HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) All Versions of this Article: M300100-JLR200v1 44/9/1728    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Khovidhunkit, W. Articles by Feingold, K. R. Search for Related Content PubMed PubMed Citation Articles by Khovidhunkit, W. Articles by Feingold, K. R. Social Bookmarking                      What's this?

Journal of Lipid Research, Vol. 44, 1728-1736, September 2003
Copyright © 2003 by American Society for Biochemistry and Molecular Biology

Endotoxin down-regulates ABCG5 and ABCG8 in mouse liver and ABCA1 and ABCG1 in J774 murine macrophages

Weerapan Khovidhunkit^1,*,, Arthur H. Moser^*, Judy K. Shigenaga^*,, Carl Grunfeld^*, and Kenneth R. Feingold^2,*,

^* Metabolism Section, Department of Veterans Affairs Medical Center, San Francisco, CA 94121
Department of Medicine, University of California, San Francisco, CA 94143

Published, JLR Papers in Press, June 1, 2003. DOI 10.1194/jlr.M300100-JLR200

¹ Present address for W. Khovidhunkit: Endocrinology and Metabolism Unit, Department of Medicine, King Chulalongkorn Memorial Hospital, Chulalongkorn University, Bangkok, Thailand.

² To whom correspondence should be addressed. e-mail: kfngld{at}itsa.ucsf.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Several of the ATP binding cassette (ABC) transporters have recently been shown to play important roles in reverse cholesterol transport (RCT) and prevention of atherosclerosis. In the liver, ABCG5 and ABCG8 have been proposed to efflux sterols into the bile for excretion. ABCG5 and ABCG8 also limit absorption of dietary cholesterol and plant sterols in the intestine. In macrophages, ABCA1 and ABCG1 mediate cholesterol removal from these cells to HDL. Many of these ABC transporters are regulated by the liver X receptor (LXR). We have previously shown that endotoxin (lipopolysaccharide) down-regulates LXR in rodent liver. In the present study, we examined the in vivo and in vitro regulation of these ABC transporters by endotoxin. We found that endotoxin significantly decreased mRNA levels of ABCG5 and ABCG8 in the liver, but not in the small intestine. When endotoxin or cytokines (tumor necrosis factor and interleukin-1) were incubated with J774 murine macrophages, the mRNA levels of ABCA1 were decreased. This effect was rapid and sustained, and was associated with a reduction in ABCA1 protein levels. Endotoxin and cytokines also decreased ABCG1 mRNA levels in J774 cells. Although LXR is a positive regulator of ABCA1 and ABCG1, we did not observe a reduction in protein levels of LXR or in binding of nuclear proteins to an LXR response element in J774 cells.

The decrease in ABCG5 and ABCG8 levels in the liver as well as a reduction in ABCA1 and ABCG1 in macrophages during the host response to infection and inflammation coupled with other previously described changes in the RCT pathway may aggravate atherosclerosis.

Abbreviations: ABC, ATP binding cassette; APR, acute-phase response; cpt-cAMP, 8-(4-chlorophenylthio) adenosine 3', 5'-cyclic monophosphate; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; IL-1, interleukin-1; LPS, lipopolysaccharide; LXR, liver X receptor; RCT, reverse cholesterol transport; RXR, retinoid X receptor; TNF, tumor necrosis factor

Supplementary key words ATP binding cassette transporters • lipopolysaccharide • cytokine • acute-phase response • reverse cholesterol transport • high density lipoprotein metabolism • liver X receptor • retinoid X receptor

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
In epidemiological studies, plasma levels of HDL cholesterol are inversely correlated with the risk of coronary artery disease; therefore, HDL is postulated to protect against atherosclerosis (1). Reverse cholesterol transport (RCT) is an HDL-mediated pathway by which cholesterol is removed from peripheral cells and transported to the liver for excretion and/or catabolism (2, 3). Cholesterol efflux, the first step of RCT, begins when HDL or its major apolipoprotein, apoA-I, accepts cholesterol from cells. Cholesterol on HDL is returned to the liver by several routes. Once delivered to the liver, most cholesterol is metabolized by a series of hepatic enzymes into bile acids. The remaining cholesterol is excreted directly into the bile, along with bile acids.

Accumulating evidence has suggested a possible relationship between atherosclerosis and chronic infections and inflammatory diseases (4). How infections and inflammatory states, especially those outside the arterial wall, can promote atherosclerosis is not clear. However, it is known that the acute-phase response (APR) is induced during infection and inflammation. During the APR, multiple alterations in lipid and lipoprotein metabolism occur (5). Plasma triglyceride levels increase, and there is an increase in small, dense LDL (6). These particular changes have been recognized as risk factors for atherosclerosis.

Considerable evidence also suggests that, during the APR, RCT is impaired. First, HDL cholesterol levels decrease in most species (7). Second, we and others have shown that levels of several proteins involved in RCT pathway decrease, including lecithin:cholesterol acyltransferase, cholesterol ester transfer protein, phospholipid transfer protein, hepatic lipase, and scavenger receptor class B type I (8–14). Third, there is an impairment of both cholesterol efflux from cells and cholesterol ester uptake into the liver (14–17). Fourth, a series of enzymes that catabolize cholesterol into bile acids, and several proteins in the bile acid transport pathway, are down-regulated (18–21). Collectively, several steps in RCT are impaired during the APR that may contribute to the increased risk of atherosclerosis.

Recently, several key proteins in the RCT pathway have been discovered, a number of which are members of the ATP-binding cassette (ABC) transporter superfamily (22). ABCA1 and ABCG1 are ABC transporters that are involved in the movement of cholesterol from cells to HDL and its apolipoproteins (23–28). ABCG5 and ABCG8 regulate sterol absorption from the small intestine and its excretion from the liver into the bile (29–32).

Identification of factors that regulate ABC transporters should provide insights into the mechanisms by which RCT is affected in physiological and pathological states. Previously, our laboratory has shown that in rodents, hepatic mRNA levels of liver X receptor (LXR) and retinoid X receptor (RXR) were rapidly decreased in response to endotoxin (33). LXR is a nuclear hormone transcription factor that heterodimerizes with RXR and with activation increases the expression of ABCA1, ABCG1, ABCG5, and ABCG8 (25, 29, 34–38). We therefore hypothesized that endotoxin treatment would decrease these ABC transporters in the liver. In the present study, we report that endotoxin decreases mRNA levels of ABCG5 and ABCG8 in mouse liver. In J774 murine macrophages, endotoxin and cytokines decrease levels of ABCA1 and ABCG1. However, there was no reduction in levels of LXR or in binding of nuclear proteins to an LXR response element in macrophages. Thus, while LXR may mediate the decrease in these proteins in the liver, these data demonstrate that, in macrophages, the effects of endotoxin on the transporters may not be mediated through LXR.

	MATERIALS AND METHODS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Materials
Endotoxin [lipopolysaccharide (LPS) from Escherichia coli serotype 055:B5] was purchased from Difco Laboratories (Detroit, MI). Recombinant tumor necrosis factor (TNF) and interleukin-1ß (IL-1ß) were purchased from R and D Systems (Minneapolis, MN). Polyclonal antibody against ABCA1 was purchased from Novus Biologicals (Littleton, CO). Antibodies against LXR and LXRß were purchased from Affinity Bioreagents (Golden, CO). Antibodies against RXR, RXRß, and RXR were purchased from Santa Cruz Biotechnologies (Santa Cruz, CA). 8-(4-Chlorophenylthio) adenosine 3', 5'-cyclic monophosphate (cpt-cAMP), 22(R)-hydroxycholesterol, and all other chemicals were obtained from Sigma (St. Louis, MO). Supplies for immunoblot analysis were purchased from Amersham Biosciences (Piscataway, NJ).

Animal experiments
C57BL/6 mice (6–8 weeks of age) were obtained from Jackson Laboratory (Bar Harbor, ME) and provided with rodent chow and water ad libitum. Animals were injected intraperitoneally with indicated doses of endotoxin (0.1–100 µg/mouse), whereas control animals were injected with normal saline. The highest dose of endotoxin used in our study (100 µg/animal) was able to induce the APR but is far below the lethal dose (LD₅₀ 5 mg/100 g body weight) required to cause death in rodents in our laboratory. Because endotoxin can cause anorexia, food was withdrawn from endotoxin-injected mice and control mice after the injection. At indicated time points, the animals were euthanized using halothane, and the tissue was excised and stored at -80°C. The animal procedures were approved by the Animal Studies Subcommittee of the San Francisco Veterans Affairs Medical Center, and were performed in accordance with the guidelines.

Cell culture experiments
J774 murine macrophages were obtained from the American Type Culture Collection and maintained in minimum essential media supplemented with 10% fetal bovine serum under 5% CO₂. In some experiments, cells were incubated with 0.3 mM cpt-cAMP or 10 µM 22(R)-hydroxycholesterol before being treated with endotoxin or cytokines. Endotoxin or cytokines was incubated with cells in media containing human serum albumin in the absence of serum, and at indicated time points, cells were washed and harvested.

Isolation of RNA and RNA blot analysis
Isolation of RNA and RNA blot analyses were performed as previously described (14). Total or poly(A)⁺ RNA was quantified by measuring absorption at 260 nm, and equal amounts of RNA were loaded on 1% agarose-formaldehyde gels and electrophoresed. The uniformity of sample applications was checked by UV visualization of the acridine orange-stained gels before transfer to Nytran membranes. Because endotoxin increased hepatic mRNA levels of actin, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and cyclophilin in rodent liver (39–41), the mRNA levels of actin, GAPDH, and cyclophilin, which are widely used for normalizing data, cannot be used to study endotoxin regulation of proteins in the mouse liver. However, the differing directions of changes in mRNA levels (increased for some proteins, and decreased for some proteins), the magnitude of alterations (8-fold increase or up to 75% decrease), and the relatively small standard error of the mean (SEM) make it unlikely that the changes observed were due to unequal loading of mRNA. RNA blots were hybridized with ³²P-labeled cDNA probes generated by RT-PCR from the mouse liver (ABCG5, ABCG8, and ABCA1) or J774 murine macrophages (ABCG1) using the following primers: ABCG5 upper primer, 5'-TGC CCT TTC TGA GTC CAG AG-3' and lower primer, 5'-GTG CTC TTT CAA TGT TCT CCA G-3'; ABCG8 upper primer, 5'-ATG AGC TGG AAG ACG GGC TG-3' and lower primer, 5'-GCC AGT GAG AGC AAG GCT GA-3'; ABCA1 upper primer, 5'-TCT CTG CTA TCT CCA ACC TCA TC-3' and lower primer, 5'-ACG TCT TCA CCA GGT AAT CTG AA-3'; ABCG1 upper primer, 5'-GAA GAC CTG CAC TGC GAC ATC-3' and lower primer, 5'-GTT GCA TTG CGT TGC GTT AGT C-3'. After washing, the blots were exposed to X-ray films for various durations to ensure that measurements were done on the linear portion of the curve, and the bands were quantified using the Bio-Rad imaging densitometer.

Immunoblot analysis
J774 cells were scraped into cold PBS and centrifuged to get cell pellets. Lysis buffer containing 10 mM HEPES (pH 7.9), 0.5% Nonidet P40, 1.5 mM MgCl₂, 0.2 M sucrose, 10 mM KCl, 0.5 mM dithiothreitol, and 1% (v/v) protease inhibitor cocktail (Sigma) was incubated with cells for 5 min at 4°C. The supernatant was collected after centrifugation and the protein concentrations were measured. For immunoblot analysis of LXR and RXR, nuclear proteins were isolated as previously described (33). Proteins were resolved on polyacrylamide gels and transferred to Hybond-P PVDF membrane as previously described (14). For immunodetection, the blots were blocked in PBS/0.1% Tween containing 5% nonfat dry milk before incubation with a primary antibody and a secondary antibody conjugated with horseradish peroxidase. The blots were visualized using the ECL Plus chemiluminescence detection system and subjected to autoradiography. Quantification of the signals was performed by densitometry.

Electrophoretic mobility shift assay
Nuclear extracts were prepared as described above, and an electrophoretic mobility shift assay was performed as previously described (33). The oligonucleotides corresponding to the LXR response element of ABCA1 5'GCG CAG AGG TTA CTA TCG GTC AAA3' (36) and the mutated oligonucleotides 5' GCG CAG TAG TTA CTA TCA CAC AAA3' were used.

Statistics
Data are presented as mean ± SEM. Comparisons between groups were performed using a Student's t-test. P values less than 0.05 were considered significant.

	RESULTS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Effect of endotoxin on mRNA levels of ABCG5 and ABCG8 in mouse liver and small intestine
Our laboratory has previously shown that endotoxin decreased hepatic mRNA and protein levels of LXR in hamsters (33). We have obtained similar results in mouse liver (data not shown). Because ABCG5 and ABCG8 are regulated by LXR, we examined whether these two transporters were affected by endotoxin.

A single dose of 100 µg of endotoxin rapidly decreased hepatic mRNA levels of ABCG5 and ABCG8 in mice as shown in Fig. 1A and B . The mRNA levels started to decrease at 4–8 h and continued to be significantly suppressed for 24 h after endotoxin administration. Although the chronological pattern and the magnitude of the reduction of hepatic mRNA levels of both ABCG5 and ABCG8 were relatively similar, slight differences in the degree of the inhibition suggest that the mechanisms might not be completely identical.

View larger version (12K): [in this window] [in a new window]   Fig. 1. Time course of the effect of endotoxin [lipopolysaccharide (LPS)] on ATP binding cassette (ABC)G5 mRNA (A) and ABCG8 mRNA (B) in mouse liver. Mice were injected with endotoxin (100 µg). At indicated time points, livers were harvested and RNA was isolated. Poly(A)+ RNA was hybridized with a 32P-labeled cDNA probe, and bands were analyzed by agarose gel electrophoresis followed by autoradiography as described in Materials and Methods. Data are presented as percent change versus control (mean ± SEM). n = 4–5 in each group at each time point. ** P < 0.01.

View larger version (11K): [in this window] [in a new window]   Fig. 2. Dose response curve of the effect of endotoxin (LPS) on ABCG5 mRNA (A) and ABCG8 mRNA (B) in mouse liver. Mice were injected with endotoxin (100 µg). At 16 h, livers were harvested and RNA was isolated. Poly(A)+ RNA was hybridized with a 32P-labeled cDNA probe, and bands were analyzed by agarose gel electrophoresis followed by autoradiography as described in Materials and Methods. Data are presented as percent change versus control (mean ± SEM). n = 4–5 in each group at each time point. * P < 0.05, ** P < 0.01.

To further determine whether the different results were due to differential regulation of LXR/RXR between the small intestine and the liver, we examined the mRNA levels of LXR and RXR in the small intestine in response to endotoxin. We found no significant changes in LXRß or RXR mRNA in the small intestine, and did not detect LXR, RXRß, or RXR (data not shown). Additionally, PPAR and PPAR were not detected, and PPARß/ was abundantly expressed, but was not changed by endotoxin treatment. These results suggest that the difference in the responsiveness of ABCG5 and ABCG8 between the liver and the small intestine may be due to differential regulation of LXR and RXR by endotoxin in different tissues.

Effect of endotoxin on mRNA levels of ABCA1 in J774 murine macrophages
In macrophages, ABCA1 plays a critical role in apolipoprotein-mediated cholesterol efflux (23, 24). We found that incubation of endotoxin with J774 murine macrophages resulted in a decrease in ABCA1 mRNA levels (Fig. 3) . The maximal decrease in mRNA levels of ABCA1 was observed 8 h after endotoxin and was relatively sustained until 24 h (Fig. 3A). There was also a concentration-dependent decrease in mRNA levels of ABCA1 (Fig. 3B). It is of note that the half-maximal decrease in the mRNA levels of ABCA1 was produced by the concentrations of endotoxin between 1–10 ng/ml, which corresponds to the concentrations of endotoxin found in the circulation during sepsis (42).

View larger version (13K): [in this window] [in a new window]   Fig. 3. Time course (A) and dose response curve (B) of the effect of endotoxin (LPS) on ABCA1 mRNA in J774 macrophages. Cells were incubated with indicated concentrations of endotoxin, and at indicated time points, cells were harvested and RNA was isolated. Total RNA was hybridized with a 32P-labeled cDNA probe, and bands were analyzed by agarose gel electrophoresis followed by autoradiography as described in Materials and Methods. Data are presented as percent change versus control (mean ± SEM). n = 3 in each group at each time point. * P < 0.05, ** P < 0.01.

View larger version (12K): [in this window] [in a new window]   Fig. 4. Time course (A) and dose response curve (B) of the effect of endotoxin (LPS) on ABCG1 mRNA in J774 macrophages. Cells were incubated with indicated concentrations of endotoxin and, at indicated time points, cells were harvested and RNA was isolated. Total RNA was hybridized with a 32P-labeled cDNA probe, and bands were analyzed by agarose gel electrophoresis followed by autoradiography as described in Materials and Methods. Data are presented as percent change versus control (mean ± SEM). n = 3 in each group at each time point. * P < 0.05, ** P < 0.01.

View larger version (41K): [in this window] [in a new window]   Fig. 5. The effect of tumor necrosis factor (TNF), interleukin-1 (IL-1), and endotoxin (LPS) on ABCA1 mRNA (A) and ABCG1 mRNA (B) levels in J774 macrophages. TNF (100 ng/ml), IL-1 (100 ng/ml), or endotoxin (100 ng/ml) was incubated with cells in minimal essential media with 2.5% human serum albumin in the absence of serum, and 24 h later, cells were harvested for RNA isolation as described in Materials and Methods. n = 3 in each group. * P < 0.05, ** P < 0.01.

View larger version (48K): [in this window] [in a new window]   Fig. 6. The effect of 8-(4-chlorophenylthio)adenosine 3', 5'-cyclic monophosphate (cpt-cAMP) and 22(R)-hydroxycholesterol in the presence or absence of endotoxin (LPS) on ABCA1 mRNA (A) and ABCG1 mRNA (B) levels in J774 macrophages. J774 cells were pretreated with 0.3 mM cpt-cAMP or 10 µM 22(R)-hydroxycholesterol before treatment with endotoxin (100 ng/ml) for 24 h. Cells were harvested for RNA isolation as described in Materials and Methods. n = 3 in each group. cAMP denotes cpt-cAMP and 22R denotes 22(R)-hydroxycholesterol. * P < 0.05 compared with 22(R)-hydroxycholesterol alone.

Effect of endotoxin, TNF, and IL-1 on ABCA1 protein levels in J774 murine macrophages
It has been reported that in different tissues, the mRNA levels of ABCA1 do not always correlate with the protein levels (43). Because of the reduction in mRNA levels of ABCA1 in macrophages, we investigated whether protein levels of ABCA1 were also decreased. As shown in Fig. 7 , endotoxin, TNF, and IL-1 all produced a significant decrease in the protein levels of ABCA1. Due to lack of reactive antibodies against ABCG1, the protein levels in J774 cells were not investigated.

View larger version (32K): [in this window] [in a new window]   Fig. 7. The effect of endotoxin (LPS) on ABCA1 protein levels in J774 macrophages. Endotoxin (100 ng/ml) was incubated with cells in minimal essential media with 2.5% human serum albumin in the absence of serum, and 24 h later, cells were harvested for protein isolation as described in Materials and Methods. n = 3 in each group. * P < 0.05.

View larger version (64K): [in this window] [in a new window]   Fig. 8. The effect of endotoxin (LPS) on protein levels of liver X receptor (LXR), LXRß, retinoid X receptor (RXR), RXRß, and RXR (A) and binding activities of LXR/RXR (B) in J774 macrophages. J774 cells were incubated with endotoxin (100 ng/ml) for 24 h, and nuclei fractions of the cells were prepared for immunoblot analysis and/or electrophoretic mobility shift assay as described in Materials and Methods. n = 3–5 in each group at each time point. ** P < 0.01. B: 1, no nuclear extract; 2, five different samples of nuclear extract from control cells; 3, five different samples of nuclear extract from endotoxin-treated cells; 4, unlabeled specific oligonucleotides were included at 100-fold excess for competition; 5, unlabeled nonspecific (mutated) oligonucleotides were included at 100-fold excess for competition.

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
A number of proteins in the ABC transporter superfamily have recently been discovered to play a role in cholesterol efflux and RCT (22). ABCA1 is a transporter on the plasma membrane that translocates cholesterol and phospholipid out of the cells. Mutations of ABCA1 result in defects in apolipoprotein-mediated cholesterol efflux as found in Tangier disease and familial HDL deficiency (23, 44–47). These patients have low levels of HDL, and in some cases, premature atherosclerosis has been reported (48). ABCG1 is another ABC transporter that is involved in cholesterol efflux (25). In contrast to ABCA1, ABCG1 is located primarily inside the cells. ABCG5 and ABCG8 are two ABC half-transporters that form a heterodimer in the small intestine and in the liver (29, 49). In the small intestine, the ABCG5-ABCG8 heterodimers efflux plant sterols as well as dietary cholesterol out of the intestinal cells, whereas in hepatocytes, they efflux those sterols into the bile (31, 32, 50). Mutations in ABCG5 or ABCG8 are the cause of sitosterolemia, a disorder characterized by xanthomatosis and premature atherosclerosis due to uncontrolled absorption of sterols and failure to excrete them into the bile. In addition to defects in plant sterol metabolism, patients with sitosterolemia also have abnormal cholesterol metabolism. An increase in cholesterol absorption as well as a defect in cholesterol excretion into the bile has been noted in these patients (51, 52).

Our laboratory has previously reported that endotoxin decreased LXR and RXR in rodent liver. Because ABCG5 and ABCG8 are positively regulated by LXR (29, 38), we investigated the regulation of ABCG5 and ABCG8 by endotoxin in the liver. As expected, we found that both ABCG5 and ABCG8 were coordinately down-regulated. Our data suggest that cholesterol excretion into the bile could be impaired during the APR. Previously, we and others have shown that during infection, there is a reduction in several key enzymes involved in bile acid synthesis, including CYP7A, CYP7B, and CYP27 (18, 19). In addition, there is a decrease in bile salt export pump and multidrug resistance-related protein 2, two main proteins involved in canalicular bile salt secretion, resulting in decreased bile salt excretion and cholestasis (53–55). Therefore, it appears that the majority of cholesterol excretion through bile acids is impaired during infection. Taken together, during infection not only is cholesterol excretion decreased, but there is also coordinate reduction in nearly every step of cholesterol catabolism and excretion into the bile. This reduction is likely the mechanism of cholestasis commonly observed during sepsis (20, 54). The reduction in cholesterol excretion could help retain cholesterol in the body for use during infection.

In macrophages, ABCA1 and ABCG1 are involved in cholesterol efflux. Previous studies from our laboratory and others have shown that during the APR, changes in HDL particles resulted in impairment of cholesterol efflux from cells to HDL (15, 16). Treatment of mouse peritoneal macrophages with interferon- caused a decrease in ABCA1 mRNA levels and cholesterol efflux (56). A recent study in RAW cells also reported that endotoxin treatment down-regulated ABCA1 mRNA levels (57); however, data on protein levels of ABCA1 were not provided. A study comparing mRNA and protein levels of ABCA1 in different tissues has shown that in some tissues, the abundance of mRNA levels and protein levels are not well correlated (43). For example, in spleen and thymus, the mRNA levels of ABCA1 were low, but the levels of protein found were higher than expected (43). Therefore, we examined both mRNA levels and protein levels of ABCA1 in response to endotoxin treatment in our studies using J774 cells. We found that endotoxin decreased both ABCA1 mRNA and protein levels. We also provide new information that TNF and IL-1 treatment, like endotoxin, could decrease ABCA1 mRNA and protein levels. Collectively, our data on ABCA1 as well as ABCG1 provide the mechanism for previous findings that cholesterol efflux was impaired during the APR (16, 57).

In macrophages, both ABCA1 and ABCG1 are up-regulated by LXR, but we found that the effect could not be explained by a decrease in LXR. Data from immunoblot analysis showed that both isoforms of LXR, LXR and LXRß, did not decrease with endotoxin. When RXR, a partner of LXR heterodimerization, was examined in J774 cells, changes in the levels of the three isoforms of RXR were different. Endotoxin decreased RXR but increased RXRß and RXR isoforms. Because the relative abundance of different LXR and RXR isoforms vary among different cell types, an electrophoretic mobility shift assay was performed to detect the binding of LXR/RXR heterodimers to the LXR response element of ABCA1. Again, we did not find differences between nuclei preparations from control cells or cells treated with endotoxin. Therefore, our data did not support the hypothesis that a decrease in ABCA1 levels in J774 cells was mediated through a reduction in either LXR or RXR. A recent study using an inhibitor of NF-B reported that NF-B might be involved in the down-regulation of ABCA1 by endotoxin (57).

Our current study demonstrates that endotoxin, TNF, and IL-1 decreased ABCA1 mRNA and protein levels in J774 macrophages. A study in RAW264.7 cells using endotoxin also reported similar changes in mRNA levels (57). Another study using mouse peritoneal macrophages reported that interferon- decreased ABCA1 (56). However, in human THP-1 cells, ABCA1 was found to be up-regulated by endotoxin (58). It is not clear whether the discrepancy is due to different cell types, species specificity, or other unknown factors. It is of note that the up-regulation of ABCA1 by endotoxin in THP-1 cells was also reported to be mediated by an LXR-independent mechanism (58).

In summary, our study showed that endotoxin down-regulated ABCG5 and ABCG8 in the liver. This effect likely impairs cholesterol excretion from hepatocytes into the bile. Endotoxin also decreased ABCA1 and ABCG1 in macrophages, thus providing the mechanism for previous findings that cholesterol efflux from macrophages was impaired during the APR. While a decrease in LXR may mediate the decrease in levels of these proteins in the liver, the down-regulation of ABCA1 by endotoxin in macrophages is not likely to be mediated by LXR. The present study adds to the accumulating evidence that multiple steps in RCT are impaired during the APR. Although decreased RCT may redirect cholesterol to peripheral cells (e.g., leukocytes) to acutely promote host defense, prolongation of impaired RCT may contribute to an increased risk of atherosclerosis observed in chronic infections and inflammatory states.

	ACKNOWLEDGMENTS

 
This work was done during the tenure of a fellowship from the American Heart Association, Western States Affiliate (W.K.), and supported by grants from the Research Service of the Department of Veterans Affairs (C.G. and K.R.F.). W.K. was an Anandamahidol Foundation scholar under the Royal Patronage of the King of Thailand.

Manuscript received March 5, 2003 and in revised form May 30, 2003.

	REFERENCES

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

1. Gordon, D. J., and B. M. Rifkind. 1989. High-density lipoprotein—the clinical implications of recent studies. N. Engl. J. Med. 321: 1311–1316.[Medline]

2. Tall, A. R. 1990. Plasma high density lipoproteins. Metabolism and relationship to atherogenesis. J. Clin. Invest. 86: 379–384.

3. Fielding, C. J., and P. E. Fielding. 1995. Molecular physiology of reverse cholesterol transport. J. Lipid Res. 36: 211–228.[Abstract]

4. Libby, P., D. Egan, and S. Skarlatos. 1997. Roles of infectious agents in atherosclerosis and restenosis: an assessment of the evidence and need for future research. Circulation. 96: 4095–4103.[Free Full Text]

5. Khovidhunkit, W., R. A. Memon, K. R. Feingold, and C. Grunfeld. 2000. Infection and inflammation-induced proatherogenic changes of lipoproteins. J. Infect. Dis. 181(Suppl.): 462–472.[CrossRef]

6. Feingold, K. R., R. M. Krauss, M. Pang, W. Doerrler, P. Jensen, and C. Grunfeld. 1993. The hypertriglyceridemia of acquired immunodeficiency syndrome is associated with an increased prevalence of low density lipoprotein subclass pattern B. J. Clin. Endocrinol. Metab. 76: 1423–1427.[Abstract]

7. Cabana, V. G., J. N. Siegel, and S. M. Sabesin. 1989. Effects of the acute phase response on the concentration and density distribution of plasma lipids and apolipoproteins. J. Lipid Res. 30: 39–49.[Abstract]

8. Ettinger, W. H., L. D. Miller, J. J. Albers, T. K. Smith, and J. S. Parks. 1990. Lipopolysaccharide and tumor necrosis factor cause a fall in plasma concentration of lecithin:cholesterol acyltransferase in cynomolgus monkeys. J. Lipid Res. 31: 1099–1107.[Abstract]

9. Ly, H., O. L. Francone, C. J. Fielding, J. K. Shigenaga, A. H. Moser, C. Grunfeld, and K. R. Feingold. 1995. Endotoxin and TNF lead to reduced plasma LCAT activity and decreased hepatic LCAT mRNA levels in Syrian hamsters. J. Lipid Res. 36: 1254–1263.[Abstract]

10. Masucci-Magoulas, L., P. Moulin, X. C. Jiang, H. Richardson, A. Walsh, J. L. Breslow, and A. Tall. 1995. Decreased cholesteryl ester transfer protein (CETP) mRNA and protein and increased high density lipoprotein following lipopolysaccharide administration in human CETP transgenic mice. J. Clin. Invest. 95: 1587–1594.

11. Hardardóttir, I., A. H. Moser, J. Fuller, C. Fielding, K. Feingold, and C. Grünfeld. 1996. Endotoxin and cytokines decrease serum levels and extra hepatic protein and mRNA levels of cholesteryl ester transfer protein in syrian hamsters. J. Clin. Invest. 97: 2585–2592.[Medline]

12. Jiang, X. C., and C. Bruce. 1995. Regulation of murine plasma phospholipid transfer protein activity and mRNA levels by lipopolysaccharide and high cholesterol diet. J. Biol. Chem. 270: 17133–17138.[Abstract/Free Full Text]

13. Feingold, K. R., R. A. Memon, A. H. Moser, J. K. Shigenaga, and C. Grunfeld. 1999. Endotoxin and interleukin-1 decrease hepatic lipase mRNA levels. Atherosclerosis. 142: 379–387.[CrossRef][Medline]

14. Khovidhunkit, W., A. H. Moser, J. K. Shigenaga, C. Grunfeld, and K. R. Feingold. 2001. Regulation of scavenger receptor class B type I in hamster liver and Hep3B cells by endotoxin and cytokines. J. Lipid Res. 42: 1636–1644.[Abstract/Free Full Text]

15. Khovidhunkit, W., J. K. Shigenaga, A. H. Moser, K. R. Feingold, and C. Grunfeld. 2001. Cholesterol efflux by acute-phase high density lipoprotein. Role of lecithin:cholesterol acyltransferase. J. Lipid Res. 42: 967–975.[Abstract/Free Full Text]

16. Artl, A., G. Marsche, S. Lestavel, W. Sattler, and E. Malle. 2000. Role of serum amyloid A during metabolism of acute-phase HDL by macrophages. Arterioscler. Thromb. Vasc. Biol. 20: 763–772.[Abstract/Free Full Text]

17. Artl, A., G. Marsche, P. Pussinen, G. Knipping, W. Sattler, and E. Malle. 2002. Impaired capacity of acute-phase high density lipoprotein particles to deliver cholesteryl ester to the human HUH-7 hepatoma cell line. Int. J. Biochem. Cell Biol. 34: 370–381.[CrossRef][Medline]

18. Feingold, K. R., D. K. Spady, A. S. Pollock, A. H. Moser, and C. Grunfeld. 1996. Endotoxin, TNF, and IL-1 decrease cholesterol 7 alpha-hydroxylase mRNA levels and activity. J. Lipid Res. 37: 223–228.[Abstract]

19. Memon, R. A., A. H. Moser, J. K. Shigenaga, C. Grunfeld, and K. R. Feingold. 2001. In vivo and in vitro regulation of sterol 27-hydroxylase in the liver during the acute phase response. potential role of hepatocyte nuclear factor-1. J. Biol. Chem. 276: 30118–30126.[Abstract/Free Full Text]

20. Trauner, M., M. Arrese, H. Lee, J. L. Boyer, and S. J. Karpen. 1998. Endotoxin downregulates rat hepatic ntcp gene expression via decreased activity of critical transcription factors. J. Clin. Invest. 101: 2092–2100.[Medline]

21. Beigneux, A. P., A. H. Moser, J. K. Shigenaga, C. Grunfeld, and K. R. Feingold. 2002. Reduction in cytochrome P-450 enzyme expression is associated with repression of CAR (constitutive androstane receptor) and PXR (pregnane X receptor) in mouse liver during the acute phase response. Biochem. Biophys. Res. Commun. 293: 145–149.[CrossRef][Medline]

22. Schmitz, G., W. E. Kaminski, and E. Orso. 2000. ABC transporters in cellular lipid trafficking. Curr. Opin. Lipidol. 11: 493–501.[CrossRef][Medline]

23. Lawn, R. M., D. P. Wade, M. R. Garvin, X. Wang, K. Schwartz, J. G. Porter, J. J. Seilhamer, A. M. Vaughan, and J. F. Oram. 1999. The Tangier disease gene product ABC1 controls the cellular apolipoprotein-mediated lipid removal pathway. J. Clin. Invest. 104: R25–R31.

24. Bortnick, A. E., G. H. Rothblat, G. Stoudt, K. L. Hoppe, L. J. Royer, J. McNeish, and O. L. Francone. 2000. The correlation of ATP-binding cassette 1 mRNA levels with cholesterol efflux from various cell lines. J. Biol. Chem. 275: 28634–28640.[Abstract/Free Full Text]

25. Klucken, J., C. Buchler, E. Orso, W. E. Kaminski, M. Porsch-Ozcurumez, G. Liebisch, M. Kapinsky, W. Diederich, W. Drobnik, M. Dean, R. Allikmets, and G. Schmitz. 2000. ABCG1 (ABC8), the human homolog of the Drosophila white gene, is a regulator of macrophage cholesterol and phospholipid transport. Proc. Natl. Acad. Sci. USA. 97: 817–822.[Abstract/Free Full Text]

26. Attie, A. D., J. P. Kastelein, and M. R. Hayden. 2001. Pivotal role of ABCA1 in reverse cholesterol transport influencing HDL levels and susceptibility to atherosclerosis. J. Lipid Res. 42: 1717–1726.[Abstract/Free Full Text]

27. Oram, J. F., and R. M. Lawn. 2001. ABCA1. The gatekeeper for eliminating excess tissue cholesterol. J. Lipid Res. 42: 1173–1179.[Abstract/Free Full Text]

28. Santamarina-Fojo, S., A. T. Remaley, E. B. Neufeld, and H. B. Brewer, Jr. 2001. Regulation and intracellular trafficking of the ABCA1 transporter. J. Lipid Res. 42: 1339–1345.[Abstract/Free Full Text]

29. Berge, K. E., H. Tian, G. A. Graf, L. Yu, N. V. Grishin, J. Schultz, P. Kwiterovich, B. Shan, R. Barnes, and H. H. Hobbs. 2000. Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science. 290: 1771–1775.[Abstract/Free Full Text]

30. Lee, M. H., K. Lu, S. Hazard, H. Yu, S. Shulenin, H. Hidaka, H. Kojima, R. Allikmets, N. Sakuma, R. Pegoraro, A. K. Srivastava, G. Salen, M. Dean, and S. B. Patel. 2001. Identification of a gene, ABCG5, important in the regulation of dietary cholesterol absorption. Nat. Genet. 27: 79–83.[Medline]

31. Yu, L., R. E. Hammer, J. Li-Hawkins, K. Von Bergmann, D. Lutjohann, J. C. Cohen, H. H. Hobbs, K. E. Berge, J. D. Horton, G. A. Graf, W. P. Li, R. D. Gerard, I. Gelissen, and A. White. 2002. Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion. Proc. Natl. Acad. Sci. USA. 99: 16237–16242.[Abstract/Free Full Text]

32. Yu, L., J. Li-Hawkins, R. E. Hammer, K. E. Berge, J. D. Horton, J. C. Cohen, H. H. Hobbs, G. A. Graf, W. P. Li, R. D. Gerard, I. Gelissen, and A. White. 2002. Overexpression of ABCG5 and ABCG8 promotes biliary cholesterol secretion and reduces fractional absorption of dietary cholesterol. J. Clin. Invest. 110: 671–680.[CrossRef][Medline]

33. Beigneux, A. P., A. H. Moser, J. K. Shigenaga, C. Grunfeld, and K. R. Feingold. 2000. The acute phase response is associated with retinoid X receptor repression in rodent liver. J. Biol. Chem. 275: 16390–16399.[Abstract/Free Full Text]

34. Venkateswaran, A., B. A. Laffitte, S. B. Joseph, P. A. Mak, D. C. Wilpitz, P. A. Edwards, and P. Tontonoz. 2000. Control of cellular cholesterol efflux by the nuclear oxysterol receptor LXR alpha. Proc. Natl. Acad. Sci. USA. 97: 12097–12102.[Abstract/Free Full Text]

35. Schwartz, K., R. M. Lawn, and D. P. Wade. 2000. ABC1 gene expression and ApoA-I-mediated cholesterol efflux are regulated by LXR. Biochem. Biophys. Res. Commun. 274: 794–802.[CrossRef][Medline]

36. Costet, P., Y. Luo, N. Wang, and A. R. Tall. 2000. Sterol-dependent transactivation of the ABC1 promoter by the liver X receptor/retinoid X receptor. J. Biol. Chem. 275: 28240–28245.[Abstract/Free Full Text]

37. Kennedy, M. A., A. Venkateswaran, P. T. Tarr, I. Xenarios, J. Kudoh, N. Shimizu, and P. A. Edwards. 2001. Characterization of the human ABCG1 gene: liver X receptor activates an internal promoter that produces a novel transcript encoding an alternative form of the protein. J. Biol. Chem. 276: 39438–39447.[Abstract/Free Full Text]

38. Repa, J. J., K. E. Berge, C. Pomajzl, J. A. Richardson, H. Hobbs, and D. J. Mangelsdorf. 2002. Regulation of ATP-binding cassette sterol transporters ABCG5 and ABCG8 by the liver X receptors alpha and beta. J. Biol. Chem. 277: 18793–18800.[Abstract/Free Full Text]

39. Feingold, K. R., I. Hardardottir, R. Memon, E. J. Krul, A. H. Moser, J. M. Taylor, and C. Grunfeld. 1993. Effect of endotoxin on cholesterol biosynthesis and distribution in serum lipoproteins in Syrian hamsters. J. Lipid Res. 34: 2147–2158.[Abstract]

40. Morrow, J. F., R. S. Stearman, C. G. Peltzman, and D. A. Potter. 1981. Induction of hepatic synthesis of serum amyloid A protein and actin. Proc. Natl. Acad. Sci. USA. 78: 4718–4722.[Abstract/Free Full Text]

41. Memon, R. A., K. R. Feingold, A. H. Moser, J. Fuller, and C. Grunfeld. 1998. Regulation of fatty acid transport protein and fatty acid translocase mRNA levels by endotoxin and cytokines. Am. J. Physiol. 274: E210–E217.

42. Levin, J., T. E. Poore, N. P. Zauber, and R. S. Oser. 1970. Detection of endotoxin in the blood of patients with sepsis due to gran-negative bacteria. N. Engl. J. Med. 283: 1313–1316.

43. Wellington, C. L., E. K. Walker, A. Suarez, A. Kwok, N. Bissada, R. Singaraja, Y. Z. Yang, L. H. Zhang, E. James, J. E. Wilson, O. Francone, B. M. McManus, and M. R. Hayden. 2002. ABCA1 mRNA and protein distribution patterns predict multiple different roles and levels of regulation. Lab. Invest. 82: 273–283.[CrossRef][Medline]

44. Bodzioch, M., E. Orso, J. Klucken, T. Langmann, A. Bottcher, W. Diederich, W. Drobnik, S. Barlage, C. Buchler, M. Porsch-Ozcurumez, W. E. Kaminski, H. W. Hahmann, K. Oette, G. Rothe, C. Aslanidis, K. J. Lackner, and G. Schmitz. 1999. The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease. Nat. Genet. 22: 347–351.[CrossRef][Medline]

45. Brooks-Wilson, A., M. Marcil, S. M. Clee, L. H. Zhang, K. Roomp, M. van Dam, L. Yu, C. Brewer, J. A. Collins, H. O. Molhuizen, O. Loubser, B. F. Ouelette, K. Fichter, K. J. Ashbourne-Excoffon, C. W. Sensen, S. Scherer, S. Mott, M. Denis, D. Martindale, J. Frohlich, K. Morgan, B. Koop, S. Pimstone, J. J. Kastelein, and M. R. Hayden. 1999. Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. Nat. Genet. 22: 336–345.[CrossRef][Medline]

46. Rust, S., M. Rosier, H. Funke, J. Real, Z. Amoura, J. C. Piette, J. F. Deleuze, H. B. Brewer, N. Duverger, P. Denefle, and G. Assmann. 1999. Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1. Nat. Genet. 22: 352–355.[CrossRef][Medline]

47. Marcil, M., A. Brooks-Wilson, S. M. Clee, K. Roomp, L. H. Zhang, L. Yu, J. A. Collins, M. van Dam, H. O. Molhuizen, O. Loubster, B. F. Ouellette, C. W. Sensen, K. Fichter, S. Mott, M. Denis, B. Boucher, S. Pimstone, J. Genest, Jr., J. J. Kastelein, and M. R. Hayden. 1999. Mutations in the ABC1 gene in familial HDL deficiency with defective cholesterol efflux. Lancet. 354: 1341–1346.[CrossRef][Medline]

48. Serfaty-Lacrosniere, C., F. Civeira, A. Lanzberg, P. Isaia, J. Berg, E. D. Janus, M. P. Smith, Jr., P. H. Pritchard, J. Frohlich, R. S. Lees, G. F. Barnard, J. M. Ordovas, and E. J. Schaefer. 1994. Homozygous Tangier disease and cardiovascular disease. Atherosclerosis. 107: 85–98.[CrossRef][Medline]

49. Graf, G. A., W. P. Li, R. D. Gerard, I. Gelissen, A. White, J. C. Cohen, and H. H. Hobbs. 2002. Coexpression of ATP-binding cassette proteins ABCG5 and ABCG8 permits their transport to the apical surface. J. Clin. Invest. 110: 659–669.[CrossRef][Medline]

50. Lu, K., M. H. Lee, and S. B. Patel. 2001. Dietary cholesterol absorption: more than just bile. Trends Endocrinol. Metab. 12: 314–320.[CrossRef][Medline]

51. Miettinen, T. A. 1980. Phytosterolaemia, xanthomatosis and premature atherosclerotic arterial disease: a case with high plant sterol absorption, impaired sterol elimination and low cholesterol synthesis. Eur. J. Clin. Invest. 10: 27–35.[Medline]

52. Salen, G., V. Shore, G. S. Tint, T. Forte, S. Shefer, I. Horak, E. Horak, B. Dayal, L. Nguyen, and A. K. Batta. 1989. Increased sitosterol absorption, decreased removal, and expanded body pools compensate for reduced cholesterol synthesis in sitosterolemia with xanthomatosis. J. Lipid Res. 30: 1319–1330.[Abstract]

53. Vos, T. A., G. J. Hooiveld, H. Koning, S. Childs, D. K. Meijer, H. Moshage, P. L. Jansen, and M. Muller. 1998. Up-regulation of the multidrug resistance genes, Mrp1 and Mdr1b, and down-regulation of the organic anion transporter, Mrp2, and the bile salt transporter, Spgp, in endotoxemic rat liver. Hepatology. 28: 1637–1644.[CrossRef][Medline]

54. Hartmann, G., A. K. Cheung, and M. Piquette-Miller. 2002. Inflammatory cytokines, but not bile acids, regulate expression of murine hepatic anion transporters in endotoxemia. J. Pharmacol. Exp. Ther. 303: 273–281.[Abstract/Free Full Text]

55. Tygstrup, N., K. Bangert, P. Ott, and H. C. Bisgaard. 2002. Messenger RNA profiles in liver injury and stress: a comparison of lethal and nonlethal rat models. Biochem. Biophys. Res. Commun. 290: 518–525.[CrossRef][Medline]

56. Panousis, C. G., and S. H. Zuckerman. 2000. Interferon-gamma induces downregulation of Tangier disease gene (ATP-binding-cassette transporter 1) in macrophage-derived foam cells. Arterioscler. Thromb. Vasc. Biol. 20: 1565–1571.[Abstract/Free Full Text]

57. Baranova, I., T. Vishnyakova, A. Bocharov, Z. Chen, A. T. Remaley, J. Stonik, T. L. Eggerman, and A. P. Patterson. 2002. Lipopolysaccharide down regulates both scavenger receptor B1 and ATP binding cassette transporter A1 in RAW cells. Infect. Immun. 70: 2995–3003.[Abstract/Free Full Text]

58. Kaplan, R., X. Gan, J. G. Menke, S. D. Wright, and T. Q. Cai. 2002. Bacterial lipopolysaccharide induces expression of ABCA1 but not ABCG1 via an LXR-independent pathway. J. Lipid Res. 43: 952–959.[Abstract/Free Full Text]

CiteULike

Complore

Connotea

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				F. C. McGillicuddy, M. de la Llera Moya, C. C. Hinkle, M. R. Joshi, E. H. Chiquoine, J. T. Billheimer, G. H. Rothblat, and M. P. Reilly Inflammation Impairs Reverse Cholesterol Transport In Vivo Circulation, March 3, 2009; 119(8): 1135 - 1145. [Abstract] [Full Text] [PDF]

				J.-Q. Gu, S. Ikuyama, P. Wei, B. Fan, J.-i. Oyama, T. Inoguchi, and J. Nishimura Pycnogenol, an extract from French maritime pine, suppresses Toll-like receptor 4-mediated expression of adipose differentiation-related protein in macrophages Am J Physiol Endocrinol Metab, December 1, 2008; 295(6): E1390 - E1400. [Abstract] [Full Text] [PDF]

				A. Baldan, A. V. Gomes, P. Ping, and P. A. Edwards Loss of ABCG1 Results in Chronic Pulmonary Inflammation J. Immunol., March 1, 2008; 180(5): 3560 - 3568. [Abstract] [Full Text] [PDF]

				W. Hu, S. Abe-Dohmae, M. Tsujita, N. Iwamoto, O. Ogikubo, T. Otsuka, Y. Kumon, and S. Yokoyama Biogenesis of HDL by SAA is dependent on ABCA1 in the liver in vivo J. Lipid Res., February 1, 2008; 49(2): 386 - 393. [Abstract] [Full Text] [PDF]

				D. Yan, M. I. Mayranpaa, J. Wong, J. Perttila, M. Lehto, M. Jauhiainen, P. T. Kovanen, C. Ehnholm, A. J. Brown, and V. M. Olkkonen OSBP-related Protein 8 (ORP8) Suppresses ABCA1 Expression and Cholesterol Efflux from Macrophages J. Biol. Chem., January 4, 2008; 283(1): 332 - 340. [Abstract] [Full Text] [PDF]

				B. Fontaine-Bisson, T. M. Wolever, J.-L. Chiasson, R. Rabasa-Lhoret, P. Maheux, R. G Josse, L. A Leiter, N W. Rodger, E. A Ryan, P. W Connelly, et al. Genetic polymorphisms of tumor necrosis factor-{alpha} modify the association between dietary polyunsaturated fatty acids and fasting HDL-cholesterol and apo A-I concentrations Am. J. Clinical Nutrition, September 1, 2007; 86(3): 768 - 774. [Abstract] [Full Text] [PDF]

				X. Wang, H. Mu, H. Chai, D. Liao, Q. Yao, and C. Chen Human Immunodeficiency Virus Protease Inhibitor Ritonavir Inhibits Cholesterol Efflux from Human Macrophage-Derived Foam Cells Am. J. Pathol., July 1, 2007; 171(1): 304 - 314. [Abstract] [Full Text] [PDF]

				M. Chen, W. Li, N. Wang, Y. Zhu, and X. Wang ROS and NF-{kappa}B but not LXR mediate IL-1beta signaling for the downregulation of ATP-binding cassette transporter A1 Am J Physiol Cell Physiol, April 1, 2007; 292(4): C1493 - C1501. [Abstract] [Full Text] [PDF]

				Y. J. Jiang, B. Lu, P. Kim, P. M. Elias, and K. R. Feingold Regulation of ABCA1 expression in human keratinocytes and murine epidermis J. Lipid Res., October 1, 2006; 47(10): 2248 - 2258. [Abstract] [Full Text] [PDF]

				M. Lee-Rueckert, R. Vikstedt, J. Metso, C. Ehnholm, P. T. Kovanen, and M. Jauhiainen Absence of endogenous phospholipid transfer protein impairs ABCA1-dependent efflux of cholesterol from macrophage foam cells J. Lipid Res., August 1, 2006; 47(8): 1725 - 1732. [Abstract] [Full Text] [PDF]

				T. R. Sweeney, A. H. Moser, J. K. Shigenaga, C. Grunfeld, and K. R. Feingold Decreased nuclear hormone receptor expression in the livers of mice in late pregnancy Am J Physiol Endocrinol Metab, June 1, 2006; 290(6): E1313 - E1320. [Abstract] [Full Text] [PDF]

				I. Zanotti, F. Poti, E. Favari, K. R. Steffensen, J.-A. Gustafsson, and F. Bernini Pitavastatin Effect on ATP Binding Cassette A1-Mediated Lipid Efflux from Macrophages: Evidence for Liver X Receptor (LXR)-Dependent and LXR-Independent Mechanisms of Activation by cAMP J. Pharmacol. Exp. Ther., April 1, 2006; 317(1): 395 - 401. [Abstract] [Full Text] [PDF]

				Y. Masuda, H. Itabe, M. Odaki, K. Hama, Y. Fujimoto, M. Mori, N. Sasabe, J. Aoki, H. Arai, and T. Takano ADRP/adipophilin is degraded through the proteasome-dependent pathway during regression of lipid-storing cells J. Lipid Res., January 1, 2006; 47(1): 87 - 98. [Abstract] [Full Text] [PDF]

				L. K. Curtiss, D. T. Valenta, N. J. Hime, and K.-A. Rye What Is So Special About Apolipoprotein AI in Reverse Cholesterol Transport? Arterioscler. Thromb. Vasc. Biol., January 1, 2006; 26(1): 12 - 19. [Abstract] [Full Text] [PDF]

				R. Ohashi, H. Mu, X. Wang, Q. Yao, and C. Chen Reverse cholesterol transport and cholesterol efflux in atherosclerosis QJM, December 1, 2005; 98(12): 845 - 856. [Abstract] [Full Text] [PDF]

				Y. Wang, A. H. Moser, J. K. Shigenaga, C. Grunfeld, and K. R. Feingold Downregulation of liver X receptor-{alpha} in mouse kidney and HK-2 proximal tubular cells by LPS and cytokines J. Lipid Res., November 1, 2005; 46(11): 2377 - 2387. [Abstract] [Full Text] [PDF]

				Y. Takata, V. Chu, A. R. Collins, C. J. Lyon, W. Wang, F. Blaschke, D. Bruemmer, E. Caglayan, W. Daley, J. Higaki, et al. Transcriptional Repression of ATP-Binding Cassette Transporter A1 Gene in Macrophages: A Novel Atherosclerotic Effect of Angiotensin II Circ. Res., October 28, 2005; 97(9): e88 - e96. [Abstract] [Full Text] [PDF]

				M. R. Kazemi, C. M. McDonald, J. K. Shigenaga, C. Grunfeld, and K. R. Feingold Adipocyte Fatty Acid-Binding Protein Expression and Lipid Accumulation Are Increased During Activation of Murine Macrophages by Toll-Like Receptor Agonists Arterioscler. Thromb. Vasc. Biol., June 1, 2005; 25(6): 1220 - 1224. [Abstract] [Full Text] [PDF]

				S Soumian, C Albrecht, A. Davies, and R. Gibbs ABCA1 and atherosclerosis Vascular Medicine, May 1, 2005; 10(2): 109 - 119. [Abstract] [PDF]

				J. F.P. Berbee, L. M. Havekes, and P. C.N. Rensen Apolipoproteins modulate the inflammatory response to lipopolysaccharide Innate Immunity, April 1, 2005; 11(2): 97 - 103. [Abstract] [PDF]

				W. Khovidhunkit, M.-S. Kim, R. A. Memon, J. K. Shigenaga, A. H. Moser, K. R. Feingold, and C. Grunfeld Thematic review series: The Pathogenesis of Atherosclerosis. Effects of infection and inflammation on lipid and lipoprotein metabolism mechanisms and consequences to the host J. Lipid Res., July 1, 2004; 45(7): 1169 - 1196. [Abstract] [Full Text] [PDF]

				G. A. Graf, J. C. Cohen, and H. H. Hobbs Missense Mutations in ABCG5 and ABCG8 Disrupt Heterodimerization and Trafficking J. Biol. Chem., June 4, 2004; 279(23): 24881 - 24888. [Abstract] [Full Text] [PDF]

				S. Bas, B. R. Gauthier, U. Spenato, S. Stingelin, and C. Gabay CD14 Is an Acute-Phase Protein J. Immunol., April 1, 2004; 172(7): 4470 - 4479. [Abstract] [Full Text] [PDF]

				L. Liu, A. E. Bortnick, M. Nickel, P. Dhanasekaran, P. V. Subbaiah, S. Lund-Katz, G. H. Rothblat, and M. C. Phillips Effects of Apolipoprotein A-I on ATP-binding Cassette Transporter A1-mediated Efflux of Macrophage Phospholipid and Cholesterol: FORMATION OF NASCENT HIGH DENSITY LIPOPROTEIN PARTICLES J. Biol. Chem., October 31, 2003; 278(44): 42976 - 42984. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: M300100-JLR200v1 44/9/1728    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Khovidhunkit, W. Articles by Feingold, K. R. Search for Related Content PubMed PubMed Citation Articles by Khovidhunkit, W. Articles by Feingold, K. R. Social Bookmarking                      What's this?