© 2001 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Effect of Probucol in Lecithin-Cholesterol Acyltransferase–Deficient Mice
Inhibition of 2 Independent Cellular Cholesterol–Releasing Pathways In Vivo
From the Departments of Biochemistry 1 (S.T., M.T., S.Y.) and Internal Medicine 1 (S.T., T.F., S.I., M.I.), Medical School, and the Department of Pathology (T.T.), School of Nursing, Nagoya City University, Nagoya; the Laboratory of Chemistry (M.O.), College of Liberal Arts and Science, Tokyo Medical and Dental University, Ichikawa; and the School of Allied Health Science (S.U.), Tokyo Medical and Dental University, Tokyo, Japan.
Correspondence to Shinji Yokoyama, MD, PhD, FRCPC, Biochemistry 1, Nagoya City University, Kawasumi 1, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan. E-mail syokoyam{at}med.nagoya-cu.ac.jp
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Abstract |
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Abstract—Cellular cholesterol release takes place by at least 2 distinct mechanisms: the lecithin-cholesterol acyltransferase (LCAT)-driven net efflux by cholesterol diffusion and the generation of high density lipoprotein (HDL) with cellular cholesterol and phospholipid on the cell-apolipoprotein interaction. Therefore, LCAT deficiency impairs the former pathway, and the latter can be inhibited by probucol, which interferes with the apolipoprotein-cell interaction. Hence, probucol was given to the LCAT-deficient mice in the attempt to suppress both of these pathways. The mice were fed low (0.2%) and high (1.2%) cholesterol diets containing 0.5% probucol for 2 weeks. LCAT deficiency and probucol markedly decreased plasma HDL, and the effects were synergistic. Tissue cholesterol content was lower in the adrenal glands and ovaries in the LCAT-deficient mice and in the probucol-treated mice, suggesting that HDL is a main cholesterol provider for these organs. It was also moderately decreased in the spleen of the low cholesterol–fed female mice and in the thyroid gland of the low cholesterol–fed male mice. On the other hand, the esterified cholesterol content in the liver was substantially increased by the probucol treatment with a high cholesterol diet in the LCAT-deficient mice but not in the wild-type mice. Among the groups, there was no significant difference in the tissue cholesterol levels in other organs, such as the liver, spleen, thymus, brain, erythrocytes, thyroid gland, testis, and aorta, resulting from either LCAT deficiency or probucol. Thus, the apolipoprotein-mediated mechanism plays a significant role in the export of cellular cholesterol in the liver, indicating that the liver is a major site of the HDL assembly. Otherwise, tissue cholesterol homeostasis can largely be maintained in mice even when the assembly of new HDL is inhibited by probucol in the absence of LCAT. Nonspecific diffusion of cholesterol perhaps adequately maintains the homeostasis in the experimental condition.
Key Words: high density lipoproteins • lecithin-cholesterol acyltransferase • cholesterol efflux • cholesterol homeostasis • probucol
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Introduction |
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High density lipoprotein (HDL) is given a key role in the hypothesis of a cholesterol transport pathway from the peripheral tissues to the liver. The physiological importance of this transport system lies in the fact that cholesterol is not catabolized in the peripheral tissues and must be transported to its catabolic sites, mainly, the liver (for its conversion to bile acids) and, to a much lesser extent, the steroidogenic cells. The hypothesis is extended to the "antiatherogenic" function of this transport pathway, which is based on experimental data indicating that HDL removes the accumulated cholesterol from the cells in vitro1 and epidemiological evidence indicating that the plasma HDL level is negatively correlated with the risk of coronary heart disease.2
The most critical biological step of this pathway is the release of cholesterol from the cells. At least 2 distinct mechanisms are identified for this reaction: (1) spontaneous cholesterol efflux by diffusion through the aqueous phase in which lecithin-cholesterol acyltransferase (LCAT)-mediated extracellular cholesterol esterification is a driving force for the net efflux and (2) apolipoprotein-cell interaction to generate new HDL particles with cellular cholesterol and phospholipid.3 Both mechanisms seem to function in maintaining the plasma HDL level, inasmuch as the genetic defect of LCAT results in low HDL in human patients4 and in gene-manipulated mice,5 6 and low HDL is caused by the impairment of the apolipoprotein-mediated generation of HDL in probucol-treated animals7 8 9 and in patients with Tangier disease, in whom the ATP-binding cassette transporter 1 (ABC1) is mutated.10 11 12 13 14 15 16 17 The 2 systems apparently back up each other so that neither LCAT deficiency nor Tangier disease produces general or serious cholesterol accumulation in the tissues, except for a few specific organs in each disease.4 18 Therefore, the following is an important physiological question: what is the proportional contribution of the LCAT-mediated net cholesterol efflux and the apolipoprotein-mediated HDL generation in cellular cholesterol homeostasis in vivo? The answer to this question may also provide us with a view about the major source organs for plasma HDL cholesterol.
LCAT deficiency causes severe reduction of plasma HDL in mice. Cholesterol content in the steroidogenic cells is markedly reduced in these animals, perhaps because of the low delivery of esterified cholesterol from HDL via scavenger receptor B1 (SRB1).6 19 On the other hand, probucol has been shown to interfere with apolipoprotein-cell interaction and inhibit the generation of HDL in vitro.7 This compound severely reduced plasma HDL in mice by this mechanism without changing other factors in the regulation of plasma HDL levels, such as the message levels of apoA-I, apoE, LCAT, SRB1, phospholipid transfer protein, and ABC1 and the fractional clearance rate of plasma cholesteryl ester and cholesteryl ester transfer protein,9 which is consistent with the findings in patients with Tangier disease.18 On the basis of these findings in the animal models, probucol was given to the LCAT-deficient mice in an attempt to inhibit the 2 systems for cellular cholesterol removal simultaneously.
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Methods |
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Animals
The LCAT-deficient DBAxC57BL/6 mice [Lcat(-/-) mice] were kindly provided by Dr E. Rubin at Laurence Berkeley Laboratory (Berkeley, Calif).6 The control wild-type DBAxC57BL/6 mice [Lcat(+/+) mice] were purchased from the local experimental animal supplier. The Lcat(-/-) mice were bred with the Lcat(+/+) mice in the Animal Experimental Laboratory of Nagoya City University Medical School, Nagoya, Japan. The newborn mice were weaned and sexually segregated at 3 weeks. The Lcat(-/-), Lcat(+/-), and Lcat(+/+) mice were identified at 5 weeks by the multiplex polymerase chain reaction genotype analysis of the tail genomic DNA.6 The forward primers either hybridize specificity to the neo-resistant gene (5'-AAGCAAAACCAAATTAAGGGC-3') or to the targeted region (5'-GCTCCTCAATGTGCCTTCC-3') and share a common reverse primer that hybridizes to exon 3 of the LCAT gene (5'-GTACTCAACAGATTCGGTCTTGC-3').
LCAT Assay and Plasma Lipoprotein
Analysis
One hundred microliters of blood was collected from
the caudal vein of the mice at 8 weeks. A 30 µL aliquot was mixed
with 30 µL of 1.3 mmol/L EDTA. The diluted blood (45 µL) was
further diluted with 405 µL of 10 mmol/L sodium phosphate buffer
(pH 7.4) containing 0.15 mol/L NaCl and 0.5 mmol/L EDTA (PBS).
Blood cells were removed by centrifugation, and 200
µL of the diluted plasma was removed for the analysis of
lipoproteins by a high-performance liquid
chromatography (HPLC) system with 4 tandem gel
permeation columns (TSK gel Lipopropak XL, 7.5 mmx300 mm,
Tosoh Co, Tokyo, Japan) and an online enzymatic detection system
for total
cholesterol.20
The remaining 70 µL of blood was mixed with 10 µL of 0.5 mol/L EDTA
and centrifuged to obtain the plasma. Agarose gel
electrophoresis was performed for the lipoprotein analysis with
the 3 µL plasma in a Beckman LIPO system stained with Sudan black.
For the LCAT activity assay, substrate lipoprotein was prepared by
sonication of 30 mg human HDL apoprotein with 30 mg egg
phosphatidylcholine, 18 mg cholesterol, and 50 µCi
[14C]cholesterol in 60 mL PBS
for 30 minutes under argon.21
The substrate solution, 100 µL, was preincubated with 25 µL of the
5% BSA solution and 25 µL of 32 mmol/L ß-mercaptoethanol at
37°C for 15 minutes and then incubated with 20 µL of the mouse
plasma at 37°C for 1 hour. The reaction was terminated by adding 600
µL of chloroform:methanol (2:1), and the organic fraction was
analyzed by thin-layer chromatography to detect
the radioactivity in cholesterol and cholesteryl ester by
an imaging scanner (Fuji Film BAS-2500). For the mouse plasma whose
LCAT activity was measured, the HDL cholesterol
concentration was determined as the bottom fraction of the
ultracentrifugal separation at 1.21 g/mL in a Hitachi GX Micro
Ultracentrifuge.
Probucol Treatment
Probucol [4,4'-(isopropylidenedithio)bis(2,
6-di-tert-butylphenol)] was a
gift from Daiichi Pharmaceutical Co (Tokyo, Japan). Mouse basal
growth chow containing 2.0 mg or 12.0 mg cholesterol per
gram (low and high cholesterol diets, respectively) was
mixed with probucol (0.5% by weight) and was made into pellets (Chubu
Kagaku Shizai Co Ltd). The
Lcat(+/+) and
Lcat(-/-) mice were each
divided into 4 groups at 8 weeks and fed either a low or high
cholesterol diet with or without probucol for 2 weeks. The
uptake of food and probucol was monitored by weighing the remaining
chow, and the animals were weighed weekly. The environment was
controlled at 25°C with a light cycle of 12-hour daylight and
darkness, and the animals had free access to water and
food.
Plasma and Tissue
Cholesterol Analysis
At the end of the 2-week feeding experiment, 30 µL
of blood was collected from the mouse eye orbit, and plasma lipoprotein
cholesterol was analyzed by HPLC as described
above. After exsanguination by cardiac puncture, the whole animal body
was perfused with PBS by infusing the buffer into the heart. The
animals were euthanized by cervical dislocation, and the major organs
were removed and mechanically homogenized. The free and
esterified cholesterol content in these tissue samples was
determined by an enzymatic method for total and free
cholesterol after the extraction of lipid with the organic
solvent.
The experimental procedures described above were approved by the institutional animal care and research advisory committee.
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Results |
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The Lcat(+/+), Lcat(+/-), and Lcat(-/-) mice were identified by genotyping by means of the multiplex polymerase chain reaction (Figure 1
, which can be accessed online at
http://atvb.ahajournals.org). Plasma LCAT activity was 15.87±6.13,
12.65±4.30, and 0.8±0.92 nmol/mL per hour in the
Lcat(+/+),
Lcat(+/-), and
Lcat(-/-) mice,
respectively. The activity of the
Lcat(+/-) mice was lower than
the level of the wild-type mice but not to statistical significance
(online Figure 1). Plasma lipoprotein profiles by HPLC of the mice fed
the low cholesterol diet are shown in online Figure 1. The
level of HDL is a function of the plasma LCAT activity and so is LDL.
VLDL seems to be increased in the
Lcat(-/-) mice.
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The body weight, cholesterol, and probucol
intake of the mice in each feeding group are listed in the
Table.
There is no significant change in these parameters after
the 2-week probucol treatment among the 16 feeding groups.
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The effects of probucol on the lipoprotein profiles are
shown in Figures 2 and 3 (which can be accessed online at
http://atvb.ahajournals.org). Figure 2 represents agarose gel
electrophoresis of the plasma of the mice fed the low
cholesterol diet. Probucol caused marked decrease of HDL
and LDL in the Lcat(+/+) and
Lcat(-/-) mice. Figure 3
demonstrates the quantitative lipoprotein profile by HPLC in terms of
lipoprotein cholesterol. The same effect was observed in
the high cholesterol– and low cholesterol–fed
animals.
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Because the HDL level is already very low in the
Lcat(-/-) mice, the effect
of probucol on the HDL level was further analyzed as a function
of the plasma LCAT activity. As shown in
Figure 1
, the HDL concentration correlated with the LCAT
activity in the control and probucol-fed groups regardless of the LCAT
genotypes. The slope of the linear regression was lower with
the probucol-fed group, indicating that probucol decreased the plasma
HDL level independently of the LCAT activity in plasma.
Tissue cholesterol content was
analyzed in the male and female mice with respect to the LCAT
mutation, the probucol treatment, and high and low
cholesterol diet. In the female mice
(Figure 2), the cholesteryl ester content markedly decreased
in the ovaries and adrenal glands, presumably because of the reduction
of plasma HDL resulting from LCAT deficiency and/or from probucol
treatment in the high cholesterol– and low
cholesterol–fed groups. In the high
cholesterol–fed group, unesterified
cholesterol in the adrenal glands of the
Lcat(-/-) mice was further
decreased by probucol. There was also a decrease of unesterified and
esterified cholesterol in the spleen brought about by
lowering HDL in the low cholesterol–fed group. A
nonsignificant decrease of unesterified cholesterol brought
about by lowering HDL was observed in the thyroid glands of the low
cholesterol–fed group. In the high
cholesterol–fed group, a significant increase of
esterified cholesterol was observed in the liver, which was
brought about by probucol treatment of the
Lcat(-/-) mice. Examination
of the aorta demonstrated no significant deposition of lipid by lipid
staining with oil red O (data not shown) regardless of the
Lcat expression and the
probucol treatment. Cholesterol contents of the aortic wall
measured for the mice fed 0.2% cholesterol were 14.2±7.1
(n=3), 13.1±4.3 (n=3), 18.8±3.2 (n=2), and 17.9±4.1 (n=2) mg/g
tissue protein for Lcat(+/+)
probucol(-), Lcat(+/+)
probucol(+), Lcat(-/-)
probucol(-), and
Lcat(-/-) probucol(+),
respectively, showing no differences among the groups
either.
The reduction of cholesterol content in
the adrenal glands brought about by LCAT deficiency was more prominent
in the male mice
(Figure 3) than in the female mice. In addition to this
reduction, there was another effect of probucol in the male. Esterified
cholesterol was significantly decreased in the testis by
the lowering of HDL in the high cholesterol–fed mice. The
decrease in unesterified cholesterol brought about by
lowering HDL was significant in the thyroid gland of the low
cholesterol–fed group. The increase of esterified
cholesterol was again observed in the liver of the high
cholesterol–fed group after probucol treatment of the
Lcat(-/-)
mice.
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Discussion |
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Two distinct mechanisms are known for cellular cholesterol release.3 In 1 of these pathways, LCAT is believed to be a driving force for net cholesterol removal from cells.22 It creates and maintains the gradient of cholesterol content between the lipoprotein surface and cell membrane; therefore, the net flow of cholesterol is generated through its bidirectional diffusion through the aqueous phase. LCAT functions by decreasing the cholesterol influx from lipoproteins to the cells and by increasing the efflux only when cholesterol diffusion from the cell membrane is high enough not to limit the rate of the flow.23 LCAT reaction may not be the absolute requirement for the net release of cholesterol by diffusion, but it is necessary to synthesize mature and stable HDL with a core of esterified cholesterol. Therefore, the lack of LCAT activity results in reduction of the plasma HDL level.4 6
The other pathway is the assembly of HDL particles mediated by apolipoprotein-cell interaction brought about by removing cellular cholesterol and phospholipid.24 This pathway requires an apolipoprotein interaction site on the cell surface to generate HDL with cellular phospholipid,25 signal transduction to initiate the mobilization of intracellular cholesterol,26 and a specific intracellular cholesterol transport system for the HDL assembly.26 Probucol, which reduces plasma HDL, has been shown to interfere with the cell-apolipoprotein interaction to inhibit the generation of HDL in vitro7 8 and in vitro9 and to induce tissue cholesterol accumulation in a certain strain of mouse.27 Tangier disease was shown to be caused by the impairment of the apolipoprotein-cell interaction to generate HDL,10 11 and the causative mutations were identified in the genes of ABC1 for Tangier disease and other types of familial HDL deficiency.12 13 14 15 16 17 Thus, the apolipoprotein-cell interaction was shown to be a major source of plasma HDL.
Patients with LCAT deficiency exhibit cholesterol accumulation only in certain organs, such as erythrocytes and the cornea.4 Chronic renal problems may develop only later in their lives. Thus, cholesterol efflux is impaired in this disease in only the organs that might lack the other system, the apolipoprotein-cell interaction. As a matter of fact, erythrocytes lack this reaction, and no HDL is generated with apolipoprotein.23 25 On the other hand, patients with Tangier disease may suffer from cholesterol accumulation in certain organs, namely, in the reticuloendothelial system, such as the tonsils and spleen.18 Thus, the 2 systems seem to back up each other to maintain cellular cholesterol homeostasis. There seems to be a variation in the relative dependency of cellular cholesterol homeostasis on the 2 distinct cholesterol release pathways among the various organs and types of cell. Therefore, it is an important and relevant to ask how these 2 systems contribute to the cholesterol homeostasis in different organs in vivo.
To determine this, we used 2 animal models: (1) LCAT
deficiency, in which at least the LCAT-driven net
cholesterol efflux through the diffusion is impaired, and
(2) probucol treatment, which inhibits apolipoprotein-cell interaction
and the subsequent HDL generation. In addition, probucol was given to
LCAT-deficient animals in the attempt to inhibit both the potential
cell cholesterol removal mechanisms. Probucol induced the
reduction of HDL, which was independent of the LCAT activity in plasma
(Figure 1).
Conclusions were as follows: (1) There was a marked reduction of cholesterol in certain organs brought about by LCAT deficiency and by probucol treatment. The effects were synergistic in the adrenal glands. (2) Cholesterol was increased by simultaneous inhibition of the 2 pathways in only the livers of the high cholesterol–fed mice.
In the mice, steroidogenic cells were shown to depend
heavily on HDL for their sources of cholesterol
(Figures 2 and 3). This is consistent with previous
reports that SRB1 is responsible for the uptake of HDL cholesteryl
ester as a major source of cholesterol in these organs in
mice.6 19 The
reduction of cholesteryl ester was greater in the adrenal glands than
in other steroidogenic organs, such as the ovaries or testes, and the
synergistic effect of the LCAT defect and probucol treatment was
demonstrated only in the adrenal glands of mice fed a high
cholesterol diet. This shows that the adrenal glands are
more sensitive to the plasma HDL levels with respect to the external
cholesterol supply.
More important, the liver demonstrated the increase of cholesteryl ester by probucol in the high cholesterol–fed LCAT-deficient mice. This indicates that inhibition of HDL neogenesis caused the cholesteryl ester accumulation in the cholesterol-loaded liver in the absence of an LCAT reaction. Thus, HDL assembly with apolipoproteins is 1 of the major cholesterol release pathways in the mouse liver. This result also suggests that the liver is a major source of plasma HDL supply in mice.
Surprisingly, there was no other drastic change in the tissue cholesterol by inhibiting the 2 cholesterol release mechanisms, even after the HDL levels became virtually zero by giving probucol to the Lcat(-/-) mice. This fact indicates that cellular cholesterol homeostasis can well be maintained even without LCAT and the apolipoprotein-mediated HDL generation on a short-term basis. Even in the erythrocytes, where significant cholesterol accumulation is usually observed in humans with LCAT deficiency, cholesterol accumulation was not visible even in the high cholesterol–fed Lcat(-/-) mice. This is probably due to the efficient nonspecific diffusion from the cells of cholesterol molecules, which can substantially be picked up by albumin, globulin, and other potential "acceptors." However, the long-term influence of such an environment for the cells may not be completely healthy and may raise the risk for many disorders, including atheromatous vascular lesions.
Probucol has been a controversial drug for a long time. It has been known for a specific effect of reducing skin xanthoma in patients with familial hypercholesterolemia despite the decrease of HDL28 and also for the prevention of atherogenesis in hypercholesterolemic experimental animals.29 30 These effects are thought to be due to its strong antioxidative activity and hydrophobic nature, which prevent LDL-lipid oxidation. It has also been implicated that this compound has an anti-inflammatory effect, the prevention of cell proliferation.31 However, under certain conditions, opposite observations have been reported; in mice, probucol has been shown to induce the deposition of cholesterol in tissues.27 32 The controversy may be related to the balance between the antioxidative and anti-inflammatory actions of the drug and its strong HDL-reducing effect.33 Therefore, the effect of probucol on tissue cholesterol accumulation may have to be evaluated carefully. In the context of the dual effect of probucol, the lack of general cholesterol accumulation in the tissues may have resulted in part from such antioxidative or anti-inflammatory effects. Also, if cholesterol is substantially provided by the HDL-SRB1 pathway not only to the specific steroidogenic organs but also to other tissues in mice, low HDL itself may also contribute to the prevention of cholesterol accumulation in the tissues.
Tissue cholesterol deposit varies by mouse strains, and the C57BL/6 strain is known for the induction of cholesterol deposit by probucol.27 The LCAT-deficient mice used in the present study were DBAxC57BL/6, and the behavior of this mixed strain was apparently different from that of the C57BL/6 strain with respect to the response to probucol. Thus, the use of a strain more susceptible to tissue cholesterol accumulation may yield a more distinct outcome.
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Acknowledgments |
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This work has been supported in part by research funds provided by the Ministry of Science, Education, and Culture, by the Ministry of Health and Welfare, and by the Uehara Memorial Foundation. The authors thank K. Komoriya at Tokyo Medical and Dental University for his contribution to the HPLC analysis of lipoprotein and N. Akita, a summer student from Nagoya City University Medical School, for his contribution to the characterization of the experimental animals.
Received May 4, 2000; accepted September 18, 2000.
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