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J. Biol. Chem., Vol. 277, Issue 25, 22426-22429, June 21, 2002

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Helical Apolipoproteins Stabilize ATP-binding Cassette Transporter A1 by Protecting It from Thiol Protease-mediated Degradation^*

Reijiro Arakawa^§ and Shinji Yokoyama^¶

From  Biochemistry, Cell Biology, and Metabolism, Nagoya City University Graduate School of Medical Sciences, Kawasumi 1, Mizuho-cho, Mizuho-ku, Nagoya, Aichi 467-8601, Japan and the ^§ Research and Development Division, Grelan Pharmaceutical Co., Ltd., Sakaecho 3-4-3, Hamura, Tokyo 205-0002, Japan

Received for publication, March 28, 2002, and in revised form, April 4, 2002

	ABSTRACT

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

ATP-binding cassette transporter (ABC) A1 was increased by apolipoprotein A-I without an increase of its message in THP-1 cells. The pulse label study demonstrated that apoA-I retarded degradation of ABCA1. Similar changes were demonstrated by apoA-II, but the effect of high density lipoprotein was almost negligible on the basis of equivalent protein concentration. Thiol protease inhibitors (leupeptin and N-acetyl-Leu-Leu-norleucinal (ALLN)) increased ABCA1 and slowed its decay in the cells, whereas none of the proteosome-specific inhibitor lactacystin, other protease inhibitors, or the lysosomal inhibitor NH₄Cl showed such effects. The effects of apoA-I and ALLN were additive for the increase of ABCA1, and the apoA-I-mediated cellular lipid release was enhanced by ALLN. The data suggest that ABCA1 is rapidly degraded by a thiol protease(s) in the cells unless helical apolipoproteins in their lipid-free form stabilize ABCA1 by protecting it from protease-mediated degradation.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

Helical apolipoproteins such as apoA-I, apoA-II, apoA-IV, and apoE interact with cell surfaces and generate high density lipoprotein (HDL)¹ by removing cellular phospholipid and cholesterol (1-3). The reaction is recognized as one of the major pathways of cellular cholesterol release along with the diffusion-mediated nonspecific cholesterol efflux (4). Fibroblasts from patients with a genetic defect of plasma HDL lack the interaction with apolipoprotein, indicating that this reaction is a main source of plasma HDL (5, 6). This view is supported by the finding that probucol, which markedly reduces plasma HDL, blocks the cell-apolipoprotein interaction (7-9). Mutations were identified in ATP-binding cassette transporter (ABC) A1 with many HDL-deficient families (10-12), so that this protein is considered as a key for generation of HDL by the apolipoprotein-cell interaction and release of cellular cholesterol by this pathway.

Regulation of ABCA1 expression is primarily by cellular cholesterol level through oxysterol as a ligand for the nuclear receptor liver X receptor (LXR) that acts in a heterodimer with retinoid X receptor (RXR) (13-15). The ligands for RXR (such as retinoids) in this receptor system also up-regulate the ABCA1 gene expression (14, 15). In certain types of cell such as RAW264, cyclic AMP and its analogues markedly increase the ABCA1 message and protein by an unknown mechanism (16, 17). In THP-1 cells, differentiation by phorbol ester induces an increase in ABCA1 message level (18). ABCA1 was found in early and late endosomes so that the lysosomal pathway was suggested for its degradation (19). More recently, proteolytic degradation was indicated as a factor involved in regulation of the cellular level of ABCA1 (20).

	EXPERIMENTAL PROCEDURES

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

Cell Culture-- THP-1 cells were maintained in RPMI 1640 (Iwaki) containing 10% fetal bovine serum (PAA laboratories) in a humidified atmosphere of 5% CO₂ and 95% air. Differentiation of THP-1 monocytes into macrophages was induced by culturing the cells at a density of 3.0 × 106 cells/well in a six-well plate in the presence of 3.2 × 10⁷ M phorbol 12-myristate 13-acetate (PMA) (Wako Pure Chemical) for 72 h (18). The differentiated and undifferentiated cells were cultured in RPMI 1640 and 0.2% bovine serum albumin (BSA) for 24 h and then used for the experiments. ABCA1 expression was enhanced by 4 µg/ml 9-cis-retinoic acid (Wako) in some occasions throughout the incubation.

Preparation of Cell Membrane-- The cells were cultured in 0.2% BSA/RPMI 1640 for 24 h. After incubation with apoA-I, apoA-II, or HDL (all prepared from fresh human plasma) and/or protease inhibitors including N-acetyl-Leu-Leu-norleucinal (ALLN), aprotinin, pepstatin A, leupeptin, phosphoramidon (all purchased from Sigma), and lactacystin (Wako), the cells were harvested and suspended in 5 mM Tris-HCl buffer (pH 8.5) containing 1% protease inhibitor cocktails (Sigma) and placed on ice for 30 min with occasional mixing by a vortex. The cell suspension was centrifuged at 650 × g for 5 min, and then the supernatant was centrifuged at 105,000 × g for 30 min. Total membrane precipitated was suspended in the same buffer. After determination of protein content by a BCA method (Pierce) the membrane preparations were stored at 80 °C until use.

Immunoblotting of ABCA1-- Total membrane protein (30 µg) was dissolved in 0.9 M urea, 0.2% (v/v) Triton X-100, and 0.1% (w/v) dithiothreitol and supplied with 10% (w/v) lithium dodecylsulfate and then analyzed by electrophoresis in 7% (w/v) polyacrylamide gel containing 0.1% (w/v) sodium dodecylsulfate (SDS) followed by blotting to a polyvinylidene difluoride membrane. The membrane was blocked in 5% skim milk and incubated with rabbit anti-human ABCA1 antisera (21) for 1 h. After washing three times with 0.02 M Tris-buffered saline containing 0.05% Triton X-100 (pH 7.5), the membrane was incubated with horseradish peroxidase-conjugated anti-rabbit IgG antibody for 1 h. ABCA1 was visualized by a chemiluminescence method (ECL Western blotting detection system, Amersham Biosciences).

RNA Extraction and Reverse Transcription-Polymerase Chain Reaction (RT-PCR)-- Total RNA was extracted by a standard acid guanidinium chiocyanate-phenol-chloroform method. Briefly the cells were lysed in the presence of phenol and guanidinium, and RNA was recovered in the aqueous phase with addition of chloroform and by subsequent centrifugation. RNA was precipitated with isopropanol, and the pellet was washed with ethanol and dried. Total RNA content was determined by measuring the optical absorbance ratio at 260/280 nm after the sample was dissolved in diethylpirocarbonate-treated water. First-strand cDNA was synthesized from the total RNA (5 µg) in a SuperScript preamplification system (Invitrogen). The cDNA of ABCA1 was amplified by polymerase chain reaction with primers previously described (18) for 26 cycles using the Taq polymerase (Takara Shuzo). Glyceraldehyde-3-phosphate dehydrogenase cDNA was also amplified as an intracellular standard (18). DNA was visualized by SYBR Gold nucleic acid gel stain after 2% agarose gel electrophoresis.

Labeling of Cellular Protein with ³⁵S-Amino Acid and Immunoprecipitation of ABCA1-- The differentiated cells were cultured in RPMI 1640 without methionine and cysteine (ICN Pharmaceuticals) for 30 min and incubated in the presence of 200 µCi/ml of EXPRE³⁵S³⁵S [³⁵S]-protein labeling mix (PerkinElmer Life Sciences) for a further 2 h. The cells were washed twice with phosphate-buffered saline and incubated for various periods of time in 0.2% BSA/RPMI -1640 supplemented with 2 mM methionine and 2 mM cysteine, which contained 10 µg/ml apoA-I or apoA-II or 50 µM ALLN or lactacystin. Cells were dissolved in 50 mM Tris-HCl (pH 7.5) containing 0.15 M NaCl, 1% (v/v) Triton X-100, 1% (w/v) sodium deoxycholate, 10 mM EDTA, 0.1% (w/v) SDS, and 1% (v/v) protease inhibitor mixture and incubated at 4 °C for 20 min with gentle rotation. The cell lysate was centrifuged at 13,000 × g for 20 min at 4 °C. The supernatant was collected, and protein concentration was measured by BCA method. The lysate samples (500 µg of protein) were pretreated with a 20-µl solution of normal rabbit antibody-protein A-agarose complex at 4 °C for 1 h and then incubated with 20 µl of anti-human ABCA1 rabbit antisera bound to protein A-agarose (Santa Cruz Biotechnology) at 4 °C for 2 h. The samples were washed three times with the lysis buffer and once with phosphate-buffered saline, and they were analyzed by electrophoresis in 7% polyacrylamide gel in the presence of 0.1% SDS. The gels were air-dried, and the ³⁵S-labeled ABCA1 was detected by fluorography at 80 °C (EN-HANCE, PerkinElmer Life Sciences).

Measurement of apoA-I-mediated Cellular Lipid Release-- The differentiated cells were incubated with 10 µg/ml apoA-I in the presence or absence of 50 µM ALLN for 7 h. Lipid in the culture media was extracted with chloroform/methanol (2:1, v/v), and cholesterol and choline/phospholipid were determined enzymatically (Kyowa Medics) (18). The cells were dissolved in 0.1 N NaOH for protein determination by a BCA method.

	RESULTS

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

Expression of ABCA1 was markedly increased in THP-1 cells by PMA-mediated differentiation reflecting the increase of its message demonstrated previously (18) (Fig. 1a). In both the differentiated and undifferentiated stages of the cell, ABCA1 was further increased when the cells were incubated with 9-cis-retinoic acid (Fig. 1b) because its message was amplified by this treatment (Fig. 1c). In any condition described above, treatment of the cells with apoA-I increased ABCA1 (Fig. 1b) without changing its message expression level (Fig. 1c).

View larger version (40K): [in this window] [in a new window]   Fig. 1.   Increase of ABCA1 in THP-1 cells by apoA-I. a, THP-1 cells were treated with PMA for 72 h. ABCA1 was analyzed by immunoblotting in the non-treated undifferentiated cells (undif.) and the PMA-treated differentiated cells (dif). The cells were cultured in 0.2% BSA/RPMI 1640 for 48 h. Total membrane fraction was prepared for the analysis as described under "Experimental Procedures." b, undifferentiated and differentiated cells were stimulated by 9-cis-retinoic acid (9-cis-RA) to enhance ABCA1 expression via the retinoid X receptor (RXR) pathway, and ABCA1 was analyzed in the presence and absence 10 µg/ml apoA-I. The cells were cultured first in 0.2% BSA/RPMI 1640 for 24 h and then in the same medium with or without 10 mg/ml apoA-I for a further 24 h. The media contained 4 µg/ml 9-cis-retinoic acid for stimulation of ABCA1 expression during the these incubations. ABCA1 was analyzed by immunoblotting. c, specific messages of ABCA1 and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were quantitated by RT-PCR.

To examine whether ABCA1 protein level is regulated by its proteolytic degradation, ABCA1 in the differentiated cells was examined in the presence of various protease inhibitors (Fig. 2). Thiol protease inhibitors, leupeptin and ALLN (22), increased ABCA1, whereas other inhibitors, pepstatin A, aprotinin, and phosphoramidon did not (Fig. 2a). On the other hand, none of these inhibitors changed the message of ABCA1 in the cells (Fig. 2b). Neither lactacystin, a proteosome-specific inhibitor (23), nor NH₄Cl, a lysosomal inhibitor, influenced the level of ABCA1 (Fig. 2c).

View larger version (52K): [in this window] [in a new window]   Fig. 2.   Increase of ABCA1 by protease inhibitors. The differentiated THP-1 cells were cultured in 0.2% BSA/RPMI 1640 for 24 h and then incubated in the medium containing protease inhibitors for 1 h. ABCA1 protein (a) and its mRNA (b) were analyzed by immunoblotting and RT-PCR, respectively, as described under "Experimental Procedures." The message of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was analyzed as an internal control. Concentrations of the protease inhibitors are leupeptin (500 µg/ml), ALLN (50 µM), pepstatin A (20 µM), aprotinin (10 µM), and phosphoramidon (250 µg/ml). Effects of lactacystin (1 and 5 µM) and the lysosomal inhibitor NH4Cl (5 mM) on ABCA1 is also shown by immunoblotting (c).

Time-dependent change of ABCA1 is demonstrated in the differentiated THP-1 cells in Fig. 3. Both apoA-I and ALLN caused an increase in ABCA1. The initial rate of the increase was apparently higher with the given dose of ALLN. Because ALLN seemingly damages the cell after several hours as indicated by the detachment of the cell from the culture plates, the time course was unable to continue beyond this period.

View larger version (44K): [in this window] [in a new window]   Fig. 3.   Time-dependent increase of ABCA1 by apoA-I and ALLN in the differentiated THP-1 cells. The cells were cultured in 0.2% BSA/RPMI 1640 for 24 h and then incubated in the presence of apoA-I (10 µg/ml) or ALLN (50 µM). The incubation was terminated, and total membrane was prepared at the indicated incubation time point as described under "Experimental Procedures." ABCA1 was analyzed by immunoblotting.

To confirm that clearance of ABCA1 is retarded by apoA-I, decay of the pulse label in the protein was examined. After pulse labeling of the protein with [³⁵S[Met/Cys, a slow decrease of radioactivity was demonstrated in the immunoprecipitated ABCA1 when apoA-I was present in the medium (Fig. 4a). A similar slow-down effect was also shown by ALLN (Fig. 4b).

View larger version (30K): [in this window] [in a new window]   Fig. 4.   Clearance rate of ABCA1. The differentiated cells were cultured in 0.2% BSA/RPMI 1640 for 24 h. Cells were then incubated in the methionine/cysteine-deficient RPMI 1640 medium for 30 min and pulse-labeled with 200 µCi/ml EXPRE35S35S [35S]-protein labeling mixture for 2 h in the same medium. The cells were washed and incubated in 0.2% BSA/RPMI 1640 containing 10 µg/ml apoA-I or 50 µM ALLN for the periods of time indicated. The cells were lysed, and ABCA1 was immunoprecipitated by the anti-human ABCA1 rabbit antisera and visualized by fluorography to detect its radioactivity as detailed under "Experimental Procedures."

Increase of ABCA1 was demonstrated in a dose-dependent manner on apoA-I and apoA-II (Fig. 5a). On the other hand, HDL did not increase ABCA1 as much as either of its apolipoproteins, apoA-I or apoA-II, on the basis equivalent protein concentrations (Fig. 5a). Retardation of ABCA1 clearance was shown in the presence of apoA-I and apoA-II, but not by HDL (Fig. 5b).

View larger version (29K): [in this window] [in a new window]   Fig. 5.   Dose-dependent effect of apoA-I, apoA-II, and HDL on ABCA1 metabolism. The cells were incubated with apoA-I, apoA-II, or HDL of the indicated amount (as protein), and ABCA1 was analyzed by immunoblotting (a). Decay of the pulse-labeled ABCA1 was also examined in the same condition by an immunoprecipitation technique (b). Details of the method are described under "Experimental Procedures."

ALLN and leupeptin increased ABCA1 even in the presence of apoA-I (Fig. 6). Reflecting these results, the apoA-I-mediated lipid release from THP-1 cells was increased by ALLN (Fig. 6).

View larger version (22K): [in this window] [in a new window]   Fig. 6.   Effect of ALLN on ABCA1/apoA-I-mediated cellular lipid release. The differential cells were incubated with the various protease inhibitors (concentrations indicated in the legend for Fig. 2) in the presence and absence of 10 µg/ml apoA-I for 4 h, and ABCA1 was analyzed by immunoblotting. The release of cellular cholesterol and choline/phospholipid into the medium was measured after a 6-h incubation of the cells in the presence of apoA-I (10 µg/ml), ALLN (50 µM), or both. Lipid data represent the mean ± S.E. of six samples. For cholesterol, both apoA-I and ALLN increased the release significantly in comparison to respective control (p < 0.01 for each case using Student's t test) For phospholipid, apoA-I significantly increased the release from respective control (p < 0.01 for each case using the Student`s t test), but the additional increase of the apoA-I-mediated release by ALLN was insignificant in the experimental condition.

	DISCUSSION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

The results of these experiments are summarized as follows. Degradation of ABCA1 is strongly blocked by the thiol protease inhibitors leupeptin and ALLN (22) so that this protein is very likely catabolized by a thiol protease-mediated pathway such as calpain or cathepsin. Because lactacystin did not influence the level of ABCA1, proteosome may be excluded from the potential pathways responsible for catabolism of ABCA1 (23). It is also unlikely that lysosomal degradation is primarily responsible because the effect of NH₄Cl was negative. Interestingly, apoA-I and apoA-II increased ABCA1 in the differentiated THP-1 cells by retarding its degradation. Thus, helical apolipoproteins in their free form apparently stabilize ABCA1 by protecting it from this protease-mediated catabolic pathway and lead to the increase of the level of this protein in the cells. Inhibition of thiol protease further increases ABCA1 and the apoA-I-mediated cellular lipid release, accordingly.

When apolipoproteins were given as HDL, their effect on ABCA1 stabilization was negligible. This result indicates that lipid-free HDL apolipoproteins are mainly responsible for the ABCA1-related events. A certain small proportion of helical apolipoproteins should always remain in a free form because of the reversible nature of their interaction with lipid surface in the interstitial fluid to which most of cells in the body are directly exposed (24). In addition, an active mechanism(s) by lipid transfer proteins may be involved in the cycling of HDL apolipoproteins between lipid-bound and -free forms (25). However, it is difficult to estimate what proportion of apolipoproteins is actually in a lipid-free form because the parameters that regulate the equilibrium are mostly undetermined. Nevertheless, free helical apolipoprotein concentration is a regulatory factor for stability of ABCA1 and HDL assembly by the apolipoprotein-cell interaction.

The nature of the apolipoprotein-ABCA1 interaction is not fully understood; therefore, the exact mechanism of the protection of ABCA1 by helical apolipoprotein from proteolysis remains to be investigated. It is possible that conformational alteration of ABCA1 is induced by its direct (26, 27) or indirect (28) interaction with apolipoproteins, which may render ABCA1 resistant to proteolysis by the cytosol thiol proteases. Alternatively, inhibition of proteolytic degradation can be achieved through deactivation of the enzyme(s). One of the thiol protease candidates for catabolizing ABCA1 is calpain, and this enzyme is reportedly activated by certain types of association with membrane phospholipid (29, 30). Because helical apolipoproteins remove various phospholipid molecules from the membrane to generate HDL, this process may result in deactivation of the enzyme. Apolipoprotein-cell interaction may trigger a signaling pathway(s) that could lead to activation of intracellular cholesterol trafficking, and this process may also be associated with deactivation of a certain thiol protease in order to catabolize ABCA1.

Extracellular helical apolipoproteins function to assemble HDL with cellular lipid. However, it is not fully understood whether the reaction takes place entirely extracellularly or if intracellular events such as exo- and endocytotic recycling may be partially involved (31). From such a viewpoint, it is interesting to examine whether apolipoprotein is co-degraded with ABCA1 in the pathway indicated here.

ALLN alone increased the baseline lipid release without apoA-I (Fig. 5). This may suggest that an increase of the lipid release mediated by endogenous apoE is also mediated by ABCA1 (32).

	ACKNOWLEDGEMENTS

We thank Dr. Jin-ichi Ito for helpful discussion and Michiyo Asai for excellent technical assistance.

	FOOTNOTES

^* This work was supported by grants-in-aid from the Ministry of Science, Technology, Education, and Culture of Japan and from the Ministry of Welfare, Health, and Labour of Japan.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Dept. of Biochemistry, Cell Biology, and Metabolism, Nagoya City University Graduate School of Medical Sciences, Kawasumi 1, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan. Tel.: 81-52-853-8139; Fax: 81-52-841-3480; E-mail: syokoyam@med.nagoya-cu.ac.jp.

Published, JBC Papers in Press, April 11, 2002, DOI 10.1074/jbc.M202996200

	ABBREVIATIONS

The abbreviations used are: HDL, high density lipoprotein; ABC, ATP-binding cassette transporter; PMA, phorbol 12-myristate 13-acetate; BSA, bovine serum albumin; ALLN, N-acetyl-Leu-Leu-norleucinal; RT-PCR, reverse transcriptase-PCR.

	REFERENCES

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

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