Metabolic-associated fatty liver disease (MAFLD) represents a spectrum of disease states ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). Hepatic macrophages, specifically Kupffer cells (KCs), are suggested to play important roles in the pathogenesis of MAFLD through their activation, although the exact roles played by these cells remain unclear. Here, we demonstrated that KCs were reduced in MAFLD being replaced by macrophages originating from the bone marrow. Recruited macrophages existed in two subsets with distinct activation states, either closely resembling homeostatic KCs or lipid-associated macrophages (LAMs) from obese adipose tissue. Hepatic LAMs expressed Osteopontin, a biomarker for patients with NASH, linked with the development of fibrosis. Fitting with this, LAMs were found in regions of the liver with reduced numbers of KCs, characterized by increased Desmin expression. Together, our data highlight considerable heterogeneity within the macrophage pool and suggest a need for more specific macrophage targeting strategies in MAFLD.

代谢相关脂肪肝 (MAFLD) 代表一系列疾病状态，从简单的脂肪变性到非酒精性脂肪性肝炎 (NASH)。肝巨噬细胞，特别是库普弗细胞 (KCs)，被认为通过激活在 MAFLD 的发病机制中发挥重要作用，尽管这些细胞发挥的确切作用仍不清楚。在这里，我们证明了 KCs 在 MAFLD 中减少，被源自骨髓的巨噬细胞取代。招募的巨噬细胞存在于两个具有不同激活状态的亚群中，它们与来自肥胖脂肪组织的稳态 KC 或脂质相关巨噬细胞 (LAM) 非常相似。肝 LAM 表达骨桥蛋白，这是 NASH 患者的生物标志物，与纤维化的发展有关。配合这个，在 KCs 数量减少的肝脏区域中发现了 LAM，其特征是结蛋白表达增加。总之，我们的数据突出了巨噬细胞池内相当大的异质性，并表明需要在 MAFLD 中制定更具体的巨噬细胞靶向策略。