Neutrophils Promote Metabolic Dysfunction‐Associated Steatotic Liver Disease Through Extracellular Vesicle‐mediated Lipid Transfer

ABSTRACT

Metabolic dysfunction‐associated steatotic liver disease (MASLD) and metabolic dysfunction‐associated steatohepatitis are leading causes of chronic liver disease, yet the contribution of neutrophils to early hepatocellular lipid accumulation remains poorly understood. Here, we investigated the role of neutrophils in hepatic lipid deposition during early MASLD development. Neutrophils acquired extracellular fatty acids (FAs) via FATP2 and CD36 and stored them as triglycerides (TGs). These lipid‐laden neutrophils (LNs) did not utilize FAs for energy production or lipid mediator synthesis but instead transferred lipid cargo to hepatocytes through extracellular vesicles (EVs). Neutrophil‐derived EVs were enriched with TGs and lipid metabolism‐regulating microRNAs, augmenting TG accumulation in hepatocytes. Peripheral neutrophils isolated from high‐fat diet‐fed mice exhibited a lipid‐laden phenotype, and adoptive transfer of LNs and EVs derived from LNs increased hepatic fat accumulation in recipient mice. In patients with MASLD, circulating neutrophils showed lipid droplet accumulation with increased TGs and enrichment of lipid‐associated miRNAs while plasma EVs were also enriched with TGs and lipid‐associated miRNAs. Single‐cell RNA sequencing of peripheral immune cells identified a neutrophil subpopulation characterized by enhanced lipid‐handling and EV‐related gene expression. These findings identify neutrophil‐mediated lipid transfer via EVs as a mechanistic link between innate immune activation and hepatic lipid accumulation during early MASLD.