Apolipoprotein E isoforms and their Cys‐thiol modifications impact LRP1‐mediated metabolism of triglyceride‐rich lipoproteins

The low‐density lipoprotein (LDL) receptor‐related protein (LRP)1 participates in the metabolism of apolipoprotein (apo) E‐containing lipoproteins (apoE‐LP). We investigated the effects of modifications of cysteine (Cys)‐thiol of apoE on LRP1‐mediated metabolism. Among the three isoforms, apoE2‐LP exhibited the lowest affinity for LRP1 but was significantly catabolized, whereas apoE4‐LP was sufficiently bound to LRP1 but showed the lowest catabolic capability. The reduction enhanced the binding and suppressed the catabolism of apoE3‐LP, but had no effect on apoE2‐LP. The formation of disulfide‐linked complexes with apoAII suppressed binding, but enhanced the catabolism of apoE2‐LP. Redox modifications of apoE‐Cys‐thiol may modulate the LRP1‐mediated metabolism of apoE2‐ or apoE3‐LP, but not apoE4‐LP. The failure of this function may be involved in the pathophysiology of dyslipidemia. The current study offers a novel perspective on the physiological role of apolipoprotein (apo) E in lipid metabolism. The redox status of Cys‐thiol in the apoE molecule significantly influences lipoprotein metabolism via the low‐density lipoprotein receptor‐related protein (LRP) 1. Our findings are instrumental in understanding the pathology of various apoE‐related diseases, including various atherosclerotic diseases and Alzheimer's disease.