Abstract 931: Lrp6 Mediates Cellular Cholesterol Uptake
LRP6 mutation (LRP6R611C) is associated with coronary artery disease (CAD) and several metabolic phenotypes including hyperlipidemia. Mutation carriers all have elevated LDL and VLDL cholesterols. The clinical profile of these patients has revealed that hyperlipidemia precedes all other metabolic phenotypes by in average 10 years, raising the possibility that hyperlipidemia may be the underlying cause of the metabolic syndrome and CAD in LRP6 mutation. The pathophysiology of hyperlidemia in LRP6R611C remains unknown. The mechanism by which LRP6 mediates lipid metabolism has not been previously studied. In the current study we show that lymphoblastoid cells of LRP6 mutation carriers display increased LDL uptake. This uptake is independent of LDL receptor, which is expressed at a lower level in the mutant cells. LRP6 membrane expression is increased in lipid free medium suggesting involvement of this receptor in the feedback mechanism for the LDL cholesterol uptake. LRP6 and LRP6R611C both show colocalizations with di-LDL, suggesting involvement of the LRP6 in LDL uptake(fig. c & f⇓). In LRP6R611C lymphoblastoid cells the LRP6 receptor and the LDL molecules are both localized mainly in the juxtanuclear region(fig. d & e⇓). This is in sharp contrast to the wild type LRP6 lymphoblastoid cells, in which both the LRP6 receptor and the LDL molecules are localized to the cell membrane and the vesicles that represent early and late endosomes(fig. a & b⇓). Increased localization of LDL in the endoplasmic reticulum is associated with increased rate of apoptosis. The mechanisms by which wild type and mutant LRP6 mediate LDL uptake was investigated by immune coprecipitation and binding assays.