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J Biol Chem, Vol. 274, Issue 52, 36912-36920, December 24, 1999
From the Expression of human lecithin
cholesterol acyltransferase (LCAT) in mice (LCAT-Tg) leads to increased
high density lipoprotein (HDL) cholesterol levels but paradoxically,
enhanced atherosclerosis. We have hypothesized that the absence of
cholesteryl ester transfer protein (CETP) in LCAT-Tg mice facilitates
the accumulation of dysfunctional HDL leading to impaired reverse
cholesterol transport and the development of a pro-atherogenic state.
To test this hypothesis we cross-bred LCAT-Tg with CETP-Tg mice. On
both regular chow and high fat, high cholesterol diets, expression of
CETP in LCAT-Tg mice reduced total cholesterol (
Cholesteryl Ester Transfer Protein Corrects Dysfunctional
High Density Lipoproteins and Reduces Aortic Atherosclerosis in
Lecithin Cholesterol Acyltransferase Transgenic Mice*
§,§,,,,
,,,, and
Molecular Disease Branch and
** Laboratory of Animal Medicine/Surgery, NHLBI, National
Institutes of Health, Bethesda, Maryland 20892, ¶ The Jackson
Laboratory, Bar Harbor, Maine 04609-1500, and Faculte de
Pharmacie-Institut, Pasteur, INSERM U325, Lille, France
39% and 13%,
respectively; p < 0.05), reflecting a decrease in HDL
cholesterol levels. CETP normalized both the plasma clearance of
[3H]cholesteryl esters ([3H]CE) from HDL
(fractional catabolic rate in days
1: LCAT-Tg = 3.7 ± 0.34, LCATxCETP-Tg = 6.1 ± 0.16, and
controls = 6.4 ± 0.16) as well as the liver uptake of
[3H]CE from HDL (LCAT-Tg = 36%, LCATxCETP-Tg = 65%, and controls = 63%) in LCAT-Tg mice. On the pro-atherogenic
diet the mean aortic lesion area was reduced by 41% in LCATxCETP-Tg
(21.2 ± 2.0 µm2 × 103) compared with
LCAT-Tg mice (35.7 ± 2.0 µm2 × 103;
p < 0.001). Adenovirus-mediated expression of
scavenger receptor class B (SR-BI) failed to normalize the plasma
clearance and liver uptake of [3H]CE from LCAT-Tg HDL.
Thus, the ability of SR-BI to facilitate the selective uptake of CE
from LCAT-Tg HDL is impaired, indicating a potential mechanism leading
to impaired reverse cholesterol transport and atherosclerosis in these
animals. We conclude that CETP expression reduces atherosclerosis in
LCAT-Tg mice by restoring the functional properties of LCAT-Tg mouse
HDL and promoting the hepatic uptake of HDL-CE. These findings provide
definitive in vivo evidence supporting the proposed
anti-atherogenic role of CETP in facilitating HDL-mediated reverse
cholesterol transport and demonstrate that CETP expression is
beneficial in pro-atherogenic states that result from impaired reverse
cholesterol transport.
*
This study was supported in part by National Institutes of
Health Grants HL 30086 and HL 32087.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: National Institutes
of Health, Molecular Disease Branch, NHLBI, Bldg. 10, Rm. 7N115, 10 Center Dr. MSC 1666, Bethesda, MD 20892-1666. Tel.: 301-496-5095; Fax:
301-402-0190.
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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