Although recent evidence suggests the involvement of iron accumulation in the pathogenesis of NASH, the underlying mechanisms remain poorly understood. Previously, Y. Kanamori et al. (Nagoya, Japan) reported a unique histological structure termed ‘‘crown-like structure (CLS),’’ where liver-resident macrophages (Kupffer cells) surround dead hepatocytes, scavenge their debris, and induce inflammation and fibrosis in NASH.
In this study, using magnetic column separation, the authors show that iron-rich Kupffer cells exhibit proinflammatory and profibrotic phenotypic changes during the development of NASH, at least partly, through activation of MiT/TFE transcription factors, that mediate iron-induced Kupffer cells’ phenotypic changes. Activation of MiT/TFE transcription factors is observed in Kupffer cells forming CLSs in murine and human NASH. Iron chelation effectively attenuates liver fibrosis in a murine NASH model.
This study provides insight into the pathophysiologic role of iron in NASH. A unique macrophage subset rich in iron contributes to crown-like structure formation and serves as a driver of liver fibrosis.