Published online before print July 10, 2008, doi: 10.1161/ATVBAHA.108.169482
© 2008 American Heart Association, Inc.
Cell Biology/Signaling |
ApoA-I Facilitates ABCA1 Recycle/Accumulation to Cell Surface by Inhibiting Its Intracellular Degradation and Increases HDL Generation
From Biochemistry, Nagoya City University Graduate School of Medical Sciences, Japan.
Correspondence to Shinji Yokoyama at Biochemistry, Nagoya City University Graduate School of Medical Sciences, 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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Objective— Calpain-mediated proteolysis is one of the major regulatory factors for activity of ATP-binding cassette transporter (ABC) A1. Helical apolipoproteins protect ABCA1 against this degradation and increase generation of HDL. We investigated the mechanism for this reaction focusing on roles of endocytotic internalization of ABCA1.
Methods and Results— Surface ABCA1 was labeled with biotin and traced for its internalization and degradation. ABCA1 in the cell surface was internalized within 10 minutes regardless of the presence of apoA-I. ABCA1 was intracellularly degraded and was protected against this only when exposed to extracellular apoA-I before its endocytosis. Consequently, recycle of ABCA1 to the surface was enhanced, and surface ABCA1 was increased by apoA-I. Direct inhibition of ABCA1 endocytosis led to decrease of its degradation and increase of surface ABCA1. Generation of HDL increased in parallel with surface ABCA1.
Conclusion— Surface ABCA1 is internalized and degraded, and apoA-I interferes with only the latter step to recycle ABCA1 to the surface. Increase of surface ABCA1 results in the increase of generation of HDL.
Key Words: ABCA1 • calpain • HDL • endocytosis • apoA-I • cholesterol
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Introduction |
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High density lipoprotein (HDL) is biogenerated with helical apolipoproteins and cellular lipid being mediated by the membrane protein ATP-binding cassette transporter (ABC) A1.1 Helical apolipoprotein, mainly apolipoprotein A-I (apoA-I), is delivered and liberated by plasma HDL to somatic cells that do not synthesize apolipoproteins for biogenesis of new HDL,2 whereas apoA-I is likely secreted from hepatocytes in a free form and interacts with its own ABCA1 in an autocrine manner.3 HDL particles are formed with apolipoprotein and membrane phospholipid, and cholesterol is integrated into this particle being dependent on various cellular factors.4,5 ABCA1 expression is upregulated mainly by the liver X receptor as sensing a cellular oxysterol level,6 but it is also under the regulation by sterol regulatory element binding protein 2 in the liver perhaps to properly maintain whole body cholesterol homeostasis.7 Interestingly, it is downregulated by activator protein 2
,8 but its physiological role is unknown. On the other hand, ABCA1 is rapidly degraded by calpain and it seems an important regulation system for its activity of generation of HDL.9 This proteolytic degradation is retarded when ABCA1 interacting with helical apolipoproteins9,10 suggesting that this is a positive feedback system for HDL biogenesis. This must be a steady state ongoing in vivo in most of the cells that are chronically exposed to helical apolipoproteins such as apoA-I, although this view is yet to be proven for its relevance. It was proposed that ABCA1 is internalized by endocytosis and seems recycled,11,12 and HDL biogenesis is associated with such endocytotic reactions.13–16 Involvement of adaptor proteins is also suggested in the endocytosis and degradation of ABCA1.17,18 Deletion of PEST sequence of ABCA1 inhibited its endocytosis, degradation by calpain, and HDL biogenesis, suggesting that endocytosis of ABCA1 is a key process for these all.19 However, there are other views that HDL biogenesis takes place rather in the cell surface20–22 than in the endosomes, where ABCA1 is entrapped. Most of these studies were carried out with ABCA1 transfected and overexpressed. In this work, we attempted to understand this complicated process by labeling the endogenous ABCA1 in cell surface and tracing it. |
Materials and Methods |
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Cell Culture and ApoA-I
BALB/3T3 clone A31 cells were maintained and incubated in 5% Eagle minimum essential medium (MEM) with low glucose and 30% Ham F-12 (Wako) with 10% fetal calf serum (FCS) at 37°C in a humidified atmosphere of 5% CO2.23 THP1 cells were differentiated to macrophages by incubating in 10% FCS in the presence of 3.2x10–7 mol/L of phorbol 12-myristate 13-acetate (PMA; Wako) for 24 hours.23 Human apoA-I was isolated from human plasma HDL as described previously.24 It was used at 10 µg/mL in the medium for all the experiments unless otherwise specified.
Labeling and Tracing ABCA1
Cell surface proteins were biotinylated with sulfosuccinimidyl 2-(biotinamido)-rthyl-1, 3-dithiopropionate (sulfo-SS-biotin) (Pierce) for 1 hour at 4°C according to the methods previously reported.25 After quenching the reaction, cells were washed and lysed, and the membrane fraction was prepared as described previously.9 Biotinylated membrane proteins were isolated by incubating with streptavidin-agarose beads (Sigma) at 4°C for 1 hour.26 After recovering the beads, proteins bound to the beads were eluted by incubating in the sample buffer for sodium dodecylsulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and then analyzed for Western immunoblotting by using specific antibody against ABCA1 as previously described.9 To trace the labeled surface ABCA1 for internalization, biotinylation of the cell surface proteins was cleaved by incubating the cells with 50 mmol/L reduced glutathione (Sigma) in pH 7.8 three times for 20 minutes,26 and the remaining biotinylated ABCA1 was analyzed as above as the internalized portion. Intracellular ABCA1 degradation was measured as the time-dependent decrease of biotinylated ABCA1 after the surface biotin was cleaved after the incubation of the biotinylated cells for 1 hour at 37°C. To examine recycle of ABCA1, intracellular ABCA1 was prelabeled as above. At the various period of the incubation, the cell surface biotin was cleaved again and the remaining biotinylated ABCA1 was analyzed and compared with the biotinylated ABCA1 without the second cleavage to estimate the resurfaced ABCA1.
Cellular Lipid Release
Cellular lipid release by apoA-I was measured as described elsewhere. After incubation of the cells with apoA-I for the indicated time, concentration of cholesterol and choline-phospholipid in the medium were evaluated by enzymatic measurement.27
Quantification of Western Blotting Results
The bands were digitally scanned by using an EPSON GT-X700 and analyzed with Adobe Photoshop software.
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Results |
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Figure 1A shows time-dependent internalization of ABCA1 in THP-1 cells. Most of the biotinylated ABCA1 in the surface was recovered as the internalized protein after incubating the cells at 37°C longer than 10 minutes, by cleaving the surface biotinylation with glutathione after the incubation. The internalized ABCA1 apparently decreased after 30 minutes of incubation, and this decrease was inhibited by a calpain inhibitor, calpeptin, both in THP-1 cells and BALB/3T3 cells (Figure 1B and 1C). ABCA1 was thus shown degraded by calpain after the internalization.
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Degradation of ABCA1 by calpain was shown inhibited by helical apolipoproteins, such as apoA-I.9 Therefore, the internalization of ABCA1 was examined in the presence of apoA-I. After 10 minutes of the incubation, most of the surface-labeled ABCA1 was internalized regardless of the presence of apoA-I (Figure 2A). This process was not modified any further even by the presence of calpeptin, indicating that ABCA1 was protected by apoA-I against the calpain-mediated degradation (Figure 2B). To investigate whether ABCA1 is "preprotected" by apoA-I before its internalization or extracellular apoA-I protects ABCA1 even after it is internalized, degradation of the internalized ABCA1 was examined for timing of adding apoA-I (Figure 2C). When apoA-I was present in the medium for the period before the internalization of the prebiotinylated surface ABCA1, degradation of ABCA1 was retarded (apoA-I (+)). However, when apoA-I was added to the medium after the prelabeled ABCA1 was internalized, the degradation was not much retarded (Chased). This result indicates that the protective effect of apoA-I on ABCA1 against its degradation is achieved before ABCA1 is internalized, and not by cell-apoA-I interaction to cause a distant effect on the internalized ABCA1.
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ABCA1 in the whole cell membrane increased up to 4 hours of the incubation, and this increase was parallel between the whole cell and cell surface (Figure 3A and 3B). To examine the mechanism for this increase of the surface ABCA1, recycle to the surface of the internalized ABCA1 was examined. After the prelabeled ABCA1 was internalized and surface biotinylation was cleaved, the cells were further incubated for certain periods of time and the surface biotinylation was cleaved again to assess the recycled ABCA1 to the surface (Figure 3C). In the absence of apoA-I, the internalized ABCA1 rapidly disappeared, and only its small portion was found recycled to the surface. In the presence of apoA-I, clearance of the internalized ABCA1 was substantially retarded as presented above, and a large portion of it was found recycled to the surface. Thus, apoA-I increased recycling of ABCA1 apparently by blocking the intracellular calpain-mediated degradation.
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To examine whether internalization of ABCA1 is mandatory for the HDL biogenesis reaction, clathrin-mediated endocytosis was inhibited by cytochalasin D.28,29 ABCA1 in the cell was decreased within 60 minutes in the absence of helical apolipoproteins when its synthesis was inhibited by cycloheximide (Figure 4A). When the endocytosis was inhibited by cytochalasin D, ABCA1 did not decrease. The increase of cellular ABCA1 by cytochalasin D was shown attributable to its increase in the cell surface (Figure 4B) as its endocytosis was strongly inhibited (Figure 4C).
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Finally, generation of HDL was evaluated by measuring release of cellular phospholipid and cholesterol by apoA-I5,30 when the endocytosis of ABCA1 was inhibited and its amount in the cell surface was increased. As shown in Figure 5, releases of phospholipid and cholesterol were both increased by this treatment. As apoA-I by itself increases surface ABCA1 by increasing its recycling, the increment of the HDL biogenesis should not be to the same extent as the increase of surface ABCA1 by cytochalasin D in the absence of apoA-I. This was in fact demonstrated in Figure 5B. The relative increase of the surface ABCA1 by cytochalasin D was to a less extent in the presence of apoA-I because the surface ABCA1 is already increased by apoA-I even in the absence of cytochalasin D. The increase of ABCA1 by cytochalasin D in the presence of apoA-I was parallel to the increase of lipid release by apoA-I (Figure 5C).
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Discussion |
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In summary, we have shown that: (1) ABCA1 is rapidly degraded intracellularly by calpain after its clathrin-mediated endocytotic internalization in the absence of helical apolipoprotein; (2) Helical apolipoproteins, represented by apoA-I, protect ABCA1 from the degradation, not by inhibiting the internalization but by inhibiting the intracellular proteolysis; (3) This inhibition is achieved by preexposure of ABCA1 to extracellular apoA-I before the internalization and not by the exposure of the cells after ABCA1 is internalized; (4) ABCA1 that escaped from the intracellular proteolysis is recycled to the cell surface, and apoA-I therefore enhances this process to increase cell surface ABCA1; (5) Generation of HDL is directly proportional to the surface ABCA1 level. The results are summarized in supplemental Figure I (available online at http://atvb.ahajournals.org).
It is well recognized that activity of ABCA1 is a rate-limiting factor for biogenesis of HDL and therefore plasma HDL concentration in vivo.1 Expression of the gene has been shown to regulate it in vitro and in vivo,6–8 but the degradation of ABCA1 protein seems an important regulatory factor for its activity as a posttranslational regulation at the cellular level,9,10 whose physiological relevance, however, is yet to be proven.
We used THP-1 cells and BALB/3T3 fibroblasts as models for generation of HDL. HDL biogenesis in vivo is largely in the liver and intestine,31 but any peripheral cells must carry on the HDL biogenesis reaction for their cholesterol homeostasis.1 Indeed, it was proposed that peripheral tissue may be a significant source of plasma HDL in human.32 Therefore, the use of these cells is justified to investigate mechanism for HDL biogenesis by the ABCA1/apolipoprotein system. ABCA1 seems stabilized in hepatocytes in an autocrine mechanism by a large amount of apoA-I produced and secreted by themselves, and the effects of additional apoA-I may not be apparent.3
When HDL generation is ongoing, helical apolipoproteins interact with ABCA1 before its internalization and make ABCA1 resistant to the calpain-mediated degradation. Consequently, a large portion of ABCA1 is recycled to the surface without degradation for further HDL generation. This view is consistent with most of the previous findings that apoA-I/ABCA1 complex recycles and apoA-I may be released by exocytosis during the HDL generation reactions.11,12 Most of the cells in the body are chronically exposed to HDL, which liberates apoA-I for generation of HDL.2 Therefore, in the physiological environment in vivo, ABCA1 seems protected from the degradation and its clearance rate should be rather slow. Recently, 2 independent articles proposed that HDL biogenesis by ABCA1 mainly takes place on cell surface rather than in the endosomes by tracing the labeled apoA-I in the presence of transfected ABCA1.21,22 The conclusion in the present work is consistent with these proposals and may not agree with the view that HDL biogenesis occurs intracellularly.13–16
In the steady state of HDL generation, ABCA1 should be increased in cell surface from the baseline condition without apolipoprotein. It is therefore of interest whether there is a room for further increase of surface ABCA1 and consequently for the increase of HDL biogenesis by inhibiting the endocytotic internalization of ABCA1. Inhibition of the endocytosis by cytochalasin D increased surface ABCA1x50 to 60% as well as HDL biogenesis in parallel (Figure 5C).
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Acknowledgments |
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Sources of Funding
This works was supported in part by Grants-in-aids from Ministry of Education, Culture and Sports, Science and Technology of Japan, and from Japan Health Science Foundation/Ministry of Health, Labor and Welfare of Japan, and by the Program for the Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation of Japan.
Disclosures
Shinji Yokoyama is involved in establishment of a Venture Company, HYKES Laboratories.
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Footnotes |
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R.L. and R.A. contributed equally to this study.
Original received May 1, 2008; final version accepted June 25, 2008.
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