© 2000 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Oxidized VLDL Induces Less Triglyceride Accumulation in J774 Macrophages Than Native VLDL Due to an Impaired Extracellular Lipolysis
From TNO-Prevention and Health, Gaubius Laboratory (M.C.J., W.L.H., L.C.v.V., V.E.H.D., L.M.H.), and the Departments of Pediatrics (J.E.M.G.) and of Cardiology and Internal Medicine (L.M.H.), Leiden University Medical Center, Leiden, Netherlands.
Correspondence to Dr M.C. Jong, TNO-Prevention and Health, Gaubius Laboratory, Zernikedreef 9, 2333 CK Leiden, PO Box 2215, 2301 CE Leiden, Netherlands. E-mail mc.jong{at}pg.tno.nl
Abstract—The present study
examined the relative contributions of the different pathways by which
oxidatively modified VLDL (oxVLDL) promotes the uptake and
intracellular accumulation of lipids in J774 macrophages. VLDL
was oxidized for a maximum of 4 hours, resulting in an increase in
thiobarbituric acid–reactive substances and an increased
electrophoretic mobility on agarose gel. The lipid composition of the
relatively moderately oxidized VLDL samples did not differ
significantly from that of nonoxidized VLDL samples. The uptake of
125I-labeled VLDL by the J774 cells increased with
oxidation time and was completely blocked on coincubation with
polyinosinic acid (PolyI), indicating that oxVLDL is taken up by the
cells via the scavenger receptor only. Despite the 2-fold increased
uptake of oxVLDL protein, the cell association of
triglyceride (TG)-derived fatty acids by the J774
macrophages after incubation with oxVLDL was only 50% of that
with native VLDL. In line with these observations, the induction of de
novo synthesis of TG by J774 cells was 
3-fold less efficient after
incubation with oxVLDL than after incubation with native VLDL. The
induction of de novo synthesis of TG with oxVLDL was even further
decreased on simultaneous incubation with PolyI, whereas
PolyI did not affect the native VLDL-induced TG synthesis. These
results indicate that oxVLDL induces endogenous TG
synthesis predominantly through particle uptake via the scavenger
receptor and much less via the extracellular lipoprotein lipase
(LPL)–mediated hydrolysis of TG, as is the case for native VLDL. In
line with these observations, we showed that the suitability of VLDL as
a substrate for LPL decreases with oxidation time. Addition of oxVLDL
to the LPL assay did not interfere with the lipolysis of native VLDL.
However, enrichment of the oxidized lipoprotein particle with native
apoC2 was able to fully restore the impaired lipolysis. Thus, from
these studies it can be concluded that on oxidation, VLDL becomes less
efficient in inducing TG accumulation in J774 cells as a consequence of
a defect in apoC2 as an activator for the LPL-mediated
extracellular lipolysis.
Key Words: oxidized VLDL • lipolysis • lipid accumulation • macrophages
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