{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Apolipoprotein M (apoM) is a liver‐ and kidney‐expressed lipocalin that predominantly associates with high‐density lipoprotein (HDL). By virtue of its conserved, uncleaved hydrophobic signal peptide, apoM is anchored to HDL, a feature essential for its function and stability in plasma."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Structural studies have demonstrated that apoM contains an amphiphilic binding pocket typical of lipocalins, enabling it to carry small lipophilic molecules such as retinoids and, most notably, sphingosine‐1‐phosphate (S1P)."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Through its selective binding of S1P, apoM serves as a chaperone that delivers S1P to its receptors on diverse target cells. In endothelial cells, this mechanism is central to maintaining vascular integrity by promoting receptor internalization, downstream MAPK/Akt signaling, adherens junction formation, and anti‐inflammatory responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "7"}]}, {"type": "t", "text": " Additionally, apoM is instrumental in HDL remodeling; its presence facilitates the formation of preβ‐HDL particles, thereby enhancing cholesterol efflux from foam cells and contributing to antiatherogenic effects."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " ApoM–S1P signaling also modulates immune cell functions by restraining lymphopoiesis and by attenuating apoptosis in macrophages and cardiomyocytes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "12"}]}, {"type": "t", "text": " Its expression is tightly regulated by transcription factors—including HNF‐1α, LRH‐1, Foxa2—and by metabolic hormones such as leptin and insulin, linking apoM levels to metabolic and inflammatory states."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "16"}]}, {"type": "t", "text": " Collectively, these functions render apoM a key mediator of HDL’s vasoprotective, anti‐inflammatory and antiatherogenic properties, with emerging implications as a biomarker and potential therapeutic target in cardiovascular, metabolic, and inflammatory diseases."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "17", "end_ref": "19"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Christina Christoffersen, Josefin Ahnström, Olof Axler, et al. 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