|
|
|
|||||||
|
|||||||||
J. Biol. Chem., Vol. 278, Issue 28, 25448-25453, July 11, 2003
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Specific Gene Expression of ATP-binding Cassette Transporters and Nuclear Hormone Receptors in Rat Liver Parenchymal, Endothelial, and Kupffer Cells*
From the Division of Biopharmaceutics, Leiden Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, P.O. Box 9502, Leiden, Zuid-Holland 2300 RA, The Netherlands
Received for publication, February 4, 2003 , and in revised form, April 7, 2003.
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONEXPERIMENTAL PROCEDURESRESULTSDISCUSSIONREFERENCES |
|---|
Hepatic cholesterol(ester) uptake from serum coupled to intracellular processing and biliary excretion are important features in the removal of excess cholesterol from the body. ATP-binding cassette (ABC) transporters play an important role in hepatic cholesterol transport. The liver consists of different cell types, and ABC transporters may exert different physiological functions dependent on the individual cell type. Therefore, in the current study, using real time PCR we compared the mRNA expression of ABC transporters and genes involved in the regulation of cholesterol metabolism in liver parenchymal, endothelial, and Kupffer cells. It appears that liver parenchymal cells contain high expression levels compared with endothelial and Kupffer cells of scavenger receptor class BI (
3-fold), peroxisome
proliferator-activated receptor (PPAR)
and PPAR
(8–20-fold), cholesterol 7-hydroxylase A1 (>100-fold), and
ABCG5/G8 (5-fold). Liver endothelial cells show a high expression of
cholesterol 27-hydroxylase, liver X receptor (LXR)
, PPAR
, and
ABCG1, suggesting a novel specific role for these genes in endothelial cells.
In Kupffer cells, the expression level of LXR, ABCA1, and in particular
ABCG1 is high, leading to an ABCG1 mRNA expression level that is 70-fold
higher than in parenchymal cells. It can be calculated that 51% of the total
liver ABCG1 expression resides in Kupffer cells and 24% in endothelial cells,
suggesting an intrahepatic-specific role for ABCG1 in Kupffer and endothelial
cells. Because of a specific stimulation of ABCG1 in parenchymal cells by a
high cholesterol diet, the contribution of parenchymal cells to the total
liver increased from 25 to 60%. Our data indicate that for studies of the role
of ABC transporters and their regulation in liver, their cellular localization
should be taken into account, allowing proper interpretation of metabolic
changes, which are directly related to their (intra)cellular expression
level. |
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONEXPERIMENTAL PROCEDURESRESULTSDISCUSSIONREFERENCES |
|---|
Transport of cholesterol through the body is an important process in the maintenance of total body cholesterol homeostasis. One specific component is the transport of excessive cholesterol from the periphery to the liver by the high density lipoprotein (HDL).1 This process is called reverse cholesterol transport and consists of three different stages: the efflux of peripheral cellular cholesterol to HDL, the transport of cholesterol esters through the blood to the liver, and the uptake of cholesterol esters by the liver (1). Cholesterol esters are taken up into the liver through selective uptake by the HDL receptor, scavenger receptor class BI (SR-BI) (2), where they are primarily (
50%) catabolized to bile acids, through conversion by cholesterol
7-hydroxylase (CYP7A1) and sterol 27-hydroxylase (CYP27)
(3) for biliary excretion via
the bile salt export protein
(4). A second major catabolic
route (40%) is the direct efflux of cholesterol from the liver into the
bile via the ABC half-transporters ABCG5 and ABCG8, which together function as
a biliary sterol efflux regulator
(5). Additionally, cholesterol
also effluxes from the liver to produce very low density lipoproteins, which
are converted to remnants that function as precursors for low density
lipoproteins. Native HDL might also be formed by the ABC transporter A1
(ABCA1)-mediated cholesterol efflux
(6). Recently, another member
of the ABC transporter family, ABCG1, has been proposed to play a role in the
intracellular trafficking and efflux of cholesterol
(7). However, the exact role of
ABCG1 in the liver, especially in relation to ABCG5 and ABCG8, remains to be
clarified.
The identification of SR-BI and novel members of the ABC transporter family, including ABCA1, ABCG1, ABCG5, and ABCG8, has allowed the molecular characterization of the individual transporters responsible for the intracellular trafficking and excretion of cholesterol (derivatives). In the liver, it has been shown that SR-BI is responsible primarily for the selective uptake of cholesterol esters from HDL (8), whereas ABCG5/G8 and ABCG1, and ABCA1, are proposed mediators of efflux to the bile and to HDL, respectively (6, 9). However, the liver is a complex tissue and contains, in addition to the parenchymal cells, which are localized around the bile canaliculi, endothelial cells, and tissue macrophages (Kupffer cells). To assess the individual function of the ABC transporters and their regulation by nuclear hormone receptors it is therefore essential to establish their cellular localization in the liver.
Here we report that key mediators in liver cholesterol homeostasis, in
particular PPAR, PPAR, and ABCG1, are expressed differentially
in specific cell types of the rat liver. Our data stress that it is necessary
to focus on the regulation of genes involved in cholesterol homeostasis in the
different cell types of the liver to get molecular insight in their mechanism
of regulation and the consequences for liver cholesterol transport.
|
EXPERIMENTAL PROCEDURES |
|---|
|
TOPABSTRACTINTRODUCTIONEXPERIMENTAL PROCEDURESRESULTSDISCUSSIONREFERENCES |
|---|
Animals—In the study, three male Wistar WU rats (200–250 g) were fed a chow diet containing 4.3% (w/w) fat and no cholesterol, and three rats were fed a high cholesterol diet containing 2% (w/w) cholesterol, 5% olive oil (w/w), and 0.5% (w/w) cholic acid for 2 weeks. Rats were anesthetized and the vena porta was cannulated. Subsequently, the liver was perfused for 10 min with oxygenated Hanks' buffer, pH 7.4, containing HEPES (1.6 g/liter). The perfusion was continued for 10 min with Hanks'/HEPES buffer containing 0.05% (w/v) collagenase (type IV, Sigma) and 1 mM CaCl2. Parenchymal cells were isolated after mincing the liver in Hanks' buffer containing 0.3% bovine serum albumin, filtering through nylon gauze and centrifugation for three times 10 min at 50 x g. The pellets consisted of pure (>99%) parenchymal cells as judged by light microscopy. The supernatants were centrifuged for 10 min at 500 x g to harvest the non-parenchymal cells. By means of centrifugal elutriation the endothelial cells and Kupffer cells were separated (10). The purity of each cell fraction (>95% for both) was checked by light microscopy, after staining for peroxidase activity with 3,3-diaminobenzidine (Sigma).
Analysis of Gene Expression by Real Time Quantitative PCR—Total RNA was isolated from rat liver parenchymal, endothelial, and Kupffer cells using TriZol reagent (Invitrogen) according to the manufacturer's instructions. Purified RNA was DNase treated (DNase I, 10 units/µg of total RNA) and reverse transcribed (RevertAid M-MuLV reverse transcriptase) according to the protocols supplied by the manufacturer.
Quantitative gene expression analysis was performed on an ABI PRISM 7700 machine (Applied Biosystems, Foster City, CA) using SYBR Green technology. PCR primers (Table I) were designed using Primer Express 1.7 software with the manufacturer's default settings (Applied Biosystems) and validated for identical efficiencies (slope = –3.3 for a plot of the threshold cycle number (Ct) versus log ng cDNA). In 96-wells optical plates, 12.5 µl of SYBR Green master mix was added to 12.5 µl of cDNA (corresponding to 50 ng of total RNA input) and 300 nM forward and reverse primers in water. Plates were heated for 2 min at 50 °C and 10 min at 95 °C. Subsequently 40 PCR cycles consisting of 15 s at 95 °C and 60 s at 60 °C were applied. At the end of the run, samples were heated to 95 °C with a ramp time of 20 min to construct dissociation curves to check that single PCR products were obtained. The absence of genomic DNA contamination in the RNA preparations was confirmed by using total RNA samples that had not been subjected to reverse transcription. Hypoxanthine-guanine phosphoribosyltransferase (HPRT) was used as the standard housekeeping gene. Ratios of target gene and HPRT expression levels (relative gene expression numbers) were calculated by subtracting the Ct of the target gene from the Ct of HPRT and raising 2 to the power of this difference. Ct values are defined as the number of PCR cycles at which the fluorescent signal during the PCR reaches a fixed threshold. Target gene mRNA expressions are thus expressed relative to HPRT expression.
|
Data Analysis—The significance of differences in relative gene expression numbers among the different liver cell types, from three different cell isolations, measured by real time quantitative PCR was calculated using a two-tailed Student's t test on the differences in Ct (Ct(HPRT)–Ct(target gene)). Probability values less than 0.05 were considered significant.
|
RESULTS |
|---|
|
TOPABSTRACTINTRODUCTIONEXPERIMENTAL PROCEDURESRESULTSDISCUSSIONREFERENCES |
|---|
The last step in reverse cholesterol transport is the hepatic uptake and cellular processing of cholesterol esters from HDL by SR-BI (1). The mRNA expression of SR-BI in the different cell types of the liver was investigated with quantitative real time PCR to determine which cell type is mainly expressing SR-BI. A significantly higher SR-BI expression was observed in parenchymal cells compared with endothelial (p < 0.05) and Kupffer cells (p < 0.01) (Fig. 1).
|
In the liver, cholesterol is used for bile acid synthesis. Therefore, the mRNA expression patterns of two key enzymes in bile acid synthesis, CYP7A1 and CYP27, in the different hepatic cell types were examined. A relatively high level of CYP7A1 expression was observed in parenchymal cells, which was more than 200-fold (p < 0.001) higher than the expression levels found in endothelial and Kupffer cells (Fig. 2a). Accordingly, CYP27 expression (Fig. 2b) was observed in parenchymal cells and also in endothelial cells.
|
Because a second route of cholesterol disposal from the liver is through direct excretion of cholesterol into the bile via the half-transporters ABCG5 and ABCG8, we investigated whether the expression of ABCG5/8 is also higher in parenchymal cells than in non-parenchymal cells. Fig. 3 clearly indicates that ABCG5 (a) and ABCG8 (b) expression was indeed 5–10-fold higher in parenchymal cells compared with endothelial and Kupffer cells.
|
In the liver, ABCA1 was recently suggested to be involved in the efflux of
cholesterol for production of HDL
(6). Although no conclusive
evidence has been shown, in the liver ABCG1, like ABCG5/G8, is proposed to
play a role in biliary efflux
(11). In macrophages, ABCA1
and ABCG1 expression is induced in response to cholesterol loading, and both
proteins are potentially involved in cholesterol efflux to apoA-I
(12). Because both ABCA1 and
ABCG1 are implicated in the same physiological functions, we determined
whether both genes also have a comparable expression distribution profile over
the different cell types of the liver. Contrary to the assumption, ABCA1 was
expressed mainly in parenchymal and Kupffer cells
(Fig. 4a), whereas
ABCG1 was expressed 76-fold (p < 0.001) and 27-fold (p
< 0.01) higher in Kupffer and endothelial cells than in parenchymal cells,
respectively (Fig.
4b). In contrast to ABCA1, ABCG1 is thus mainly expressed
in non-parenchymal cells, which suggests a limited role of ABCG1 in the
excretion of cholesterol directly into the bile under the standard feeding
conditions. In addition, ABCG1 expression was analyzed in the different
hepatic cells isolated from rats on a high cholesterol diet. Interestingly,
hepatic parenchymal cell ABCG1 expression increased 4-fold (p
< 0.05) in response to a high cholesterol diet, whereas no significant
effect on endothelial and Kupffer cell ABCG1 expression was observed
(Fig. 5). Although ABCG1 levels
were significantly increased in parenchymal cells in response to a high
cholesterol diet, ABCG1 expression levels were still, respectively, 10- and
12-fold higher in endothelial and Kupffer cells compared with parenchymal
cells.
|
|
Analysis of LXR expression in the different cell types was performed to
investigate a potential relation with expression patterns of the ABC
transporters. LXR had a distribution pattern comparable to that found
for ABCA1, with a relatively high expression in parenchymal (p <
0.01) and Kupffer cells compared with endothelial cells
(Fig. 6a). A
significantly higher expression of LXR was found in endothelial liver
cells compared with parenchymal (p < 0.05) and Kupffer cells
(p < 0.05), respectively (Fig.
6b), which suggests that LXR may be a more
important mediator in endothelial cells.
|
It has been shown that PPAR activators are able to regulate LXR
expression, and thereby indirectly influence ABCA1 mRNA levels
(13), and that ligands for
PPAR directly regulate the expression of ABCA1 via an unknown mechanism
(14). Therefore, we also
investigated the PPAR gene expression in the different cell types.
Fig. 7a clearly indicates that
PPAR expression is found mostly in parenchymal cells, with an 82- and
23-fold higher expression (p < 0.001 in both cases) in these cells
than in endothelial cells and Kupffer cells, respectively. The PPAR
distribution pattern is comparable with that found for PPAR
(Fig. 7b), suggesting
a major function of these genes in parenchymal cells. PPAR mRNA levels
were almost equal in the different cells, although endothelial cell
PPAR expression was somewhat higher as compared with parenchymal and
Kupffer cells (Fig.
7c). These data indicate that within the various liver
cell types PPAR will have a more general function.
|
|
DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONEXPERIMENTAL PROCEDURESRESULTSDISCUSSIONREFERENCES |
|---|
Hepatic cholesterol uptake from serum coupled with intracellular processing and bile excretion are important features in the last step of reverse cholesterol transport. It has been shown that disruption of cholesterol homeostasis plays an essential role in the pathology of many diseases such as cholestasis (15) and atherosclerosis (16).
In the liver, SR-BI plays a crucial role in the selective uptake of cholesterol esters from HDL (2). Additionally, studies on ABC transporters suggested that hepatic ABCA1 is involved in HDL production (6), whereas ABCG5/G8 and ABCG1 were indicated to mediate biliary efflux of cholesterol from the liver (7, 9). Repa et al. (17) showed that treatment of mice with synthetic ligands of LXR markedly increased liver ABCG5/G8 expression. In vitro observations by Malerod et al. (18) also indicate that LXR is able to regulate hepatic SR-BI expression through a direct interaction with a newly discovered LXR/retinoid X receptor response element in the SR-BI promoter. It is however still unclear how hepatic ABCA1 and ABCG1 expression is regulated and what the precise consequence of their regulation is on hepatic cholesterol levels and transport.
The liver consists of several different cell types, including parenchymal, endothelial, and Kupffer cells. It is therefore important to study the expression levels of SR-BI and the ABC transporters in the individual hepatic cell types to get a more detailed view of their specific functions and regulatory mechanisms in the liver.
Earlier studies performed by Pieters et al. (19) showed that uptake of HDL cholesterol esters into liver parenchymal cells is efficiently coupled to a rapid synthesis of bile acids. Accordingly, Fluiter et al. (20) observed that the receptor responsible for the selective uptake of cholesterol esters into the liver, SR-BI, has a relatively high expression in parenchymal cells compared with endothelial and Kupffer cells. These combined observations stressed an important role for parenchymal cells in the last step of the reverse cholesterol transport process.
In the current study, using real time quantitative PCR, we investigated the mRNA expression of genes involved in hepatic cholesterol transport and metabolism in liver parenchymal, endothelial, and Kupffer cells. Real time PCR is a highly sensitive method to quantify mRNA expression levels in vitro and in vivo. mRNA levels have been shown to correlate strongly with protein expression levels, indicating that a substantial portion of changes in protein levels is a consequence of altered mRNA levels rather than post-transcriptional modifications (21).
Importantly, Wellington et al.
(22) showed a high concordance
of ABCA1 mRNA and protein levels in the liver. Additionally, we observed in
the present study the highest SR-BI mRNA expression in the parenchymal cells
compared with endothelial and Kupffer cells, which is in accordance with the
high Western blot protein expression data for SR-BI as reported by Fluiter
et al. (20). We thus
suggest that our quantitative mRNA data for the various cell types are
indicative for the activity of the particular genes of interest and their
metabolic function. For SR-BI, the mRNA and protein expression data in
parenchymal cells are consistent with our data that the parenchymal
cholesterol ester uptake is reduced dramatically in SR-BI deficient mice as
compared with non-transgenic
littermates.2 CYP7A1
and CYP27 are the key enzymes in classical and alternative bile acid synthesis
pathways (23). The relatively
high expression of these two bile acid synthesis enzymes observed in
parenchymal cells is in agreement with the data provided by Pieters et
al. (19), as it was shown
that uptake of HDL cholesterol esters by the parenchymal cells is coupled
efficiently to bile acid synthesis. Interestingly, an equally high expression
of CYP27 compared with parenchymal cells was observed in liver endothelial
cells. In agreement, Reiss et al.
(24) have detected the same
high levels of CYP27 activity in cultured vascular endothelial cells. The
observed difference between the CYP7A1 and CYP27 expression patterns suggests
differential functions for these bile acid synthesizing enzymes.
Interestingly, Babiker et al.
(25) suggested that
CYP27-mediated elimination of cholesterol from macrophages and endothelial
cells may be an alternative or complement to HDL-mediated reverse cholesterol
transport under low HDL conditions. They observed a high secretion of
3-hydroxycholestenoic acid, an intermediate of the CYP27-mediated
alternative bile acid formation pathway, from endothelial cells and
macrophages to albumin containing medium.
Efflux of hepatic cholesterol to the serum compartment by ABCA1 for the
production of native HDL is a second important route in maintaining
cholesterol homeostasis (6). An
equally high relative expression of ABCA1 was observed in parenchymal and
Kupffer cells, whereas a 4-fold lower expression of ABCA1 was seen in
liver endothelial cells. In macrophages, ABCA1 is a critical regulator of the
specific ATP-dependent cholesterol efflux to apoA-I, leading to an inhibition
of foam cell formation (26).
Kupffer cells are liver macrophages, which play an important role in the
uptake of (modified) lipoproteins
(19,
27). The high uptake and an
accordingly high efflux of cholesterol from Kupffer cells might be the
metabolic mechanism for the relatively high ABCA1 expression level observed in
these cells. Haghpassand et al.
(28) and Van Eck et
al. (29) have shown that
monocyte/macrophage ABCA1 only minimally contributes to the overall plasma HDL
levels. The observed high expression levels of ABCA1 in parenchymal cells,
combined with the observation that ABCA1 functions on the basolateral surface
of hepatocytes (30), suggest
that the liver does contribute to HDL production by the efflux of
cholesterol from parenchymal cells via ABCA1.
A third catabolic route for hepatic cholesterol is the direct excretion
into the bile, which accounts for 40% of the total liver catabolism.
Recently, two members of the ABC transporters, ABCG5 and ABCG8, have been
shown to participate coordinately in the hepatic sterol secretion into bile
(31). Mutations in either
ABCG5 or ABCG8 are sufficient to cause sitosterolemia, a disorder that is
characterized by elevated plasma levels of sterols
(32). Because parenchymal
cells are responsible for bile acid formation, a relatively high expression of
the biliary transporters such as ABCG5/G8 in these cells compared with
endothelial and Kupffer cells is consistent with their suggested function. The
expression pattern of ABCG5 resembled ABCG8, which is in agreement with the
statements that these transporters operate as heterodimers to regulate biliary
cholesterol efflux (9,
33).
Interestingly, a novel member of the ABC transporter family, ABCG1, has
also been proposed to have a function in the intracellular trafficking and
biliary efflux of cholesterol in the liver
(11). Contrary to the
expectations, ABCG1 expression was observed mainly in non-parenchymal cells of
the rat liver. A 76-fold and 27-fold higher ABCG1 expression was observed in
Kupffer and endothelial cells than in parenchymal cell under standard feeding
conditions. Although Kupffer and endothelial cells only contribute 2.5 and
3.3% to the total liver protein, they do contain 51 and 24% of total liver
ABCG1 expression, respectively. Such a high specific ABCG1 expression in
Kupffer cells was not expected, although ABCG1 has also been proposed to play
a role in the cholesterol efflux from peripheral macrophages
(7). Importantly, after putting
rats on a high cholesterol diet for 2 weeks, ABCG1 expression increased 4-fold
in parenchymal cells, whereas no significant change in ABCG1 expression in
endothelial and Kupffer cells was observed. The absence of a similar induction
of ABCG1 in endothelial and Kupffer cells in response to diet feeding may well
be caused by an already maximal activity of ABCG1 in these cells even on a
chow diet. Also, the differences in expression and intracellular localization
of direct activators (e.g. LXR) and repressors (e.g.
ZNF202) of ABCG1 might contribute to the difference in its transcriptional
regulation between different cell types as earlier mentioned by Schmitz and
Langmann (11). Although
endothelial and Kupffer cell ABCG1 expressions were still 10- and 12-fold
higher than that in parenchymal cells, the relative contribution of ABCG1 in
the parenchymal cells to total liver increased from 25 to 60%. This suggests
that under high cholesterol conditions ABCG1 might indeed contribute to the
transport of cholesterol in the parenchymal cells.
Recent pharmacological interest is focused upon the regulation of SR-BI and the ABC transporters by newly discovered nuclear hormone receptors, the LXRs and PPARs, respectively (34, 35). Therefore, we also studied their cellular localization in the different cell types of the liver.
Two different types of the LXR have been discovered so far, LXR and
LXR. A relatively high expression of LXR was observed in
parenchymal cells. In the liver, LXR plays an essential role in the
regulation of CYP7A1 and thus the formation of bile acids
(36). CYP7A1 was found almost
exclusively in the parenchymal cells, which coincides with the high expression
of LXR in these cells. Contrarily, equally high LXR expression
levels were observed in Kupffer cells, where CYP7A1 expression was almost
absent. In macrophages, however, LXR plays a crucial role in the
regulation of lipid efflux via ABCA1
(37). Kupffer cells also
contain high expression levels of ABCA1, which is consistent with a role for
LXR in the regulation of ABCA1 in these cells. Among the different cell
types of the liver, LXR was ubiquitously expressed, with a somewhat
higher expression in endothelial cells versus parenchymal and Kupffer
cells. The expression distribution of LXR thus does not resemble that
found for LXR, which suggests that in the liver, LXR may have a
function different from that of LXR.
In the liver, PPAR is suggested to play a role in the formation of
bile acids because it is able to bind a PPAR response element in the sterol
12-hydroxylase promoter, leading to increased levels of cholic acid
(38). This might explain the
extremely high expression of PPAR found in parenchymal cells compared
with endothelial and Kupffer cells. The high expression of PPAR
observed in parenchymal cells suggests that PPAR, like PPAR,
also has a major function in these cells. Contrarily, PPAR is expressed
ubiquitously among the different cell types of the liver, suggesting a more
general function for PPAR in all cell types of the liver.
In conclusion, we have provided data that several ABC transporters and nuclear hormone receptors involved in liver cholesterol homeostasis are expressed differentially in the specific cell types of the liver. To study their intracellular transport function inside the liver it appears to be essential to take into account their cellular localization, as especially evident for ABCG1. This appears specifically true for studies on the regulation of the transporters by nuclear receptors because metabolic changes are coupled directly to the specific (intra)cellular expression level of the cholesterol transporters.
|
FOOTNOTES |
|---|
* This work was supported by The Netherlands Organization for Scientific Research Grant 902-23-194. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Supported by Grant 2001 D041 from the Netherlands Heart Foundation.
To whom correspondence should be addressed. Tel.: 31-71-527-6238; Fax:
31-71-527-6032; E-mail:
Hoekstra{at}LACDR.Leidenuniv.nl.
1 The abbreviations used are: HDL, high density lipoprotein; ABC, ATP-binding
cassette; Ct, threshold cycle number; CYP7A1, cholesterol
7-hydroxylase; CYP27, cholesterol 27-hydroxylase; HPRT,
hypoxanthine-guanine phosphoribosyltransferase; LXR, liver X receptor; PPAR,
peroxisome proliferator-activated receptor; SR-BI, scavenger receptor class
BI.
2 J. K. Kruijt and Th. J. C. van Berkel, unpublished data.
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONEXPERIMENTAL PROCEDURESRESULTSDISCUSSIONREFERENCES |
|---|
- Glomset, J. A. (1980) Adv. Intern. Med. 25, 91–116[Medline] [Order article via Infotrieve]
- Acton, S., Rigotti, A., Landschulz, K. T., Xu, S., Hobbs, H. H., and Krieger, M. (1996) Science 271, 518–520[Abstract]
- Chiang, J. Y. L. (1998) Front. Biosci. 3, D176–D193[Medline] [Order article via Infotrieve]
- Akita, H., Suzuki, H., Ito, K., Kinoshita, S., Sato, N., Takikawa, H., and Sugiyama, Y. (2001) Biochim. Biophys. Acta 1511, 7–16[Medline] [Order article via Infotrieve]
- Lu, K., Lee, M. H., Hazard, S., Brooks-Wilson, A., Hidaka, H., Kojima, H., Ose, L., Stalenhoef, A. F., Mietinnen, T., Bjorkhem, I., Bruckert, E., Pandya, A., Brewer, H. B., Jr., Salen, G., Dean, M., Srivastava, A., and Patel, S. B. (2001) Am. J. Hum. Genet. 69, 278–290[CrossRef][Medline] [Order article via Infotrieve]
- Tall, A. R., Wang, N., and Mucksavage, P. (2001) J. Clin. Invest. 108, 1273–1275[CrossRef][Medline] [Order article via Infotrieve]
- Klucken, J., Buchler, C., Orso, E., Kaminski, W. E.,
Porsch-Ozcurumez, M., Liebisch, G., Kapinsky, M., Diederich, W., Drobnik, W.,
Dean, M., Allikmets, R., and Schmitz, G. (2000) Proc.
Natl. Acad. Sci. U. S. A. 97,
817–822
[Abstract/Free Full Text] - Landschulz, K. T., Pathak, R. K., Rigotti, A., Krieger, M., and Hobbs, H. H. (1996) J. Clin. Invest. 98, 984–995[Medline] [Order article via Infotrieve]
- Berge, K. E., Tian, H., Graf, G. A., Yu, L., Grishin, N. V.,
Schultz, J., Kwiterovich, P., Shan, B., Barnes, R., and Hobbs, H. H.
(2000) Science
290,
1771–1775
[Abstract/Free Full Text] - Nagelkerke, J. F., Barto, K. P., and van Berkel, T. J.
(1983) J. Biol. Chem.
258,
12221–12227
[Abstract/Free Full Text] - Schmitz, G., and Langmann, T. (2001) Curr. Opin. Lipidol. 12, 129–140[CrossRef][Medline] [Order article via Infotrieve]
- Fu, X., Menke, J. G., Chen, Y., Zhou, G., MacNaul, K. L., Wright,
S. D., Sparrow, C. P., and Lund, E. G. (2001) J. Biol.
Chem. 276,
38378–38387
[Abstract/Free Full Text] - Chawla, A., Boisvert, W. A., Lee, C. H., Laffitte, B. A., Barak, Y., Joseph, S. B., Liao, D., Nagy, L., Edwards, P. A., Curtiss, L. K., Evans, R. M., and Tontonoz, P. (2001) Mol. Cell 7, 161–171[CrossRef][Medline] [Order article via Infotrieve]
- Oliver, W. R., Jr., Shenk, J. L., Snaith, M. R., Russell, C. S.,
Plunket, K. D., Bodkin, N. L., Lewis, M. C., Winegar, D. A., Sznaidman, M. L.,
Lambert, M. H., Xu, H. E., Sternbach, D. D., Kliewer, S. A., Hansen, B. C.,
and Willson, T. M. (2001) Proc. Natl. Acad. Sci. U. S.
A. 98,
5306–5311
[Abstract/Free Full Text] - Jansen, P. L., Strautnieks, S. S., Jacquemin, E., Hadchouel, M., Sokal, E. M., Hooiveld, G. J., Koning, J. H., Jager-Krikken, A., Kuipers, F., Stellaard, F., Bijleveld, C. M., Gouw, A., Van Goor, H., Thompson, R. J., and Muller, M. (1999) Gastroenterology 117, 1370–1379[CrossRef][Medline] [Order article via Infotrieve]
- Rigotti, A., Trigatti, B. L., Penman, M., Rayburn, H., Herz, J.,
and Krieger, M. (1997) Proc. Natl. Acad. Sci. U. S.
A. 94,
12610–12615
[Abstract/Free Full Text] - Repa, J. J., Berge, K. E., Pomajzl, C., Richardson, J. A., Hobbs,
H., and Mangelsdorf, D. J. (2002) J. Biol.
Chem. 277,
18793–18800
[Abstract/Free Full Text] - Malerod, L., Juvet, L. K., Hanssen-Bauer, A., Eskild, W., and Berg, T. (2002) Biochem. Biophys. Res. Commun. 299, 916–923[CrossRef][Medline] [Order article via Infotrieve]
- Pieters, M. N., Esbach, S., Schouten, D., Brouwer, A., Knook, D. L., and van Berkel, T. J. (1994) Hepatology 19, 1459–1467[CrossRef][Medline] [Order article via Infotrieve]
- Fluiter, K., van der Westhuijzen, D. R., and van Berkel, T. J.
(1998) J. Biol. Chem.
273,
8434–8438
[Abstract/Free Full Text] - Lian, Z., Kluger, Y., Greenbaum, D. S., Tuck, D., Gerstein, M.,
Berliner, N., Weissman, S. M., and Newburger, P. E. (2002)
Blood 100,
3209–3220
[Abstract/Free Full Text] - Wellington, C. L., Walker, E. K., Suarez, A., Kwok, A., Bissada, N., Singaraja, R., Yang, Y. Z., Zhang, L. H., James, E., Wilson, J. E., Francone, O., McManus, B. M., and Hayden, M. R. (2002) Lab. Invest. 82, 273–283[Medline] [Order article via Infotrieve]
- Chiang, J. Y. (2002) Endocr.
Rev. 23,
443–463
[Abstract/Free Full Text] - Reiss, A. B., Martin, K. O., Javitt, N. B., Martin, D. W., Grossi, E. A., and Galloway, A. C. (1994) J. Lipid Res. 35, 1026–1030[Abstract]
- Babiker, A., Andersson, O., Lund, E., Xiu, R. J., Deeb, S., Reshef,
A., Leitersdorf, E., Diczfalusy, U., and Bjorkheim, I. (1997)
J. Biol. Chem. 272,
26253–26261
[Abstract/Free Full Text] - Argmann, C. A., Van Den Diepstraten, C. H., Sawyez, C. G., Edwards,
J. Y., Hegele, R. A., Wolfe, B. M., and Huff, M. W. (2001)
Arterioscler. Thromb. Vasc. Biol.
21,
2011–2018
[Abstract/Free Full Text] - de Rijke, Y. B., Hessels, E. M., and van Berkel, T. J.
(1992) Arterioscler. Thromb.
12,
41–49
[Abstract/Free Full Text] - Haghpassand, M., Bourassa, P. A., Francone, O. L., and Aiello, R. J. (2001) J. Clin. Invest. 108, 1315–1320[CrossRef][Medline] [Order article via Infotrieve]
- Van Eck, M., Bos, I. S. T., Kaminski, W. E., Orsó, E.,
Rothe, G., Twisk, J., Böttcher, A., Van Amersfoort, E. S.,
Christiansen-Weber, T. A., Fung-Leung, W.-P., van Berkel, T. J. C., and
Schmitz, G. (2002) Proc. Natl. Acad. Sci. U. S.
A. 99,
6298–6303
[Abstract/Free Full Text] - Neufeld, E. B., Demosky, S. J., Jr., Stonik, J. A., Combs, C., Remaley, A. T., Duverger, N., Santamarina-Fojo, S., and Brewer, H. B., Jr. (2002) Biochem. Biophys. Res. Commun. 297, 974–979[CrossRef][Medline] [Order article via Infotrieve]
- Yu, L., Li-Hawkins, J., Hammer, R. E., Berge, K. E., Horton, J. D., Cohen, J. C., and Hobbs, H. H. (2002) J. Clin. Invest. 110, 671–680[CrossRef][Medline] [Order article via Infotrieve]
- Heimer, S., Langmann, T., Moehle, C., Mauerer, R., Dean, M., Beil, F. U., von Bergmann, K., and Schmitz, G. (2002) Hum. Mutat. 20, 151[Medline] [Order article via Infotrieve]
- Graf, G. A., Li, W. P., Gerard, R. D., Gelissen, I., White, A., Cohen, J. C., and Hobbs, H. H. (2002) J. Clin. Invest. 110, 659–669[CrossRef][Medline] [Order article via Infotrieve]
- Fitzgerald, M. L., Moore, K. J., and Freeman, M. W. (2002) J. Mol. Med. 80, 271–281[CrossRef][Medline] [Order article via Infotrieve]
- Laffitte, B. A., and Tontonoz, P. (2002) Curr. Atheroscler. Rep. 4, 213–221[Medline] [Order article via Infotrieve]
- Chiang, J. Y., Kimmel, R., and Stroup, D. (2001) Gene (Amst.) 262, 257–265[CrossRef][Medline] [Order article via Infotrieve]
- Venkateswaran, A., Laffitte, B. A., Joseph, S. B., Mak, P. A.,
Wilpitz, D. C., Edwards, P. A., and Tontonoz, P. (2000)
Proc. Natl. Acad. Sci. U. S. A.
97,
12097–12102
[Abstract/Free Full Text] - Hunt, M. C., Yang, Y. Z., Eggertsen, G., Carneheim, C. M., Gafvels,
M., Einarsson, C., and Alexson, S. E. (2000) J. Biol.
Chem. 275,
28947–28953
[Abstract/Free Full Text]
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  M. Hoekstra, D. Ye, R. B. Hildebrand, Y. Zhao, B. Lammers, M. Stitzinger, J. Kuiper, T. J. C. Van Berkel, and M. Van Eck Scavenger receptor class B type I-mediated uptake of serum cholesterol is essential for optimal adrenal glucocorticoid production J. Lipid Res., June 1, 2009; 50(6): 1039 - 1046. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Rohrer, P. M. Ohnsorg, M. Lehner, F. Landolt, F. Rinninger, and A. von Eckardstein High-Density Lipoprotein Transport Through Aortic Endothelial Cells Involves Scavenger Receptor BI and ATP-Binding Cassette Transporter G1 Circ. Res., May 22, 2009; 104(10): 1142 - 1150. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. C. Robichaud, G. A. Francis, and D. E. Vance A Role for Hepatic Scavenger Receptor Class B, Type I in Decreasing High Density Lipoprotein Levels in Mice That Lack Phosphatidylethanolamine N-Methyltransferase J. Biol. Chem., December 19, 2008; 283(51): 35496 - 35506. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Burgess, K. Naus, J. Chan, V. Hirsch-Reinshagen, G. Tansley, L. Matzke, B. Chan, A. Wilkinson, J. Fan, J. Donkin, et al. Overexpression of Human ABCG1 Does Not Affect Atherosclerosis in Fat-Fed ApoE-Deficient Mice Arterioscler. Thromb. Vasc. Biol., October 1, 2008; 28(10): 1731 - 1737. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Hoekstra, I. Meurs, M. Koenders, R. Out, R. B. Hildebrand, J. K. Kruijt, M. Van Eck, and T. J. C. Van Berkel Absence of HDL cholesteryl ester uptake in mice via SR-BI impairs an adequate adrenal glucocorticoid-mediated stress response to fasting J. Lipid Res., April 1, 2008; 49(4): 738 - 745. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. K. Kruit, A. L. Drayer, V. W. Bloks, N. Blom, S. G. Olthof, P. J. J. Sauer, G. de Haan, I. P. Kema, E. Vellenga, and F. Kuipers Plant Sterols Cause Macrothrombocytopenia in a Mouse Model of Sitosterolemia J. Biol. Chem., March 7, 2008; 283(10): 6281 - 6287. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. L. Jacobs, S. Lingrell, Y. Zhao, G. A. Francis, and D. E. Vance Hepatic CTP:Phosphocholine Cytidylyltransferase-{alpha} Is a Critical Predictor of Plasma High Density Lipoprotein and Very Low Density Lipoprotein J. Biol. Chem., January 25, 2008; 283(4): 2147 - 2155. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Cardinal, M.-A. Raymond, M.-J. Hebert, and F. Madore Uraemic plasma decreases the expression of ABCA1, ABCG1 and cell-cycle genes in human coronary arterial endothelial cells Nephrol. Dial. Transplant., February 1, 2007; 22(2): 409 - 416. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Li, W. Chen, and J. Y. L. Chiang PXR induces CYP27A1 and regulates cholesterol metabolism in the intestine J. Lipid Res., February 1, 2007; 48(2): 373 - 384. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Hoekstra, M. Stitzinger, E. J. A. van Wanrooij, I. N. Michon, J. K. Kruijt, J. Kamphorst, M. Van Eck, E. Vreugdenhil, T. J. C. Van Berkel, and J. Kuiper Microarray analysis indicates an important role for FABP5 and putative novel FABPs on a Western-type diet J. Lipid Res., October 1, 2006; 47(10): 2198 - 2207. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Out, M. Hoekstra, R. B. Hildebrand, J. K. Kruit, I. Meurs, Z. Li, F. Kuipers, T. J.C. Van Berkel, and M. Van Eck Macrophage ABCG1 Deletion Disrupts Lipid Homeostasis in Alveolar Macrophages and Moderately Influences Atherosclerotic Lesion Development in LDL Receptor-Deficient Mice Arterioscler. Thromb. Vasc. Biol., October 1, 2006; 26(10): 2295 - 2300. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Zhang, W. Yin, D. Liao, L. Huang, C. Tang, K. Tsutsumi, Z. Wang, Y. Liu, Q. Li, H. Hou, et al. NO-1886 upregulates ATP binding cassette transporter A1 and inhibits diet-induced atherosclerosis in Chinese Bama minipigs J. Lipid Res., September 1, 2006; 47(9): 2055 - 2063. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Kobayashi, Y. Takanezawa, T. Hirata, Y. Shimizu, K. Misasa, N. Kioka, H. Arai, K. Ueda, and M. Matsuo Efflux of sphingomyelin, cholesterol, and phosphatidylcholine by ABCG1 J. Lipid Res., August 1, 2006; 47(8): 1791 - 1802. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Westerterp, W. de Haan, J. F. P. Berbee, L. M. Havekes, and P. C. N. Rensen Endogenous apoC-I increases hyperlipidemia in apoE-knockout mice by stimulating VLDL production and inhibiting LPL J. Lipid Res., June 1, 2006; 47(6): 1203 - 1211. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. P. Hewitt, P. J. Mark, and B. J. Waddell Placental Expression of Peroxisome Proliferator-Activated Receptors in Rat Pregnancy and the Effect of Increased Glucocorticoid Exposure Biol Reprod, January 1, 2006; 74(1): 23 - 28. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A.D. Hauer, P. de Vos, N. Peterse, H. ten Cate, Th.J.C. van Berkel, F.R.M. Stassen, and J. Kuiper Delivery of Chlamydia pneumoniae to the vessel wall aggravates atherosclerosis in LDLr-/- mice Cardiovasc Res, January 1, 2006; 69(1): 280 - 288. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Zhu, H. Liao, X. Xie, Y. Yuan, T.-S. Lee, N. Wang, X. Wang, J. Y.-J. Shyy, and M. B. Stemerman Oxidized LDL downregulates ATP-binding cassette transporter-1 in human vascular endothelial cells via inhibiting liver X receptor (LXR) Cardiovasc Res, December 1, 2005; 68(3): 425 - 432. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. L. Sabol, H. B. Brewer Jr., and S. Santamarina-Fojo The human ABCG1 gene: identification of LXR response elements that modulate expression in macrophages and liver J. Lipid Res., October 1, 2005; 46(10): 2151 - 2167. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 K. Nakajou, S. Horiuchi, M. Sakai, K. Hirata, M. Tanaka, M. Takeya, T. Kai, and M. Otagiri CD36 Is Not Involved in Scavenger Receptor-Mediated Endocytic Uptake of Glycolaldehyde- and Methylglyoxal-Modified Proteins by Liver Endothelial Cells J. Biochem., May 1, 2005; 137(5): 607 - 616. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Zeng, H. Liao, Y. Liu, T.-S. Lee, M. Zhu, X. Wang, M. B. Stemerman, Y. Zhu, and J. Y.-J. Shyy Sterol-responsive Element-binding Protein (SREBP) 2 Down-regulates ATP-binding Cassette Transporter A1 in Vascular Endothelial Cells: A NOVEL ROLE OF SREBP IN REGULATING CHOLESTEROL METABOLISM J. Biol. Chem., November 19, 2004; 279(47): 48801 - 48807. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. J. O'Connell, M. Denis, and J. Genest Cellular Physiology of Cholesterol Efflux in Vascular Endothelial Cells Circulation, November 2, 2004; 110(18): 2881 - 2888. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Nakamura, M. A. Kennedy, A. Baldan, D. D. Bojanic, K. Lyons, and P. A. Edwards Expression and Regulation of Multiple Murine ATP-binding Cassette Transporter G1 mRNAs/Isoforms That Stimulate Cellular Cholesterol Efflux to High Density Lipoprotein J. Biol. Chem., October 29, 2004; 279(44): 45980 - 45989. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. Nicol, M. Yoon, J. M. Ward, M. Yamashita, K. Fukamachi, J. M. Peters, and F. J. Gonzalez PPAR{gamma} influences susceptibility to DMBA-induced mammary, ovarian and skin carcinogenesis Carcinogenesis, September 1, 2004; 25(9): 1747 - 1755. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Wang, D. Lan, W. Chen, F. Matsuura, and A. R. Tall ATP-binding cassette transporters G1 and G4 mediate cellular cholesterol efflux to high-density lipoproteins PNAS, June 29, 2004; 101(26): 9774 - 9779. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
G. A. Graf, L. Yu, W.-P. Li, R. Gerard, P. L. Tuma, J. C. Cohen, and H. H. Hobbs ABCG5 and ABCG8 Are Obligate Heterodimers for Protein Trafficking and Biliary Cholesterol Excretion J. Biol. Chem., November 28, 2003; 278(48): 48275 - 48282. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |