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J Biol Chem, Vol. 275, Issue 14, 10077-10084, April 7, 2000
From the Plasma levels of high density lipoprotein (HDL)
cholesterol and its major protein component apolipoprotein (apo) A-I
are significantly reduced in both acute and chronic inflammatory
conditions, but the basis for this phenomenon is not well understood.
We hypothesized that secretory phospholipase A2
(sPLA2), an acute phase protein that has been found in
association with HDL, promotes HDL catabolism. A series of HDL
metabolic studies were performed in transgenic mice that specifically
overexpress human sPLA2 but have no evidence of local or
systemic inflammation. We found that HDL isolated from these mice have
a significantly lower phospholipid and cholesteryl ester and
significantly greater triglyceride content. The fractional catabolic
rate (FCR) of 125I-HDL was significantly faster in
sPLA2 transgenic mice (4.08 ± 0.01 pools/day)
compared with control wild-type littermates (2.16 ± 0.48 pools/day). 125I-HDL isolated from sPLA2
transgenic mice was catabolized significantly faster than
131I-HDL isolated from wild-type mice after injection in
wild-type mice (p < 0.001). Injection of
125I-tyramine-cellobiose-HDL demonstrated significantly
greater degradation of HDL apolipoproteins in the kidneys of
sPLA2 transgenic mice compared with control mice
(p < 0.05). The fractional catabolic rate of
[3H]cholesteryl ether HDL was significantly faster in
sPLA2-overexpressing mice (6.48 ± 0.24 pools/day)
compared with controls (4.80 ± 0.72 pools/day). Uptake of
[3H] cholesteryl ether into the livers and adrenals of
sPLA2 transgenic mice was significantly enhanced compared
with control mice. In summary, these data demonstrate that
overexpression of sPLA2 alone in the absence of
inflammation causes profound alterations of HDL metabolism in
vivo and are consistent with the hypothesis that
sPLA2 may promote HDL catabolism in acute and chronic
inflammatory conditions.
Overexpression of Secretory Phospholipase A2 Causes
Rapid Catabolism and Altered Tissue Uptake of High Density Lipoprotein
Cholesteryl Ester and Apolipoprotein A-I*
,,
,
Department of Medicine and Department
of Molecular and Cellular Engineering, University of Pennsylvania
Health System, Philadelphia, Pennsylvania 19104, the
§ Department of Biology, University of Delaware, Newark,
Delaware 19716, ¶ Chrysalis DNX Transgenic Sciences, Princeton,
New Jersey 08540, and the ** Department of Internal Medicine, University
of Kentucky and Veterans Affairs Medical Center,
Lexington, Kentucky 40536
*
This work was supported by National Institutes of Health
Grant HL55323 (to D. J. R.), a grant from the Deutsche
Forschungsgemeinschaft (to U. J. F. T.), and a grant
from ARCOLL, France (to C. M.).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: University of
Pennsylvania Medical Center, 614 BRB II/III, 421 Curie Blvd.,
Philadelphia, PA 19104-6100. Tel.: 215-898-4011; Fax: 215-573-6725;
E-mail: rader@mail.med.upenn.edu.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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