice to map the landscape of liver cell heterogeneity and reprogramming during NASH pathogenesis. Our analysis revealed a highly interconnected ligand-receptor signaling network among different liver cell types that is disrupted during NASH progression. Hepatic stellate cells are emerging as a hub of signaling in the liver by secreting “stellakines” and respond to vasoactive hormones. Finally, we identified TREM2-expressing macrophages as a unique disease-associated macrophage population that is linked to NASH severity in humans. This work reveals the transcriptomic landscape of liver cells at single-cell resolution and uncovers key aspects of NASH-associated reprogramming of liver non-parenchymal cells.

Disclosure

X. Xiong: None.

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