Recycling of Apolipoprotein(a) After PlgRKT-Mediated Endocytosis of Lipoprotein(a)

Abstract

Rationale: Lipoprotein(a) [Lp(a)] is a low-density lipoprotein–like lipoprotein and important cardiovascular risk factor whose cognate receptor and intracellular fate remains unknown. Objective: Our study aimed to determine the intracellular trafficking pathway for Lp(a) and the receptor responsible for its uptake in liver cells. Methods and Results: Human hepatoma cells were treated with Lp(a) purified from human plasma and Lp(a) uptake studied using Western blot analysis and intracellular localization of Lp(a) by confocal microscopy. Lp(a) was maximally internalized by 2 hours and was detected by an antiapo(a) antibody to be localized to Rab5-positive early endosomes, the trans-Golgi network, and subsequently Rab11-positive recycling endosomes. In human hepatoma cells, the apo(a) component from the internalized Lp(a) was resecreted back into the cellular media, whereas the low-density lipoprotein component was localized to the lysosomal compartment. Lp(a) internalization was reduced 0.35-fold in HAP1 and 0.33-fold in human hepatoma cells in which the plasminogen receptor (KT) was knocked out. Conversely, Lp(a) internalization was enhanced 2-fold in HAP1 and 1.6-fold in human hepatoma cells in which plasminogen receptor (KT) was overexpressed, showing for the first time the role of a specific plasminogen receptor in Lp(a) uptake. Conclusions: The novel findings that Lp(a) is internalized by the plasminogen receptor, plasminogen receptor (KT), and the apo(a) component is recycled may have important implications for the catabolism and function of Lp(a).