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(Received for publication, April 8, 1996, and in revised form, August 23, 1996)
From the Section of Experimental Atherosclerosis, NHLBI, National
Institutes of Health, Bethesda, Maryland 20892
Human monocyte-derived macrophages can efflux
accumulated cholesterol without exogenously added cholesterol acceptors
(Kruth, H. S., Skarlatos, S. I., Gaynor, P. M., and Gamble, W. (1994)
J. Biol. Chem. 269, 24511-24518). Most of the
effluxed cholesterol accumulates in the medium as apolipoprotein
E-discoidal lipid particles. In the current study, we determined
whether and to what degree cholesterol efflux from human
monocyte-macrophages depended on apolipoprotein E secretion.
Unexpectedly, 2-week-old differentiated monocyte-macrophages secreted
similar amounts of apolipoprotein E without or with cholesterol
enrichment. Apolipoprotein E mRNA levels in these macrophages were
not increased by cholesterol enrichment and were comparable with levels
in HepG2 cells. Without cholesterol enrichment, monocyte-macrophages
secreted lipid-poor apolipoprotein E with a density >1.21 g/ml. By
contrast, cholesterol enrichment of monocyte-macrophages induced the
association of apoE with phospholipid and cholesterol to form discoidal
particles that floated at densities of 1.08-1.10 g/ml. An
anti-apolipoprotein E monoclonal antibody added to the culture medium
significantly inhibited cholesterol and phospholipid efflux from the
monocyte-macrophages. This showed that apolipoprotein E was required
for most of the cholesterol efflux, and that apolipoprotein E did not
leave macrophages with lipid but rather associated with lipid after it
was secreted. Thus, 1) apolipoprotein E was constitutively secreted by
differentiated human monocyte-macrophages, 2) apolipoprotein E only
formed discoidal particles following macrophage cholesterol enrichment,
3) apolipoprotein E was necessary for cholesterol efflux to occur in
the absence of added cholesterol acceptors and, in addition 4) the
level of macrophage unesterified cholesterol was not rate-limiting for
this cholesterol efflux, and 5) net phospholipid synthesis occurred in
macrophages secondary to apoE-mediated loss of macrophage phospholipid.
In conclusion, apolipoprotein E functions in an autocrine pathway that
mediates cholesterol efflux from human monocyte-derived
macrophages.
Volume 271, Number 45,
Issue of November 8, 1996
pp. 28641-28646
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
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