Highlights d Spatial proteogenomic single-cell atlas of healthy and obese murine and human liver d Validated flow cytometry and microscopy panels for all hepatic cells d LAMs are differentially located in the lean and obese liver d Evolutionary conserved BMP9/10-ALK1 axis is essential for KC development

Summary 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.

HighlightsThe transcriptional signature of Kupffer cells & Alveolar macrophages are enriched for lipid metabolism genes.Lipid metabolism may control macrophage phenotype.Dysregulated lipid metabolism in macrophages contributes to disease pathology.