K. Fluiter et al., INCREASED SELECTIVE UPTAKE IN-VIVO AND IN-VITRO OF OXIDIZED CHOLESTERYL ESTERS FROM HIGH-DENSITY-LIPOPROTEIN BY RAT-LIVER PARENCHYMAL-CELLS, Biochemical journal, 319, 1996, pp. 471-476
Oxidation of low-density lipoprotein (LDL) leads initially to the form
ation 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 hyd
roxides (CEOH) by an intrinsic peroxidase-like activity. We have now p
erformed in vivo experiments to quantify the clearance rates and to id
entify the uptake sites of HDL-associated [H-3]Ch18:2-OH in rats. Upon
injection into rats, HDL-associated [H-3]Ch18:2-OH is removed more ra
pidly from the circulation than HDL-associated [H-3]Ch18:2. Two minute
s after administration of [H-3]Ch18:2-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 [H-3]Ch18:2-HDL. Organ distribution studie
s indicated that only the liver and adrenals exhibited preferential up
take of [H-3]Ch18:2-OH as compared with [H-3]Ch18:2, with the liver as
the major site of uptake. A cell-separation procedure, employed 10 mi
n after injection of [H-3]Ch18:2-OH-HDL or [H-3]Ch18:2-HDL, demonstrat
ed that within the liver only parenchymal cells take up HDL-CE by the
selective uptake pathway, Selective uptake by parenchymal cells of [H-
3]Ch18:2-OH was 3-fold higher than that of [H-3]Ch18:2, while Kupffer
and endothelial cell uptake of the lipid tracers reflected HDL holopar
ticle uptake (as analysed with iodinated versus cholesteryl ester-labe
lled HDL), The efficient uptake of [H-3]Ch18:2-OH by parenchymal cells
was coupled to a 3-fold increase in rate of radioactive bile acid sec
retion from [H-3]Ch18:2-OH-HDL as compared with [H-3]Ch18:2-HDL. In vi
tro studies with freshly isolated parenchymal cells showed that the as
sociation of [H-3]Ch18:2-OH-HDL at 37 degrees C exceeded [H-3]Ch18:2-H
DL 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 functi
on as an efficient protection system against potentially atherogenic C
EOOH.