Published online before print September 8, 2005, doi: 10.1161/01.ATV.0000185834.98941.3d
© 2005 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Probucol Enhances the Expression of Human Hepatic Scavenger Receptor Class B Type I, Possibly Through a Species-Specific Mechanism
From the Department of Metabolic Medicine (K.H., C.I., K.T., Z.Z., F.M., Y.-N.T., M.K., D.M., T.M., I.S., S.Y.), Graduate School of Medicine, Osaka University, and the Horizontal Medical Research Organization (Y.U.), Graduate School of Medicine, Kyoto University, Japan.
Correspondence to Ken-ichi Hirano, MD, PhD, Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan. E-mail khirano{at}kb3.so-net.ne.jp
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Abstract |
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Objective— Scavenger receptor class B type I (SR-BI) is a major receptor for high-density lipoproteins (HDL) in the liver, which is the terminus of reverse cholesterol transport. Overexpression of SR-BI attenuated experimental atherosclerosis in murine models, concomitant with a reduction in plasma HDL-cholesterol levels. Probucol is known to be a potent hypolipidemic drug to regress xanthoma formation and carotid atherosclerosis in conjunction with a marked reduction in HDL-cholesterol levels. The aim of the present study was to know the effect of probucol on the expression of SR-BI and the underlying mechanism.
Methods and Results— We found that probucol increased the expression of SR-BI proteins in in vitro human liver cells and an in vivo rabbit model, but not in wild-type C57Bl6 mice. The decay curve of SR-BI protein was markedly retarded in probucol-treated HepG2 cells in the presence of cycloheximide, indicating that probucol may stabilize human SR-BI protein. To determine the underlying mechanism for the observed species-specific effect, we conducted the following host-swap experiments, in which SR-BI was transfected or expressed in heterologous cells or hosts. Probucol did not increase human SR-BI protein in the liver of transgenic mice carrying the entire human SR-BI genome. Although probucol could stabilize even murine SR-BI, when transfected into a human cell line, HepG2, human SR-BI was not stabilized in a mouse hepatoma cell line, Hepa 1-6, treated with probucol.
Conclusion— Probucol enhances hepatic SR-BI protein expression, possibly through species-specific stabilization of the protein.
Probucol increases hepatic SR-BI, which seems to be attributable to a species-specific stabilization of the protein. Data of host-swap experiments indicate that this effect is unlikely to be the result of a direct interaction between probucol and SR-BI protein, but rather may be related to certain factors in human hepatocytes.
Key Words: atherosclerosis • high-density lipoprotein • probucol • reverse cholesterol transport • scavenger receptor class B type I
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Introduction |
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Reverse cholesterol transport (RCT) is one of the major protective systems against atherosclerosis, in which high-density lipoprotein (HDL) particles play a crucial role as shuttles carrying cholesterol derived from peripheral tissues.1 We have continued to elucidate the molecular mechanism for RCT by analyzing the pathophysiology of patients with abnormal HDL metabolism. It is believed that, in human liver, the terminus of RCT, there are at least 2 distinct pathways for the uptake of HDL-cholesterol. One is the low-density lipoprotein (LDL) receptor pathway where HDL-cholesterol is transferred to LDL by cholesteryl ester transfer protein (CETP), and cholesterol in LDL is taken up by this receptor. The other is an HDL receptor(s)–mediated pathway.2,3
One of the important candidates for hepatic HDL receptor in human is scavenger receptor class B type I (SR-BI).4,5 SR-BI, cloned by Krieger et al, is abundantly expressed in murine liver and mediates the selective uptake of HDL-lipids. Several lines of evidence indicate that this molecule is a physiologically relevant HDL receptor in mice because its hepatic overexpression of this molecule attenuated experimental atherosclerosis in mice, concomitant with a reduction in HDL-C levels and the appearance of smaller sized HDL particles.6,7 Conversely, SR-BI null mice had accelerated atherosclerosis in the apoE-negative background with the appearance of larger sized apo AI-containing particles.8,9
Probucol is a potent hypolipidemic drug, which can reduce Achilles tendon xanthoma in patients with homozygous familial hypercholesterolemia as well as attenuate atherosclerosis in Watanabe heritable hyperlipidemic (WHHL) rabbits.10,11 A unique aspect of this compound is its capability to induce hypoalphalipoproteinemia. We previously reported that probucol treatment induced not only a reduction in HDL-cholesterol levels but also the appearance of smaller-sized HDL particles,12 which very actively promoted cholesterol efflux from the cells.13 We also reported a positive correlation between the reduction in plasma HDL-cholesterol and the reduction rate of Achilles tendon xanthoma.12 However, the mechanism for the reduction of HDL-cholesterol by probucol is not known yet.
The aim of the present study was to determine the effect of probucol on the expression of SR-BI. Because the effect of probucol on atherosclerosis seems to be different among species,14–16 the experimental materials were obtained from different species including human, rabbits, and mice. We found that probucol increased hepatic SR-BI protein in a species-specific fashion. To gain further understanding of the underlying mechanism(s), we conducted the host-swap experiments, in which SR-BI was expressed in heterologous cells or hosts. Results of these experiments indicated that the upregulation of SR-BI by probucol may be attributable to a species- and host-specific stabilization of the protein.
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Materials and Methods |
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Materials
HepG2 and Hepa 1-6 cells were obtained from ATCC and maintained by the standard protocol. Two different lots of cryopreserved hepatocytes were obtained from the hepatocyte bank maintained at In Vitro Technologies (Baltimore, MD). According to information from the company, one donor was a 33-year-old Caucasian male who had died of intracranial hemorrhage. The other was a 23-year-old Hispanic female who died of cerebrovascular accident. The hepatocytes were plated on collagen-coated plates and maintained in a complete medium from In Vitro Technologies. Aprotinin, ALLN, leupeptin, pepstatin, phosphoramidon, lactacystin, and MG125 were purchased from Sigma. The polyclonal antibody against the carboxy terminus of SR-BI was generated, as described previously.17 The antibody against C-terminal linking and modulating proteins (CLAMP) was kindly provided by Dr Hiroyuki Arai (Tokyo University, Tokyo, Japan). Monoclonal antibodies against green fluorescence protein (GFP) (JL8) and glycelaldehyde-3-phosphate dehydrogenase (GAPDH) (6C5) were purchased from BD Biosciences and Research Diagnostic Inc, respectively.
In vitro treatment with probucol, isolation of lipoproteins and modification of HDL, Western blot analyses, synthesis of cDNA and real time polymerase chain reaction (PCR), lipoprotein cell association assay, generation of transgenic mice expressing human SR-BI, animal protocol, construction of GFP-tagged SR-BI plasmid, transfection of plasmid DNA, cycloheximide experiments, primers used, and statistical analyses are described under Materials and Methods section in the online data supplement available at http://atvb.ahajournals.org.
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Results |
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Probucol Increased SR-BI Protein in Human Hepatoma Cell Line, HepG2, and Human Hepatocytes
We examined the in vitro effect of probucol on the expression of SR-BI proteins in the human hepatoma cell line, HepG2 (Figure 1A), and cryopreserved hepatocytes (Figure 1B). The addition of probucol to the media increased SR-BI protein in a dose-dependent manner (solid Bars in Figure 1A and 1B). The SR-BI mRNA levels were not apparently changed in either HepG2 cells or cryopreserved hepatocytes (hatched bars in Figure 1A and 1B). Figure 1C shows the effect of probucol on the uptake of DiI-labeled HDL (upper panel) and selective uptake of HDL-lipids (lower panel) in the HepG2 cells. Fluorescent microscopy showed an increased amount of uptake of Dil-HDL in cells treated with probucol, whereas the uptake of 3H cholesteryl oleate was significantly increased by the addition of probucol to the media. In contrast, the amount of cell-associated 125I-HDL was not changed. These findings suggest that probucol increased the selective uptake of HDL-lipids, which is known to be mediated by SR-BI, and this increase appeared consistent with that reported previously by Pfeuffer et al.18
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In Vivo Effect of Probucol on the Expression of SR-BI in Rabbit and Mouse Models
We examined the in vivo effect of probucol on the expression of SR-BI in Japanese white rabbits and wild type C57Bl6J mice. Before the analyses of rabbit SR-BI (rSR-BI), its tissue distribution was investigated with a RNase protection assay. mRNA expression of rSR-BI was abundant in the liver and adrenal glands and very similar to the patterns of tissue distribution reported Ritsch et al19 (data not shown). Rabbits were kept for 1 month on normal chow diet either with or without 1% probucol. In the animals treated with probucol, plasma HDL-cholesterol levels were significantly reduced during the treatment (15.8±1.4 versus 12.2±2.3 mg/dL, P<0.05, paired t test). The expression of rSR-BI protein was markedly elevated (P<0.01), as shown in Figure 2A. The mRNA expression of rSR-BI tended to increase, but not to a statistically significant extent. (Figure 2B). Next, we tested the in vivo effect of probucol on the expression of SR-BI in mice. After a 2-week treatment with 5% probucol, the expression levels of murine SR-BI protein had not changed (Figure 2C), which was consistent with the findings reported by Rinninger et al.20
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These results indicate that probucol may increase hepatic SR-BI protein without apparent changes in its mRNA expression levels in humans or rabbits. On the other hand, this effect was not observed in probucol-treated wild-type mice. These effects may therefore be species-specific.
Probucol May Stabilize SR-BI Protein in HepG2 Cells
We next used HepG2 cells as a model to investigate the underlying mechanism for upregulation of SR-BI by probucol. Because SR-BI mRNA levels were not apparently altered in the HepG2 cells, human cryopreserved hepatocytes, or rabbit liver, we focused on the posttranscriptional regulation of SR-BI by probucol. To determine whether SR-BI protein is regulated by its proteolytic and proteasomal degradation, we tested the effect of various kinds of protease and proteasome inhibitors on the basal levels of SR-BI protein in HepG2 cells. As shown in Figure 3A (left panel), some of the inhibitors, including aprotinin, leupeptin, and pepstatin, seemed to increase the protein levels of SR-BI, but N-acetyl-leucyl-leucyl-norleucinal (ALLN) did not increase the SR-BI protein in the experiment. Proteasome inhibitors such as lactacystin and MG132 reduced SR-BI protein levels. We confirmed that apoB protein was increased by ALLN (data not shown). On the basis of these findings, we tested the hypothesis that probucol may stabilize the SR-BI protein by analyzing SR-BI with immunoblotting in the presence of cycloheximide. A decrease in SR-BI was apparent at 4 hours, and SR-BI continued to decay up to 8 hours (Figure 3B, left panel). The treatment with probucol clearly slowed down the rate of SR-BI degradation (Figure 3B, right panel). It is noted that GAPDH proteins were not decreased up to 8 hours in these experiments.
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Figures 1 through 3
demonstrate that probucol increased hepatic SR-BI protein, which may be species-specific. In the HepG2 cells treated with probucol, the degradation of SR-BI was apparently delayed, which may account for the increased levels of SR-BI proteins. This finding led to the question whether or not probucol directly affects the SR-BI genome or protein itself, or some related genes and proteins, or both. To address this issue, we have conducted the following host-swap experiments, in which SR-BI was transfected or expressed in heterologous cells or hosts.
Host-Swap Experiment 1
In Vivo Effect of Probucol on Human SR-BI Expressed in Mice
The first experiment was designed to test the in vivo effect of probucol on human SR-BI in mouse. For that purpose, we generated mouse lines expressing the entire human SR-BI genome in the murine SR-BI–/– background (Human SR-BI BAC Tg/mSR-BI–/– mice). In this model, the expression of human SR-BI was regulated by its own promoter. The mice were treated for 2 weeks with diets containing 5% probucol. As shown in Figure IA (available online at http://atvb.ahajournal.org), human SR-BI mRNA was clearly detected with the hSR-BI riboprobe by RNase protection assay and showed no difference of SR-BI mRNA between the probucol and control groups. Figure IB and IC shows the expression of human SR-BI protein in whole cell lysates as well as the cytoplasmic and membrane fractions, indicating no apparent difference of SR-BI protein levels between the probucol and control groups. These results indicated that probucol did not increase human SR-BI protein levels in mice, suggesting that the increase in SR-BI protein observed in the probucol-treated HepG2 cells and human cryopreserved hepatocytes may not have been caused by the direct or sole effect of probucol on the human SR-BI genome or the protein itself.
Host-Swap Experiment 2
Cycloheximide Experiments for Human and Mouse SR-BI Expressed in Heterologous Cells
We next examined the in vitro effect of probucol on SR-BI expressed in the heterologous cells. For this experiment, we generated the GFP-tagged constructs for human and murine SR-BI. As shown in Figure IIA (available online at http://atvb.ahajournal.org), we tested the expression of GFP-human SR-BI and GFP-murine SR-BI constructs which were transfected into HepG2 cells. Western blot analyses clearly indicated that GFP-tagged proteins were successfully expressed in HepG2 cells. We confirmed the expression of these constructs in the murine hepatoma cell lines, Hepa 1-6 (data not shown). As shown in Figure IIB, DiI-labeled HDL was significantly taken up by cells expressing GFP-tagged human and murine SR-BI. Figure IIC illustrates the uptake of radiolabeled HDL in cells transfected with GFP-hSR-BI and mSR-BI, showing that the cells expressing GFP-SR-BI chimeric proteins achieved significant selective uptake of HDL-lipids.
We finally tested the degradation of SR-BI proteins expressed in heterologous cells. The human or mouse GFP-SR-BI constructs were transfected into either of HepG2 or Hepa 1-6 cells, the latter is a murine hepatoma cell line, and the cycloheximide experiments were performed in cells treated with or without probucol. GFP-human SR-BI expression was not stabilized in the probucol-treated Hepa 1-6 cells (Figure 4A). On the other hand, when murine SR-BI was expressed in the human hepatoma cell line HepG2, probucol clearly slowed down the decay of endogenous human SR-BI and GFP-murine SR-BI proteins (Figure 4B). We also confirmed that GFP-mouse SR-BI was not stabilized in Hepa 1-6 cells, whereas GFP-human SR-BI was stabilized in Hep G2 cells (data not shown).
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The results of these 2 host-swap experiments led us to conclude that probucol may stabilize the hepatic SR-BI protein, possibly through host-specific or species-specific mechanism(s). The probucol-induced upregulation did not seem to be caused by the direct effect of probucol on the human SR-BI genome or protein itself, so that it is more likely that probucol may affect some factors existing in human liver cells, which regulate the protein levels of SR-BI. Because it was recently reported that CLAMP/PDZK1 is one of the crucial regulators for the expression of SR-BI,21,22 we examined the effect of probucol on the expression of CLAMP/PDZK1 in HepG2 cells, showing no significant changes in either the mRNA or protein levels of this molecule (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The present study for the first time demonstrates that probucol increases the expression of SR-BI proteins in human liver cells and rabbit liver. This effect seems to be species-specific, because probucol did not increase SR-BI protein in wild-type mice. Our data also indicate that the probucol-induced increase in the SR-BI protein may be caused by the slow decay of the protein. Growing evidence has established that overexpression of SR-BI attenuated atherosclerosis in many murine models.6–9 It is obvious that SR-BI is an essential molecule that determines plasma HDL-cholesterol levels and atherogenicity in these species. Therefore, this molecule is an important target for the enhancement of reverse cholesterol transport in humans. The present data indicates that the stabilization of SR-BI may be a potentially important strategy to be considered.
The initial part of this study clearly indicated that the upregulation of SR-BI by probucol may occur at posttranscriptional levels. Many literatures reported that the SR-BI protein seems to be tightly regulated at posttranscriptional levels, with an underlying mechanism that seems very complicated. SR-BI protein levels were altered without changes of its mRNA in apoE-knockout mice,23 vitamin E–fed rodents,24 and nephrotic rats.25 CLAMP/PDZK1 was reported to bind with SR-BI and regulate its cell surface expression.21,26 Gene targeting of CLAMP/PDZK1 diminished hepatic expression of SR-BI in mice.22 The small PDZK1-associated protein (SPAP/DD96/MAP17) which binds with CLAMP/PDZK1 was reported to regulate SR-BI protein expression in mice.27 As mentioned in the text, probucol treatment did not alter the mRNA and protein levels of CLAMP/PDZK1 in the HepG2 cells. Because Kodama and Noguchi et al reported that probucol regulated some proteasome gene and proteins in human endothelial cells,28 we tested the effect of some proteasome inhibitors on the expression of SR-BI in HepG2 cells. Because the proteasome inhibitors used did not increase the SR-BI protein levels, the upregulation of SR-BI by probucol may be independent of proteasomes. Although we could not clarify the precise mechanism, our study raised the following questions. Does it involve the generation of species-specific biologically active probucol derivatives or the existence of species-specific molecular and/or biochemical targets for probucol? The answers to these questions should be of great importance.
Recently, it has been reported that SR-BI is expressed in other tissues than the liver. We and others reported that SR-BI is expressed in foam cells in the human atherosclerotic lesions17,29 as well as smooth muscle cells in vitro.30 Yuhanna et al reported that SR-BI expressed in endothelial cells may play some roles in regulating nitric oxides.31 We and others reported that SR-BI is expressed in the human central nervous system.32,33 It would be of interest to know the effect of probucol on the expression of SR-BI in these kinds of cells and tissues.
Administration of probucol to both humans and animals has been shown to lower HDL-cholesterol levels. However, various different mechanisms could be responsible for probucol-mediated reduction of HDL-cholesterol. It was found that the particle size of HDL particles becomes smaller in patients and animals treated with probucol.12,34 Such small HDL particles are very active for cholesterol efflux from the cells,13 which may lead to the regression of foam cells and xanthomas.10 On the other hand, Yokoyama and others reported that probucol inhibited apoAI-mediated cholesterol efflux at least in vitro without the alteration of ABCA1 protein levels,35–37 which may lead to a reduction in the production of nascent HDL particles in vivo. In the present study, we clearly demonstrated that probucol may increase the expression of SR-BI protein in liver cells, possibly in a species-specific fashion. Recently, we demonstrated that SR-BI is expressed in human hepatic parenchymal cells by means of immunohistochemical analyses.38 We therefore concluded that the overexpression of SR-BI produced by probucol may at least partially explain the low HDL-cholesterol levels observed in patients treated with this drug.
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Acknowledgments |
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This work was partially supported by a research grant from Daiichi Pharmaceutical Co (Tokyo, Japan) for K. Hirano and S. Yamashita. This work was supported by grants-in-aid to S. Yamashita (No.07557074, No. 08671157) from the Ministry of Education, Science, Sports, and Culture of Japan. The authors gratefully thank for Dr Yuji Matsuzawa for critical discussions at the early stage of this project, Professor Hiroyuki Arai for providing the antibody against CLAMP, and Chiho Hosono for her skillful technical assistance.
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Footnotes |
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K.H. and C.I. contributed equally to this work.
Received February 12, 2005; accepted August 18, 2005.
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