The lysophosphatidylcholine-HIF-1α axis enhances apolipoprotein E sialylation and promotes electronegative LDL accumulation

Electronegative low-density lipoprotein (L5-LDL) drives vascular injury in metabolic syndrome (MetS), yet its hepatic origin remains undefined. Here, we identify a lysophosphatidylcholine (LPC)-hypoxia-inducible factor-1α (HIF-1α) axis that governs apolipoprotein E (apoE) glycosylation and lipoprotein electronegativity. LPC activates HIF-1α in hepatocytes, inducing polypeptide N -acetylgalactosaminyltransferase (GALNT2) and ST3 β-galactodise α-2,3-sialyltransferase 1 (ST3GAL1) to promote apoE O -glycosylation and sialylation. This remodeling redirects lipoprotein uptake from the LDL receptor (LDLR) to lectin-like oxidized LDL receptor-1 (LOX-1), facilitating the formation of electronegative very low-density lipoprotein (V5-VLDL) and L5-LDL. Consistently, V5-VLDL from MetS subjects exhibits hyperglycosylated apoE mirroring L5-LDL. Disruption of this pathway attenuates apoE modification and LOX-1 engagement. These findings establish a mechanistic link between hepatic lipid remodeling and vascular inflammation and suggest a therapeutic strategy for targeting residual cardiovascular risk.