Mechanisms
Plasminogen receptors PlgRKT, annexin A2 and S100A10 drive Lp(a) uptake into liver cells via macropinocytosis (Arterioscler Thromb Vasc Biol 2023)
Original title: Plasminogen Receptors Promote Lipoprotein(a) Uptake by Enhancing Surface Binding and Facilitating Macropinocytosis
Using HepG2 liver cancer cells and HAP1 fibroblast-like cells, the authors showed that overexpressing the plasminogen receptors PlgRKT, annexin A2, or S100A10 significantly increased uptake of Lp(a) and apo(a), but not LDL, while knocking out PlgRKT and S100A10 reduced this uptake. Surface-binding assays showed that only PlgRKT increased Lp(a) and apo(a) binding to the cell membrane, whereas annexin A2 and S100A10 instead promoted macropinocytosis, as shown by increased uptake of the marker dextran. A PI3K inhibitor, known to block macropinocytosis, reduced Lp(a) uptake in a concentration-dependent manner, confirming this pathway. The findings identify a novel Lp(a) endocytosis route via plasminogen receptors and macropinocytosis, potentially relevant given that PI3K inhibitors and some antidepressants already used clinically also inhibit macropinocytosis.
Original abstract
Background: High levels of Lp(a) (lipoprotein(a)) are associated with multiple forms of cardiovascular disease. Lp(a) consists of an apoB100-containing particle attached to the plasminogen homologue apo(a). The pathways for Lp(a) clearance are not well understood. We previously discovered that the plasminogen receptor PlgRKT (plasminogen receptor with a C-terminal lysine) promoted Lp(a) uptake in liver cells. Here, we aimed to further define the role of PlgRKT and to investigate the role of 2 other plasminogen receptors, annexin A2 and S100A10 (S100 calcium-binding protein A10) in the endocytosis of Lp(a).
Methods: Human hepatocellular carcinoma (HepG2) cells and haploid human fibroblast-like (HAP1) cells were used for overexpression and knockout of plasminogen receptors. The uptake of Lp(a), LDL (low-density lipoprotein), apo(a), and endocytic cargos was visualized and quantified by confocal microscopy and Western blotting.
Results: The uptake of both Lp(a) and apo(a), but not LDL, was significantly increased in HepG2 and HAP1 cells overexpressing PlgRKT, annexin A2, or S100A10. Conversely, Lp(a) and apo(a), but not LDL, uptake was significantly reduced in HAP1 cells in which PlgRKT and S100A10 were knocked out. Surface binding studies in HepG2 cells showed that overexpression of PlgRKT, but not annexin A2 or S100A10, increased Lp(a) and apo(a) plasma membrane binding. Annexin A2 and S100A10, on the other hand, appeared to regulate macropinocytosis with both proteins significantly increasing the uptake of the macropinocytosis marker dextran when overexpressed in HepG2 and HAP1 cells and knockout of S100A10 significantly reducing dextran uptake. Bringing these observations together, we tested the effect of a PI3K (phosphoinositide-3-kinase) inhibitor, known to inhibit macropinocytosis, on Lp(a) uptake. Results showed a concentration-dependent reduction confirming that Lp(a) uptake was indeed mediated by macropinocytosis.
Conclusions: These findings uncover a novel pathway for Lp(a) endocytosis involving multiple plasminogen receptors that enhance surface binding and stimulate macropinocytosis of Lp(a). Although the findings were produced in cell culture models that have limitations, they could have clinical relevance since drugs that inhibit macropinocytosis are in clinical use, that is, the PI3K inhibitors for cancer therapy and some antidepressant compounds.
Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.