Kupffer cells (KCs) are liver-resident macrophages that self-renew by proliferation in the adult independently from monocytes. However, how they are maintained during non-alcoholic steatohepatitis (NASH) remains ill defined. We found that a fraction of KCs derived from Ly-6C⁺ monocytes during NASH, underlying impaired KC self-renewal. Monocyte-derived KCs (MoKCs) gradually seeded the KC pool as disease progressed in a response to embryo-derived KC (EmKC) death. Those MoKCs were partly immature and exhibited a pro-inflammatory status compared to EmKCs. Yet, they engrafted the KC pool for the long term as they remained following disease regression while acquiring mature EmKC markers. While KCs as a whole favored hepatic triglyceride storage during NASH, EmKCs promoted it more efficiently than MoKCs, and the latter exacerbated liver damage, highlighting functional differences among KCs with different origins. Overall, our data reveal that KC homeostasis is impaired during NASH, altering the liver response to lipids, as well as KC ontogeny.

枯否细胞（KC）是驻留在肝脏的巨噬细胞，通过成年细胞的增殖而独立于单核细胞而自我更新。但是，在非酒精性脂肪性肝炎（NASH）期间如何维持它们仍不清楚。我们发现，一部分KC源自Ly-6C ⁺NASH期间的单核细胞，潜在的KC自我更新受损。随着疾病的发展，单核细胞衍生的KC（MoKC）逐渐接种了KC库，以应对胚胎衍生的KC（EmKC）死亡。与EmKC相比，这些MoKC部分不成熟，并表现出促炎状态。然而，他们长期移植了KC库，因为他们在疾病消退后仍保持成熟，同时获得了成熟的EmKC标记。尽管KC总体上支持NASH期间肝甘油三酸酯的储存，但EmKC促进MoKC的效率更高，后者加剧了肝损害，突显了不同来源的KC之间的功能差异。总体而言，我们的数据显示，NASH期间KC稳态受到损害，从而改变了肝脏对脂质以及KC个体发育的反应。