Increased selective uptake in vivo and in vitro of oxidized cholesteryl esters from high-density lipoprotein by rat liver parenchymal cells

Oxidation of low-density lipoprotein (LDL) leads initially to the formation of LDL-associated cholesteryl ester hydroperoxides (CEOOH). LDL-associated CEOOH can be transferred to high-density lipoprotein (HDL), and HDL-associated CEOOH are rapidly reduced to the corresponding hydroxides (CEOH) by an intrinsic peroxidase-like activity. We have now performed in vivo experiments to quantify the clearance rates and to identify the uptake sites of HDL-associated 3HCh18:2-OH in rats. Upon injection into rats, HDL-associated 3HCh18:2-OH is removed more rapidly from the circulation than HDL-associated 3HCh18:2. Two minutes after administration of 3HCh18:2-OH-HDL, 19.6 +/- 2.6% (S.E.M.; n = 4) of the label was taken up by the liver as compared with 2.4 +/- 0.25% (S.E.M.; n = 4) for 3HCh18:2-HDL. Organ distribution studies indicated that only the liver and adrenals exhibited preferential uptake of 3HCh18:2-OH as compared with 3HCh18:2, with the liver as the major site of uptake. A cell-separation procedure, employed 10 min after injection of 3HCh18:2-OH-HDL or 3HCh18:2-HDL, demonstrated that within the liver only parenchymal cells take up HDL-CE by the selective uptake pathway. Selective uptake by parenchymal cells of 3HCh18:2-OH was 3-fold higher than that of 3HCh18:2, while Kupffer and endothelial cell uptake of the lipid tracers reflected HDL holoparticle uptake (as analysed with iodinated versus cholesteryl ester-labelled HDL). The efficient uptake of 3HCh18:2-OH by parenchymal cells was coupled to a 3-fold increase in rate of radioactive bile acid secretion from 3HCh18:2-OH-HDL as compared with 3HCh18:2-HDL. In vitro studies with freshly isolated parenchymal cells showed that the association of 3HCh18:2-OH-HDL at 37 degrees C exceeded 3HCh18:2-HDL uptake almost 4-fold. Our results indicate that HDL-associated CEOH are efficiently and selectively removed from the blood circulation by the liver in vivo. The selective liver uptake is specifically exerted by parenchymal cells and coupled to a rapid biliary secretion pathway. The liver uptake and biliary secretion route may allow HDL to function as an efficient protection system against potentially atherogenic CEOOH.