Nonalcoholic fatty liver disease is the most prevalent liver disease worldwide, affecting 20%-25% of the adult population. In 25% of patients, nonalcoholic fatty liver disease progresses to nonalcoholic 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 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 summarize options to therapeutically interrupt this profibrogenic hepatocyte-macrophage-HSC network in NASH.

中文翻译：

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非酒精性脂肪性肝炎纤维化发展的机制。


非酒精性脂肪肝是全世界最常见的肝病，影响20%-25%的成年人口。 25% 的患者中，非酒精性脂肪肝会进展为非酒精性脂肪性肝炎 (NASH)，这会增加发生肝硬化、肝衰竭和肝细胞癌的风险。在 NASH 患者中，肝纤维化是死亡率的主要决定因素。在这里，我们回顾了不同肝细胞之间的相互作用如何最终导致 NASH 纤维化发展，重点关注肝细胞-巨噬细胞-肝星状细胞 (HSC) 串扰的触发因素和后果。我们讨论了应激和死亡肝细胞引发与 HSC 和巨噬细胞促纤维化串扰的途径，包括 TAZ、Notch 和刺猬等发育途径的重新激活；通过胞吞作用清除 NASH 中的死细胞如何影响炎症和纤维形成；以及通过单细胞 RNA 测序揭示的 HSC 和巨噬细胞异质性的见解。最后，我们总结了在 NASH 中中断促纤维化肝细胞-巨噬细胞-HSC 网络的治疗方案。