The spleen as a metabolic rheostat: orchestrating systemic lipid flux and interorgan crosstalk

This review synthesizes current evidence on how the spleen regulates systemic lipid metabolism through coordinated control of lipoprotein processing, cholesterol trafficking, and lipidimmune interactions. Splenic macrophages and lymphocytes contribute to ApoE and ApoAI production, enabling HDL formation, remnant clearance, and reverse cholesterol transport. Scavenger receptors such as SRA1, CD36, and SRB1 mediate the uptake and remodeling of modified lipoproteins, whereas LXR and PPARdependent pathways govern cholesterol efflux and fatty acid oxidation. Additional lipidlinked processes, including iron–lipid crosstalk, ceramide generation, sphingolipid signaling, and plateletderived lipid mediators, position the spleen as a central immunometabolic hub, although the strength of evidence varies from direct experimental demonstration to correlative and model-based inference. The aim of this study is to consolidate the mechanistic and experimental findings demonstrating that disruption of splenic lipid handling, including after splenectomy, promotes dyslipidemia and contributes to metabolic disease progression.