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Volume 272, Number 50, Issue of December 12, 1997
pp. 31285-31292
(Received for publication, August 18, 1997, and in revised form, October 3, 1997)
From the High density lipoprotein (HDL)
particles and HDL cholesteryl esters are taken up by both
receptor-mediated and non-receptor-mediated pathways. Here we show that
cell surface heparan sulfate proteoglycans (HSPG) participate in
hepatic lipase (HL)- and apolipoprotein (apo) E-mediated binding and
uptake of mouse and human HDL by cultured hepatocytes. The HL secreted
by HL-transfected McA-RH7777 cells enhanced both HDL binding at 4 °C
(~2-4-fold) and HDL uptake at 37 °C (~2-5-fold). The enhanced
binding and uptake of HDL were partially inhibited by the 39-kDa
protein, an inhibitor of low density lipoprotein receptor-related
protein (LRP), but were almost totally blocked by heparinase, which
removes the sulfated glycosaminoglycan chains from HSPG. Therefore, HL
may mediate the uptake of HDL by two pathways: an
HSPG-dependent LRP pathway and an
HSPG-dependent but LRP-independent pathway. The HL-mediated
binding and uptake of HDL were only minimally reduced when
catalytically inactive HL or LRP binding-defective HL was substituted
for wild-type HL, indicating that much of the HDL uptake required
neither HL binding to the LRP nor lipolytic processing. To study the
role of HL in facilitating the selective uptake of cholesteryl esters,
we used HDL into which radiolabeled cholesteryl ether had been
incorporated. HL increased the selective uptake of HDL cholesteryl
ether; this enhanced uptake was reduced by more than 80% by heparinase
but was unaffected by the 39-kDa protein. Like HL, apoE enhanced the binding and uptake of HDL (~2-fold) but had little effect on the selective uptake of HDL cholesteryl ether. In the presence of HL, apoE
did not further increase the uptake of HDL, and at a high concentration
apoE impaired or decreased the HL-mediated uptake of HDL. Therefore, HL
and apoE may utilize similar (but not identical) binding sites to
mediate HDL uptake. Although the relative importance of cell surface
HSPG in the overall metabolism of HDL in vivo remains to be
determined, cultured hepatocytes clearly displayed an
HSPG-dependent pathway that mediates the binding and uptake
of HDL. This study also demonstrates the importance of HL in enhancing
the binding and uptake of remnant and low density lipoproteins via an
HSPG-dependent pathway.
High density lipoproteins
(HDL)1 participate in the
transport of cholesterol to the liver for reutilization and excretion
(as bile acids) (1-3) and to other tissues such as the adrenal glands, ovaries, and testes for hormone synthesis (4-6). At least three processes for the clearance of plasma HDL have been proposed. First,
HDL cholesteryl esters may be transferred to very low density lipoproteins (VLDL), intermediate density lipoproteins, or chylomicron remnants by the cholesteryl ester transfer protein (7, 8) and then
delivered to the liver. Second, HDL particles may be taken up by
receptor-mediated endocytosis (9-17). Although apolipoprotein (apo)
A-I is clearly important in HDL metabolism, a specific cell surface
receptor for apoA-I has not been conclusively identified. Recently, a
scavenger receptor (SR-BI) and the low density lipoprotein (LDL)
receptor-related protein (LRP) have been proposed to be involved in the
uptake of HDL (18-21). Third, cholesteryl esters of HDL may be taken
up by the liver or extrahepatic tissues (or cultured cells) without a
parallel uptake of HDL particles. Although the mechanism of this
selective uptake is poorly defined (22-24), SR-BI has been implicated
in the process (18, 19, 21). In addition, the up-regulation of SR-BI
mRNA reported in the hepatic lipase (HL)-deficient mice (25)
indicated a possible interdependence of HL and SR-BI and suggested that
they both may contribute to the selective uptake mechanism (21).
Hepatic lipase, a 476-amino acid protein (Mr
~60,000), plays an important role in HDL metabolism (26-28). It
interacts with HDL (29) and catalyzes the hydrolysis of HDL
phospholipids and triglycerides (30, 31), converting HDL2
to HDL3 (32, 33), and it also promotes the uptake of HDL by
perfused rat liver (34, 35). In addition, pretreating HDL with HL
increases the uptake of apolipoproteins and cholesteryl esters by
cultured cells (36, 37). The importance of HL in determining plasma HDL
levels has also been demonstrated in vivo. Anti-HL antibody
or inactivation of the HL gene increased HDL levels (25, 38), whereas
overexpression of HL caused a greater than 80% decrease in HDL levels
in transgenic rabbits (39) and decreased plasma HDL concentrations and
HDL particle size in transgenic mice (40).
Apolipoprotein E is also involved in the metabolism of HDL. In humans,
apoE is associated with a subclass of HDL referred to as
HDL1; however, in lower species, such as mice, rats, and dogs, apoE is a major component of HDL, and HDL1 often
represents a major subclass (41, 42). Apolipoprotein E is a ligand for the LDL receptor (43), the LRP (44, 45), and other LDL receptor gene
family members, including gp330 (46), the VLDL receptor (47), and the
apoE receptor 2 (48). Apolipoprotein E can associate with HDL and
mediate HDL particle uptake by either the LDL receptor (12, 42, 49) or
the LRP (20). However, its role in the selective uptake of HDL
cholesteryl esters is uncertain because conflicting results have been
reported (13, 50). In contrast, HL-mediated selective uptake of
cholesteryl esters has been demonstrated in cultured hepatocytes (36,
37) and in Chinese hamster ovary cells transfected with
glycophosphatidylinositol-anchored HL (51).
Our previous studies demonstrated that cell surface HSPG are
involved in both HL- and apoE-mediated uptake of remnant lipoproteins (52-55). Kounnas et al. (56) showed that HL uptake is
mediated at least in part by the LRP in cultured cells and also by an
LRP-independent pathway that we have shown to be HSPG-mediated (55,
57). In this process, both HL and apoE promote the binding of remnant lipoproteins to HSPG or to the HSPG-LRP complex, enhancing uptake by
cultured cells and by intact liver (55, 57). A similar process also has
been found in lipoprotein lipase-mediated binding and uptake of
lipoproteins (58-60). The goal of the present study was to determine
whether the HSPG-LRP pathway or HSPG alone participate in HDL
metabolism. These pathways may be important not only in the liver,
where a large fraction of HDL is catabolized, but also in the adrenal
and ovary, where HDL (possibly in association with HL and/or apoE) may
play a major role in cholesterol homeostasis (for reviews see Refs. 61
and 62).
Lactose, tyramine, and heparinase I were
purchased from Sigma. The 3H-labeled cholesteryl linoleyl
ether (CLE) and sodium 125I were purchased from Amersham
Life Sciences. Plasmid DNA coding for the 39-kDa protein (a gift from
Dr. Joachim Herz, University of Texas Southwestern Medical
School, Dallas, TX) was transfected into Escherichia coli,
and the 39-kDa protein was purified as described (63). Human apoE2,
apoE3, and apoE4 were provided by Dr. Karl Weisgraber (Gladstone
Institute of Cardiovascular Disease).
Human and mouse HDL and HDL
subfractions were prepared by ultracentrifugation as described (64).
Unless otherwise indicated, the densities of human and mouse HDL used
in this study were 1.063-1.21 and 1.07-1.21 g/ml, respectively. The
HDL were iodinated as described by Bilheimer et al. (65).
Free iodine was removed by PD10 column chromatography. The HDL were
labeled with 1,1 Rabbit Nontransfected and human HL-transfected
McArdle rat hepatoma (McA-RH7777) cells were grown in Dulbecco's
modified Eagle's medium containing 20% fetal bovine serum. The
characteristics of the HL-transfected cells were described previously
(52).
Based on predictions from structure/function
studies of pancreatic lipase and lipoprotein lipase (71-73), HL
variants were prepared that lacked catalytic activity
(HL-CAT Wild-type HL and the HL variants were characterized by their heparin
binding properties (75-77) as follows. Conditioned medium from
transfected cells was applied to a heparin-Sepharose column and eluted
with an NaCl gradient (0.4-1.2 M). Fractions (1.1 ml) were
collected and assayed for catalytically active and immunoreactive HL as
described below. The salt concentration of every other fraction was
determined by conductance measurements.
To
compare the LRP binding activities of HL-LRP McA-RH7777 cells transfected with wild-type HL or HL-LRP The LRP membrane strips were incubated with conditioned medium
containing either wild-type HL or HL-LRP Nontransfected and
HL-transfected cells were grown in 22-mm dishes for 4-5 days (~90%
confluence), washed twice with serum-free medium, and incubated with
fresh serum-free medium at 37 °C for 2 h. The cells were placed
on ice and equilibrated for 20 min in a chamber with 7%
CO2. Labeled lipoproteins or lipoproteins plus apoE were
added to the culture medium, and the cells were incubated in the
chamber on ice in the cold room (4 °C) for 2 h, washed five
times with cold phosphate-buffered saline (PBS) containing 0.2% bovine
serum albumin (BSA) and once with PBS alone, and dissolved in 0.1 N NaOH. Bound radiolabeled lipoproteins were measured by
Nontransfected and HL-transfected
McA-RH7777 cells were plated in 22-mm tissue culture dishes and grown
to ~90% confluence, washed twice with fresh serum-free medium, and
incubated with fresh serum-free medium at 37 °C for 2 h. After
the addition of 125I-HDL or 125I-HDL plus apoE,
the cells were incubated at 37 °C for 2 h, placed on ice in the
cold room (4 °C), washed five times with PBS containing 0.2% BSA
and once with PBS alone, and dissolved in 0.1 N NaOH. The
radioactivity of the cells was measured by Nontransfected and HL-transfected cells
were grown to ~90% confluence, washed twice with serum-free medium,
and incubated for 6 h with 125I-HDL at 37 °C. After
incubation, the cells were placed on ice; the culture medium was
collected for the degradation assay (70), and the cells were washed
five times in 0.1 M PBS containing 0.2% BSA and once with
0.1 M PBS and solubilized with 0.1 N
NaOH for measurement of the protein concentration (80).
Nontransfected and HL-transfected cells were grown in 22-mm
dishes to ~90% confluence, washed twice with serum-free medium, and
incubated with fresh serum-free medium at 37 °C for 2 h. Then 125I-DLT-3H-CLE-labeled HDL with or without
exogenous apoE were added to the culture medium, and the cells were
incubated for 3 h. After incubation, the cells were placed on ice,
washed five times with PBS containing 0.2% BSA and once with PBS
alone, and dissolved in 1 ml of 0.1 N NaOH. Aliquots (0.5 ml) were precipitated with an equal volume of trichloroacetic acid to
determine trichloroacetic acid-soluble and -insoluble radioactivity
(70, 81). Another aliquot was extracted with n-hexane and
isopropanol (3:2) to measure 3H radioactivity. The relative
activities of 125I-DLT-3H-CLE-labeled HDL
particles were used to estimate the ratio of HDL protein to CLE.
Trichloroacetic acid-soluble 125I represented degraded
peptides that accumulated in the cells; trichloroacetic acid-insoluble
125I represented intact HDL particles. Therefore, the
amount of internalized CLE could be calculated based on the amount of
internalized protein. The additional 3H-CLE represented the
amount taken up selectively by cultured cells.
The cells
were treated with heparinase as described (52). Briefly, heparinase I
was added to nontransfected and HL-transfected cells at 37 °C for
2 h before they were incubated with lipoproteins or lipoproteins
plus apoE. Unless otherwise indicated, heparinase was used at a
concentration of 10 units/ml.
Nontransfected and HL-transfected cells were incubated with fresh
medium at 37 °C for 1.45 h. Fifteen minutes later, the 39-kDa protein was added to the culture medium. The labeled lipoproteins were
added to the cultured cells and incubated for an additional 2 h.
To determine if secreted HL mediates the
direct binding of HDL to the cell surface, nontransfected and
HL-transfected McA-RH7777 cells were incubated at 37 °C for 2 h
to allow HL to accumulate in the medium as described previously (52)
and placed on ice for 20 min in the cold room (4 °C) to minimize the
catalytic activity of the secreted HL. Under these conditions, the
catalytic activity of HL was typically reduced by more than 95%
compared with that at 37 °C (data not shown). Then
125I-HDL were added to the culture medium at 4 °C for
2 h, and the amount of 125I-HDL bound to the cell
surface was determined. The mouse HDL displayed 3-4-fold greater
binding, and human HDL displayed about 2-fold greater binding, to
transfected than to nontransfected cells (Fig.
1). Therefore, even with minimal
catalytic activity, HL mediated the enhanced cell surface binding of
HDL at 4 °C.
[View Larger Version of this Image (18K GIF file)]
To determine the
effect of secreted HL on the binding and uptake of HDL, nontransfected
and HL-transfected McA-RH7777 cells were incubated at 37 °C for
2 h with 125I-HDL (as a tracer of the HDL protein) or
with DiI-labeled HDL (as a tracer of HDL lipids). The binding and
uptake of 125I-mouse HDL were 3-5-fold greater by
HL-transfected cells than by nontransfected cells (Fig.
2A). The binding and uptake of
125I-human HDL were also enhanced about 2-fold by HL (Fig.
2B). After incubation with DiI-labeled HDL at 37 °C for
2 h, the HL-transfected cells showed more intense fluorescence
than the nontransfected cells (data not shown), indicating that the
lipid core of the HDL had been internalized. In addition, the
degradation of 125I-HDL by HL-transfected cells was
2-3-fold greater than that by nontransfected cells (data not shown).
Therefore, the secreted HL facilitated the binding, uptake, and
degradation of 125I-HDL by cultured hepatocytes.
[View Larger Version of this Image (18K GIF file)]
To ascertain if the
secreted HL could differentially mediate the binding and uptake of HDL
subfractions, nontransfected and HL-transfected cells were incubated
with mouse HDL (d = 1.07-1.21, 1.07-1.09, and 1.09-1.21
g/ml) or human HDL (d = 1.063-1.21, 1.063-1.125, and
1.125-1.21 g/ml) at 37 °C for 2 h. Binding and uptake of all three fractions of mouse and human HDL were increased equivalently in
HL-transfected cells compared with nontransfected cells (data not
shown).
Previous studies have shown
that HL binds to heparin and heparin-like molecules (77, 82, 83) and
that HL binding to cell surface HSPG can serve as a "bridge" to
enhance the binding and uptake of remnant lipoproteins (52). To
determine if HL has a similar role in the binding and uptake of HDL,
nontransfected and HL-transfected cells were pretreated with heparinase
for 2 h or with the 39-kDa protein for 15 min at 37 °C and then
incubated with mouse 125I-HDL for 2 h at 37 °C.
Heparinase had little effect on the binding and uptake of
125I-HDL by nontransfected cells but inhibited ~90% of
the enhanced binding and uptake mediated by HL in the transfected cells
(Fig. 3A). The 39-kDa protein
did not affect 125I-HDL binding and uptake by
nontransfected cells; however, it inhibited only about 35% of the
enhanced binding and uptake mediated by HL in transfected cells (Fig.
3A). At the concentration used in these studies, the 39-kDa
protein completely blocked the binding and degradation of
125I-
[View Larger Version of this Image (14K GIF file)]
In parallel studies, the binding and uptake of rabbit
125I- To determine the heparin binding, catalytic,
and LRP binding activities of wild-type and mutant HL, conditioned
media from clones of transfected McA-RH7777 cells that secreted
approximately equal amounts of wild-type HL, HL-CAT
[View Larger Version of this Image (19K GIF file)]
Conditioned media containing wild-type HL, HL-CAT
[View Larger Version of this Image (14K GIF file)]
In parallel studies, the binding and uptake of
125I- To determine the effect of added apoE on the
cell association of 125I-HDL, nontransfected McA-RH7777
cells were incubated at 4 °C for 2 h with 125I-HDL
that had been preincubated with exogenous human apoE2, apoE3, or apoE4
at 37 °C for 1 h. The binding of the apoE-enriched mouse or
human 125I-HDL at 4 °C was ~1.5-2-fold greater than
of control 125I-HDL without added apoE (data not shown).
Similarly, in cell association studies at 37 °C, apoE2, apoE3, and
apoE4 also enhanced the binding and uptake of mouse and human
125I-HDL by nontransfected cells ~1.8-2-fold compared
with HDL without added apoE (Fig. 6,
A and B). Thus, apoE also enhances the binding and uptake of HDL by cultured cells. Interestingly, apoE2, which is
defective in binding to the LDL receptor (42), was at least as active
as apoE3 in enhancing the binding and uptake of HDL by the
nontransfected cells, whereas apoE4 appeared to be slightly less
active.
[View Larger Version of this Image (30K GIF file)]
To evaluate the effects of heparinase and the 39-kDa
protein on the apoE-enhanced binding and uptake of
125I-HDL, nontransfected McA-RH7777 cells pretreated at
37 °C with heparinase (10 units/ml, 2 h) or with the 39-kDa
protein (10 µg/ml, 15 min) were incubated with 125I-HDL
for 2 h at 37 °C. Neither treatment inhibited the cell
association of mouse 125I-HDL alone; however, heparinase
virtually abolished the apoE-enhanced cell association, whereas the
39-kDa protein inhibited only ~40% of the enhanced binding and
uptake (Table I). These results are similar to those obtained in HL-transfected cells (Fig. 3), in which
heparinase inhibited almost all, whereas the 39-kDa protein inhibited
only ~35%, of the enhanced cell association of
125I-HDL.
Table I.
Effect of heparinase and the 39-kDa protein on binding and uptake of
mouse 125I-LDL by nontransfected McA-RH7777 cells
As shown in Fig. 6 (C and D), the enhanced binding and uptake of mouse and human HDL mediated by HL-secreting cells were not further enhanced by any of the apoE isoforms. In fact, adding apoE to the HDL appeared to inhibit the HL-mediated binding and uptake by the transfected cells. Effect of HL and ApoE on Selective Uptake of 3H-CLE of HDLThe selective uptake of 3H-CLE was measured by incubating nontransfected and HL-transfected McA-RH7777 cells with 125I-DLT-3H-CLE-labeled mouse HDL at 37 °C for 3 h. Both 125I-DLT and 3H-CLE accumulated inside cells when the double-labeled HDL were degraded (67, 68, 81). In the nontransfected cells, the selective uptake of 3H-CLE
was 348 ± 72 ng/mg of cell protein, which was about 2.5-fold
greater than that taken up in parallel with HDL particles (127 ± 14 ng/mg of cell protein as determined by 125I-DLT labeling
of HDL protein). This selective uptake was inhibited ~25% by
heparinase and only minimally by the 39-kDa protein (Fig. 7). Apolipoprotein E had little if any
effect on the selective uptake of 3H-CLE (mouse HDL, HDL + apoE2, HDL + apoE3, and HDL + apoE4 had selective uptakes of
approximately 350, 370, 340, and 340 ng of 3H-CLE/mg
of cell protein, respectively).
Fig. 7. Effects of HL and apoE on the selective uptake of 3H-CLE of mouse HDL by nontransfected and HL-transfected McA-RH7777 cells. The cells were incubated at 37 °C for 2 h with fresh medium. Some cells were incubated with medium containing heparinase (10 units/ml for 2 h) and some with medium containing the 39-kDa protein (20 µg/ml), which was added 15 min before 125I-HDL or 125I-HDL plus apoE. The 125I-DLT-3H-CLE-labeled mouse HDL (20 µg of protein/ml) or 125I-DLT-3H-CLE-labeled mouse HDL plus apoE (20 µg of HDL protein + 30 µg of apoE/ml) were incubated at 37 °C for 1 h before they were added to the cultured cells. The cells were then incubated at 37 °C for 3 h, placed on ice, washed five times with PBS containing 0.2% BSA and once with PBS, and dissolved in 1 ml of NaOH. The selective uptake of 3H-CLE of HDL was measured as described under "Experimental Procedures." Values are the mean ± S.D. of two duplicate experiments. [View Larger Version of this Image (26K GIF file)]
In the HL-transfected cells, the selective uptake of 3H-CLE was ~2.7-fold greater than in the nontransfected cells (Fig. 7). Heparinase inhibited this enhancement by ~80%, whereas the 39-kDa protein had little or no effect (Fig. 7). The addition of apoE to the double-labeled mouse HDL slightly inhibited the selective uptake of the 3H-CLE by the HL-transfected cells (data not shown). Effects of Catalytic and LRP Binding Activities of HL on Selective Uptake of 3H-CLE of HDLThe effects of the
catalytic and LRP binding activities of HL on the selective uptake of
HDL cholesteryl esters are shown in Fig.
8. Selective uptake of 3H-CLE
by nontransfected cells was 2-fold greater in medium containing wild-type HL than in control medium from nontransfected cells. This
HL-mediated enhancement of selective uptake was only slightly reduced
in medium containing HL-LRP Fig. 8. Effect of HL-LRP and
HL-CAT on the selective uptake of 3H-CLE by
nontransfected cells. Nontransfected cells were incubated in the
different conditioned media at 37 °C for 2 h with HDL
double-labeled with 125I-DLT and 3H-CLE. After
incubation, the cells were washed five times with 0.1 M PBS
containing 0.2 BSA and once with 0.1 M PBS and dissolved in
0.1 N NaOH. The cellular 125I-DLT and
3H-CLE were measured as described under "Experimental
Procedures." Values are the mean ± S.D. of two separate
experiments performed in triplicate.
[View Larger Version of this Image (17K GIF file)]
The mechanism of the HL-mediated enhanced binding and uptake of
HDL by cultured cells appears to involve several processes. Hepatic
lipase acts as a ligand that mediates an increased cell surface binding
of HDL particles. Binding studies at 4 °C with conditioned medium
from cells secreting HL-CAT The results of the present study strongly suggest that at least two
pathways are involved in the HL-mediated enhanced uptake of HDL
particles by cultured cells. The first pathway, by which about 30-40%
of HDL particles are internalized, is sensitive to the 39-kDa protein.
The 39-kDa protein binds to the LRP with very high affinity and blocks
all known ligands of the LRP (87, 88). Therefore, the 39-kDa
protein-sensitive portion of HDL uptake may be mediated by the LRP.
However, the 39-kDa protein can also interact with HSPG and block
ligand binding (57, 89). Therefore, HSPG may also be involved in the
39-kDa protein-sensitive pathway. Moreover, the binding and uptake of
125I-HDL by nontransfected cells in medium containing
HL-LRP The second pathway is solely dependent on HSPG. Hepatic lipase on the
cell surface or in the medium may associate with HDL particles, and the
resultant complex may be taken up directly by cell surface HSPG.
Heparinase abolished almost all (~80-90%) of the enhanced binding
and uptake. Previously we established that heparinase affects neither
LDL binding to the LDL receptor nor Our current findings indicate that HL is involved in the HSPG-mediated
uptake of HDL particles, although the type of HSPG required and exactly
how it mediates the uptake of HDL or other lipoproteins remain unknown.
These data implicate an HL-HSPG pathway in HDL catabolism and are
similar to our previous data demonstrating the involvement of HL in
Hepatic lipase also plays an important role in the selective uptake of HDL-CLE, a nonmetabolized surrogate for HDL cholesteryl esters. Although the mechanism of the selective uptake of HDL-CLE by cultured cells and by perfused liver is unknown, the present data are consistent with previous observations that HL stimulates the selective uptake of HDL cholesteryl esters (36, 37, 51). Recently the SR-BI receptor has been proposed as an HDL receptor for the selective uptake of HDL cholesteryl esters (18, 19, 21), and HL, but not apoE, was found to regulate this receptor and facilitate selective uptake of HDL cholesteryl esters (21). Interestingly, in the present study the selective uptake of HDL-CLE was sensitive to heparinase (Fig. 7). Thus, the HSPG pathway on the cell surface appears to be an important factor in the selective uptake of HDL cholesteryl esters by cultured cells. The HSPG interaction with the HL-HDL complexes may facilitate the transport of HDL cholesteryl esters across the plasma membrane of cells, based on the lipid gradient between the intracellular and extracellular membranes. Furthermore, HSPG binding may create a microenvironment on the cell surface for the lipolysis of HDL by HL or other phospholipases, releasing cholesteryl ester from the lipoprotein core and thereby facilitating selective uptake. Alternatively, HSPG binding of the HL-HDL complex may facilitate the uptake of HDL cholesteryl ester by anchoring the HDL in the proximity of the SR-BI receptor (18, 19, 21). Although it may not be required for the ligand function of the
molecule, the catalytic activity of HL clearly plays an important role
in HDL metabolism. This activity may be involved in the uptake of HDL
particles to a limited extent but clearly appears to be important in
the selective uptake of cholesteryl esters of HDL. The enhanced cell
association of 125I-HDL and the enhanced selective uptake
of 3H-CLE of HDL in medium containing HL-CAT There are several similarities between HL- and apoE-mediated enhancement of HDL catabolism. First, apoE mediates the enhanced binding of HDL at 4 °C and uptake of HDL at 37 °C by binding to HSPG and/or the LRP. The fact that HDL plus any of the three isoforms of apoE bound similarly to the cells supports this concept because all three apoE isoforms have similar binding affinities for HSPG and the LRP (93).2 The LRP pathway contributing to apoE-enriched HDL uptake was recently demonstrated in cultured neuronal cells (20). Second, most of the apoE-mediated cell association can be blocked by heparinase, whereas only about 40% is blocked by the 39-kDa protein, indicating that a significant portion of apoE-mediated enhancement of HDL uptake occurs via an HSPG-dependent, LRP-independent pathway. It remains to be determined whether HL and apoE mediate uptake via the same HSPG-dependent pathway. The fact that apoE did not promote an additional uptake of HDL in the presence of already enhanced uptake mediated by HL suggests that apoE and HL may compete for either HDL particles or HSPG binding sites on the cell surface. Our results also show important differences between HL- and
apoE-mediated HDL catabolism. Although exogenous apoE enhanced the
uptake of HDL particles, it had little if any effect on the selective
uptake of 3H-CLE. Therefore, the apoE-enhanced binding and
uptake of HDL are not associated with enhanced selective uptake of HDL
cholesteryl esters. In contrast, HL enhanced both the direct uptake of
the HDL particles and the selective uptake of 3H-CLE (Fig.
7). These results suggest that the enhanced selective uptake of HDL
cholesteryl esters requires both HL-mediated binding and some degree of
HL catalytic activity. In support of this concept, blocking HL-mediated
enhancement with heparinase or using medium containing
HL-CAT * This work was supported in part by National Institutes of Health Program Project Grant HL41633.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: Gladstone Inst. of
Cardiovascular Disease, P.O. Box 419100, San Francisco, CA 94141-9100. Tel.: 415-826-7500; Fax: 415-285-5632.
1 The abbreviations used are: HDL, high density lipoprotein(s); apo, apolipoprotein; BSA, bovine serum albumin; CLE, cholesteryl linoleyl ether; DiI, 1,1 -dioctadecyl-3,3,3 ,3 -tetramethylindocarbocyanine; DLT, dilactitol
tyramine; HL, hepatic lipase; HSPG, heparan sulfate proteoglycan(s);
LDL, low density lipoprotein(s); LRP, LDL receptor-related protein;
PBS, phosphate-buffered saline; VLDL, very low density lipoprotein(s);
SR, scavenger receptor.
2 Z.-S. Ji, H. L. Dichek, R. D. Miranda, and R. W. Mahley, unpublished data. We thank Dr. Stanley C. Rall, Jr. for critical reading of the manuscript and evaluation of the data, Walter Brecht for excellent technical assistance, Dr. Karl Weisgraber for providing apoE, and Drs. Yadong Huang and Thomas Innerarity for discussion of the experiments. We thank Sylvia Richmond for manuscript preparation, Stephen Ordway and Gary Howard for editorial assistance, and John C. W. Carroll and Amy Corder for graphics.
Volume 272, Number 50,
Issue of December 12, 1997
pp. 31285-31292
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E. K. Young, C. Chatterjee, and D. L. Sparks HDL-ApoE Content Regulates the Displacement of Hepatic Lipase from Cell Surface Proteoglycans Am. J. Pathol., July 1, 2009; 175(1): 448 - 457. [Abstract] [Full Text] [PDF] |
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F. T. Yen, O. Roitel, L. Bonnard, V. Notet, D. Pratte, C. Stenger, E. Magueur, and B. E. Bihain Lipolysis Stimulated Lipoprotein Receptor: A NOVEL MOLECULAR LINK BETWEEN HYPERLIPIDEMIA, WEIGHT GAIN, AND ATHEROSCLEROSIS IN MICE J. Biol. Chem., September 12, 2008; 283(37): 25650 - 25659. [Abstract] [Full Text] [PDF] |
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L. Freeman, M. J. A. Amar, R. Shamburek, B. Paigen, H. B. Brewer Jr., S. Santamarina-Fojo, and H. Gonzalez-Navarro Lipolytic and ligand-binding functions of hepatic lipase protect against atherosclerosis in LDL receptor-deficient mice J. Lipid Res., January 1, 2007; 48(1): 104 - 113. [Abstract] [Full Text] [PDF] |
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R. Liu, M. R. Hojjati, C. M. Devlin, I. H. Hansen, and X.-C. Jiang Macrophage Phospholipid Transfer Protein Deficiency and ApoE Secretion: Impact on Mouse Plasma Cholesterol Levels and Atherosclerosis Arterioscler. Thromb. Vasc. Biol., January 1, 2007; 27(1): 190 - 196. [Abstract] [Full Text] [PDF] |
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S. Azhar, S. Medicherla, W.-J. Shen, Y. Fujioka, L. G. Fong, E. Reaven, and A. D. Cooper LDL and cAMP cooperate to regulate the functional expression of the LRP in rat ovarian granulosa cells J. Lipid Res., November 1, 2006; 47(11): 2538 - 2550. [Abstract] [Full Text] [PDF] |
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H. L. Dichek, N. Agrawal, N. E. Andaloussi, and K. Qian Attenuated corticosterone response to chronic ACTH stimulation in hepatic lipase-deficient mice: evidence for a role for hepatic lipase in adrenal physiology Am J Physiol Endocrinol Metab, May 1, 2006; 290(5): E908 - E915. [Abstract] [Full Text] [PDF] |
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S. L. Karackattu, B. Trigatti, and M. Krieger Hepatic Lipase Deficiency Delays Atherosclerosis, Myocardial Infarction, and Cardiac Dysfunction and Extends Lifespan in SR-BI/Apolipoprotein E Double Knockout Mice Arterioscler. Thromb. Vasc. Biol., March 1, 2006; 26(3): 548 - 554. [Abstract] [Full Text] [PDF] |
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V. Llorente-Cortes, M. Otero-Vinas, S. Camino-Lopez, P. Costales, and L. Badimon Cholesteryl Esters of Aggregated LDL Are Internalized by Selective Uptake in Human Vascular Smooth Muscle Cells Arterioscler. Thromb. Vasc. Biol., January 1, 2006; 26(1): 117 - 123. [Abstract] [Full Text] [PDF] |
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K. Bach-Ngohou, K. Ouguerram, R. Frenais, P. Maugere, B. Ripolles-Piquer, Y. Zair, M. Krempf, and J. M. Bard Influence of Atorvastatin on Apolipoprotein E and AI Kinetics in Patients with Type 2 Diabetes J. Pharmacol. Exp. Ther., October 1, 2005; 315(1): 363 - 369. [Abstract] [Full Text] [PDF] |
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A. H. Hasty, M. R. Plummer, K. H. Weisgraber, M. F. Linton, S. Fazio, and L. L. Swift The recycling of apolipoprotein E in macrophages: influence of HDL and apolipoprotein A-I J. Lipid Res., July 1, 2005; 46(7): 1433 - 1439. [Abstract] [Full Text] [PDF] |
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R. Out, M. Hoekstra, S. C. A. de Jager, P. de Vos, D. R. van der Westhuyzen, N. R. Webb, M. Van Eck, E. A. L. Biessen, and T. J. C. Van Berkel Adenovirus-mediated hepatic overexpression of scavenger receptor class B type I accelerates chylomicron metabolism in C57BL/6J mice J. Lipid Res., June 1, 2005; 46(6): 1172 - 1181. [Abstract] [Full Text] [PDF] |
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S.-J. Lee, I. Grosskopf, S. Y. Choi, and A. D. Cooper Chylomicron remnant uptake in the livers of mice expressing human apolipoproteins E3, E2 (Arg158->Cys), and E3-Leiden J. Lipid Res., December 1, 2004; 45(12): 2199 - 2210. [Abstract] [Full Text] [PDF] |
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M. F. Khalil, W. D. Wagner, and I. J. Goldberg Molecular Interactions Leading to Lipoprotein Retention and the Initiation of Atherosclerosis Arterioscler. Thromb. Vasc. Biol., December 1, 2004; 24(12): 2211 - 2218. [Abstract] [Full Text] [PDF] |
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S. D. Proctor, D. F. Vine, and J. C.L. Mamo Arterial Permeability and Efflux of Apolipoprotein B-Containing Lipoproteins Assessed by In Situ Perfusion and Three-Dimensional Quantitative Confocal Microscopy Arterioscler. Thromb. Vasc. Biol., November 1, 2004; 24(11): 2162 - 2167. [Abstract] [Full Text] [PDF] |
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H. Gonzalez-Navarro, Z. Nong, M. J. A. Amar, R. D. Shamburek, J. Najib-Fruchart, B. J. Paigen, H. B. Brewer Jr., and S. Santamarina-Fojo The Ligand-binding Function of Hepatic Lipase Modulates the Development of Atherosclerosis in Transgenic Mice J. Biol. Chem., October 29, 2004; 279(44): 45312 - 45321. [Abstract] [Full Text] [PDF] |
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R. J. Brown, A. Gauthier, R. J. Parks, R. McPherson, D. L. Sparks, J. R. Schultz, and Z. Yao Severe Hypoalphalipoproteinemia in Mice Expressing Human Hepatic Lipase Deficient in Binding to Heparan Sulfate Proteoglycan J. Biol. Chem., October 8, 2004; 279(41): 42403 - 42409. [Abstract] [Full Text] [PDF] |
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S. Santamarina-Fojo, H. Gonzalez-Navarro, L. Freeman, E. Wagner, and Z. Nong Hepatic Lipase, Lipoprotein Metabolism, and Atherogenesis Arterioscler. Thromb. Vasc. Biol., October 1, 2004; 24(10): 1750 - 1754. [Abstract] [Full Text] [PDF] |
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H. L. Dichek, K. Qian, and N. Agrawal Divergent Effects of the Catalytic and Bridging Functions of Hepatic Lipase on Atherosclerosis Arterioscler. Thromb. Vasc. Biol., September 1, 2004; 24(9): 1696 - 1702. [Abstract] [Full Text] [PDF] |
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R. Out, J. K. Kruijt, P. C. N. Rensen, R. B. Hildebrand, P. de Vos, M. Van Eck, and T. J. C. Van Berkel Scavenger Receptor BI Plays a Role in Facilitating Chylomicron Metabolism J. Biol. Chem., April 30, 2004; 279(18): 18401 - 18406. [Abstract] [Full Text] [PDF] |
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H. L. Dichek, K. Qian, and N. Agrawal The bridging function of hepatic lipase clears plasma cholesterol in LDL receptor-deficient "apoB-48-only" and "apoB-100-only" mice J. Lipid Res., March 1, 2004; 45(3): 551 - 560. [Abstract] [Full Text] [PDF] |
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I. V. Fuki, N. Blanchard, W. Jin, D. H. L. Marchadier, J. S. Millar, J. M. Glick, and D. J. Rader Endogenously Produced Endothelial Lipase Enhances Binding and Cellular Processing of Plasma Lipoproteins via Heparan Sulfate Proteoglycan-mediated Pathway J. Biol. Chem., September 5, 2003; 278(36): 34331 - 34338. [Abstract] [Full Text] [PDF] |
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A. Soro, M. Jauhiainen, C. Ehnholm, and M.-R. Taskinen Determinants of low HDL levels in familial combined hyperlipidemia J. Lipid Res., August 1, 2003; 44(8): 1536 - 1544. [Abstract] [Full Text] [PDF] |
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S. S. Deeb, A. Zambon, M. C. Carr, A. F. Ayyobi, and J. D. Brunzell Hepatic lipase and dyslipidemia: interactions among genetic variants, obesity, gender, and diet J. Lipid Res., July 1, 2003; 44(7): 1279 - 1286. [Abstract] [Full Text] [PDF] |
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R. J. Brown, J. R. Schultz, K. W. S. Ko, J. S. Hill, T. A. Ramsamy, A. L. White, D. L. Sparks, and Z. Yao The amino acid sequences of the carboxyl termini of human and mouse hepatic lipase influence cell surface association J. Lipid Res., July 1, 2003; 44(7): 1306 - 1314. [Abstract] [Full Text] [PDF] |
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M. Brundert, J. Heeren, H. Greten, and F. Rinninger Hepatic lipase mediates an increase in selective uptake of HDL-associated cholesteryl esters by cells in culture independent from SR-BI J. Lipid Res., May 1, 2003; 44(5): 1020 - 1032. [Abstract] [Full Text] [PDF] |
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T. A. Ramsamy, J. Boucher, R. J. Brown, Z. Yao, and D. L. Sparks HDL regulates the displacement of hepatic lipase from cell surface proteoglycans and the hydrolysis of VLDL triacylglycerol J. Lipid Res., April 1, 2003; 44(4): 733 - 741. [Abstract] [Full Text] [PDF] |
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M. H. Farkas, L. L. Swift, A. H. Hasty, M. F. Linton, and S. Fazio The Recycling of Apolipoprotein E in Primary Cultures of Mouse Hepatocytes. EVIDENCE FOR A PHYSIOLOGIC CONNECTION TO HIGH DENSITY LIPOPROTEIN METABOLISM J. Biol. Chem., March 7, 2003; 278(11): 9412 - 9417. [Abstract] [Full Text] [PDF] |
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T. Nassar, B. S. Sachais, S.'e. Akkawi, M. A. Kowalska, K. Bdeir, E. Leitersdorf, E. Hiss, L. Ziporen, M. Aviram, D. Cines, et al. Platelet Factor 4 Enhances the Binding of Oxidized Low-density Lipoprotein to Vascular Wall Cells J. Biol. Chem., February 14, 2003; 278(8): 6187 - 6193. [Abstract] [Full Text] [PDF] |
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K. Conde-Knape, A. Bensadoun, J. H. Sobel, J. S. Cohn, and N. S. Shachter Overexpression of apoC-I in apoE-null mice: severe hypertriglyceridemia due to inhibition of hepatic lipase J. Lipid Res., December 1, 2002; 43(12): 2136 - 2145. [Abstract] [Full Text] [PDF] |
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A. E. Mullick, R. J. Deckelbaum, I. J. Goldberg, M. Al-Haideri, and J. C. Rutledge Apolipoprotein E and Lipoprotein Lipase Increase Triglyceride-Rich Particle Binding but Decrease Particle Penetration in Arterial Wall Arterioscler. Thromb. Vasc. Biol., December 1, 2002; 22(12): 2080 - 2085. [Abstract] [Full Text] [PDF] |
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S. Bultel-Brienne, S. Lestavel, A. Pilon, I. Laffont, A. Tailleux, J.-C. Fruchart, G. Siest, and V. Clavey Lipid Free Apolipoprotein E Binds to the Class B Type I Scavenger Receptor I (SR-BI) and Enhances Cholesteryl Ester Uptake from Lipoproteins J. Biol. Chem., September 20, 2002; 277(39): 36092 - 36099. [Abstract] [Full Text] [PDF] |
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S. T. Thuahnai, S. Lund-Katz, D. L. Williams, and M. C. Phillips Scavenger Receptor Class B, Type I-mediated Uptake of Various Lipids into Cells. INFLUENCE OF THE NATURE OF THE DONOR PARTICLE INTERACTION WITH THE RECEPTOR J. Biol. Chem., November 16, 2001; 276(47): 43801 - 43808. [Abstract] [Full Text] [PDF] |
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F. Rinninger, M. Brundert, I. Brosch, N. Donarski, R. M. Budzinski, and H. Greten Lipoprotein lipase mediates an increase in selective uptake of HDL-associated cholesteryl esters by cells in culture independent of scavenger receptor BI J. Lipid Res., November 1, 2001; 42(11): 1740 - 1751. [Abstract] [Full Text] [PDF] |
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R. B. DeMattos, L. L. Rudel, and D. L. Williams Biochemical analysis of cell-derived apoE3 particles active in stimulating neurite outgrowth J. Lipid Res., June 1, 2001; 42(6): 976 - 987. [Abstract] [Full Text] |
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H. Hidaka, M. Tozuka, E. Hidaka, K. Yamauchi, H. Ota, T. Honda, and T. Katsuyama Characterization of an Apolipoprotein E3 Variant (Arg 145 -> His) Associated with Mild Hypertriglyceridemia Ann. Clin. Lab. Sci., April 1, 2001; 31(2): 163 - 170. [Abstract] [Full Text] [PDF] |
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H. L. Dichek, S. M. Johnson, H. Akeefe, G. T. Lo, E. Sage, C. E. Yap, and R. W. Mahley Hepatic lipase overexpression lowers remnant and LDL levels by a noncatalytic mechanism in LDL receptor-deficient mice J. Lipid Res., February 1, 2001; 42(2): 201 - 210. [Abstract] [Full Text] |
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A. Zambon, S. S. Deeb, A. Bensadoun, K. E. Foster, and J. D. Brunzell In vivo evidence of a role for hepatic lipase in human apoB-containing lipoprotein metabolism, independent of its lipolytic activity J. Lipid Res., December 1, 2000; 41(12): 2094 - 2099. [Abstract] [Full Text] |
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A. A.-R. Higazi, T. Nassar, T. Ganz, D. J. Rader, R. Udassin, K. Bdeir, E. Hiss, B. S. Sachais, K. J. Williams, E. Leitersdorf, et al. The alpha -defensins stimulate proteoglycan-dependent catabolism of low-density lipoprotein by vascular cells: a new class of inflammatory apolipoprotein and a possible contributor to atherogenesis Blood, August 15, 2000; 96(4): 1393 - 1398. [Abstract] [Full Text] [PDF] |
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G. Lambert, M. J. A. Amar, P. Martin, J. Fruchart-Najib, B. Föger, R. D. Shamburek, H. B. Brewer , Jr., and S. Santamarina-Fojo Hepatic lipase deficiency decreases the selective uptake of HDL-cholesteryl esters in vivo J. Lipid Res., May 1, 2000; 41(5): 667 - 672. [Abstract] [Full Text] |
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K. W. Huggins, E. R. Burleson, J. K. Sawyer, K. Kelly, L. L. Rudel, and J. S. Parks Determination of the tissue sites responsible for the catabolism of large high density lipoprotein in the African green monkey J. Lipid Res., March 1, 2000; 41(3): 384 - 394. [Abstract] [Full Text] |
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K. A. Dugi, M. J. A. Amar, C. C. Haudenschild, R. D. Shamburek, A. Bensadoun, R. F. Hoyt Jr, J. Fruchart-Najib, Z. Madj, H. B. Brewer Jr, and S. Santamarina-Fojo In Vivo Evidence for Both Lipolytic and Nonlipolytic Function of Hepatic Lipase in the Metabolism of HDL Arterioscler. Thromb. Vasc. Biol., March 1, 2000; 20(3): 793 - 800. [Abstract] [Full Text] [PDF] |
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R. A. Sendak, D. E. Berryman, G. Gellman, K. Melford, and A. Bensadoun Binding of hepatic lipase to heparin: identification of specific heparin-binding residues in two distinct positive charge clusters J. Lipid Res., February 1, 2000; 41(2): 260 - 268. [Abstract] [Full Text] |
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A. D. Lander and S. B. Selleck The Elusive Functions of Proteoglycans: In Vivo Veritas J. Cell Biol., January 24, 2000; 148(2): 227 - 232. [Abstract] [Full Text] [PDF] |
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S. S. Deeb and R. Peng The C-514T polymorphism in the human hepatic lipase gene promoter diminishes its activity J. Lipid Res., January 1, 2000; 41(1): 155 - 158. [Abstract] [Full Text] |
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R. W. Mahley, Y. Huang, and S. C. Rall , Jr. Pathogenesis of type III hyperlipoproteinemia (dysbetalipoproteinemia): questions, quandaries, and paradoxes J. Lipid Res., November 1, 1999; 40(11): 1933 - 1949. [Abstract] [Full Text] |
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M. C. Carr, J. E. Hokanson, S. S. Deeb, J. Q. Purnell, E. S. Mitchell, and J. D. Brunzell A Hepatic Lipase Gene Promoter Polymorphism Attenuates the Increase in Hepatic Lipase Activity With Increasing Intra-abdominal Fat in Women Arterioscler. Thromb. Vasc. Biol., November 1, 1999; 19(11): 2701 - 2707. [Abstract] [Full Text] [PDF] |
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C. V. Zerbinatti and C. A. Dyer Apolipoprotein E Peptide Stimulation of Rat Ovarian Theca Cell Androgen Synthesis Is Mediated by Members of the Low Density Lipoprotein Receptor Superfamily Biol Reprod, September 1, 1999; 61(3): 665 - 672. [Abstract] [Full Text] |
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S. M. Hammad, S. Stefansson, W. O. Twal, C. J. Drake, P. Fleming, A. Remaley, H. B. Brewer Jr., and W. S. Argraves Cubilin, the endocytic receptor for intrinsic factor-vitamin B12 complex, mediates high-density lipoprotein holoparticle endocytosis PNAS, August 31, 1999; 96(18): 10158 - 10163. [Abstract] [Full Text] [PDF] |
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G. Lambert, M. B. Chase, K. Dugi, A. Bensadoun, H. B. Brewer , Jr., and S. Santamarina-Fojo Hepatic lipase promotes the selective uptake of high density lipoprotein-cholesteryl esters via the scavenger receptor B1 J. Lipid Res., July 1, 1999; 40(7): 1294 - 1303. [Abstract] [Full Text] |
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S. E. Crawford and J. Borensztajn Plasma clearance and liver uptake of chylomicron remnants generated by hepatic lipase lipolysis: evidence for a lactoferrin-sensitive and apolipoprotein E-independent pathway J. Lipid Res., May 1, 1999; 40(5): 797 - 805. [Abstract] [Full Text] |
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D. L. Silver, X.-c. Jiang, and A. R. Tall Increased High Density Lipoprotein (HDL), Defective Hepatic Catabolism of ApoA-I and ApoA-II, and Decreased ApoA-I mRNA in ob/ob Mice. POSSIBLE ROLE OF LEPTIN IN STIMULATION OF HDL TURNOVER J. Biol. Chem., February 12, 1999; 274(7): 4140 - 4146. [Abstract] [Full Text] [PDF] |
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R. W. Mahley and Z.-S. Ji Remnant lipoprotein metabolism: key pathways involving cell-surface heparan sulfate proteoglycans and apolipoprotein E J. Lipid Res., January 1, 1999; 40(1): 1 - 16. [Abstract] [Full Text] |
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M. J. A. Amar, K. A. Dugi, C. C. Haudenschild, R. D. Shamburek, B. Foger, M. Chase, A. Bensadoun, R. F. Hoyt , Jr., H. B. Brewer , Jr., and S. Santamarina-Fojo Hepatic lipase facilitates the selective uptake of cholesteryl esters from remnant lipoproteins in apoE-deficient mice J. Lipid Res., December 1, 1998; 39(12): 2436 - 2442. [Abstract] [Full Text] |
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X. Gu, B. Trigatti, S. Xu, S. Acton, J. Babitt, and M. Krieger The Efficient Cellular Uptake of High Density Lipoprotein Lipids via Scavenger Receptor Class B Type I Requires Not Only Receptor-mediated Surface Binding but Also Receptor-specific Lipid Transfer Mediated by Its Extracellular Domain J. Biol. Chem., October 9, 1998; 273(41): 26338 - 26348. [Abstract] [Full Text] [PDF] |
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H. L. Dichek, W. Brecht, J. Fan, Z.-S. Ji, S. P. A. McCormick, H. Akeefe, L. Conzo, D. A. Sanan, K. H. Weisgraber, S. G. Young, et al. Overexpression of Hepatic Lipase in Transgenic Mice Decreases Apolipoprotein B-containing and High Density Lipoproteins. EVIDENCE THAT HEPATIC LIPASE ACTS AS A LIGAND FOR LIPOPROTEIN UPTAKE J. Biol. Chem., January 23, 1998; 273(4): 1896 - 1903. [Abstract] [Full Text] [PDF] |
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T. A. Ramsamy, T. A.-M. Neville, B. M. Chauhan, D. Aggarwal, and D. L. Sparks Apolipoprotein A-I Regulates Lipid Hydrolysis by Hepatic Lipase J. Biol. Chem., October 20, 2000; 275(43): 33480 - 33486. [Abstract] [Full Text] [PDF] |
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I. V. Fuki, R. V. Iozzo, and K. J. Williams Perlecan Heparan Sulfate Proteoglycan. A NOVEL RECEPTOR THAT MEDIATES A DISTINCT PATHWAY FOR LIGAND CATABOLISM J. Biol. Chem., August 11, 2000; 275(33): 25742 - 25750. [Abstract] [Full Text] [PDF] |
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T. Seo, M. Al-Haideri, E. Treskova, T. S. Worgall, Y. Kako, I. J. Goldberg, and R. J. Deckelbaum Lipoprotein Lipase-mediated Selective Uptake from Low Density Lipoprotein Requires Cell Surface Proteoglycans and Is Independent of Scavenger Receptor Class B Type 1 J. Biol. Chem., September 22, 2000; 275(39): 30355 - 30362. [Abstract] [Full Text] [PDF] |
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