Macrophage-specific N-terminal Truncation of Plin2 Limits the Size of Lipid Droplets

Lipid droplets (LDs) are dynamic organelles that exhibit cell-type-specific heterogeneity in size, composition, and abundance to support diverse cellular functions. However, the molecular mechanisms regulating this functional diversity remain poorly understood. Here, we identified a cell-type-specific truncated isoform of Plin2, which was present in macrophages but absent in adipocytes. Using N-terminal HA- and C-terminal FLAG-tagged Plin2 constructs combined with immunoprecipitation-mass spectrometry analysis in HEK293T cells or macrophages, we confirmed the N-terminal truncation and mapped the deletion site to residues 40–44. Ectopic expression of this truncated variant significantly reduced LD size in both macrophages and HEK293T cells. These findings reveal that macrophages modulate lipid storage by expressing distinct Plin2 protein variants, suggesting new therapeutic targets for lipid metabolism disorders.