Abstract
Mammalian somatic cells do not catabolize cholesterol and therefore must export it to maintain sterol homeostasis at the levels of cells and whole body. This mechanism may reduce intracellular cholesterol accumulated in excess, and thereby contribute to prevention or cure of atherosclerotic vascular lesions. High‐density lipoprotein (HDL) plays a central role in this reaction by removing cholesterol from cells and transporting it to the liver, the major cholesterol catabolic site to bile acids. Two independent mechanisms are identified for the cellular cholesterol release. One is non‐specific diffusion‐mediated ‘efflux’ of cell cholesterol that is trapped by various extracellular acceptors including lipoproteins. Cholesterol acyl esterification on HDL provides a driving force for net outflow of cell cholesterol in this pathway, and some cellular factors may also enhance this reaction. The other is apolipoprotein‐mediated process to generate new HDL particles by removing cellular phospholipid and cholesterol. This reaction is mediated with a membrane protein, ATP binding cassette transporter (ABC) A1, and helical apolipoproteins recruit cellular phospholipid and cholesterol to assemble HDL particles. The reaction is composed of two elements: assembly of HDL particles with phospholipid by apolipoprotein, and cholesterol enrichment in this HDL. ABCA1 is essential for the former step, and apolipoproteins are dissociated from HDL or secreted from cells and interact with ABCA1 in their free form. The latter step requires other cellular factors, such that ABCA1 mediates production of cholesterol‐rich and cholesterol‐poor HDL while ABCA7 produces only cholesterol‐poor HDL.
| Abbreviations | ||
| LDL | = | low‐density lipoprotein |
| HDL | = | high‐density lipoprotein |
| LCAT | = | lecithin: cholesterol acyltransferase |
| CETP | = | cholesteryl ester transfer protein |
| ACAT | = | acylCoA cholesterol acyltransferase |
| PLTP | = | phospholipid transfer protein |
| ABC | = | ATP‐binding cassette transporter |
| HPLC | = | high‐performance liquid chromatography |
Introduction
Cholesterol constitutes a membrane domain ‘raft’ by forming a cluster with sphingolipid to provide an microenvironment for accumulation of specific membrane proteins related to intracellular signal transduction, and therefore plays essential key roles in the biological functions of the cell membrane especially for intercellular communication. Biosynthesis of cholesterol is therefore carried out in all the somatic cells in most animals requiring a complicated 37 steps in order to maintain such cellular functions. In contrast, catabolism of cholesterol is very limited in peripheral cells of vertebrates, and most of cholesterol molecules in the body are transported to the major organ for its catabolism, the liver, except for a small but important part in steroidogenic cells. In the liver, cholesterol is converted to bile acids that are heavily reused in an entero‐hepatic circulation. It should be noted that cholesterol is never converted to energy. Bile acids still contain a sterol backbone, and it is biodegraded by bacteria mostly after excretion. Thus, we recognize it as an important and valuable molecule that should not be wasted at all. We are well prepared for crisis management of cholesterol shortage, but very poorly for its overload.
The regulation of cholesterol biosynthesis and receptor‐mediated lipoprotein uptake have been extensively characterized for a long time Citation1, and the regulatory mechanism of cholesterol biosynthesis has been well established at the molecular levels such as sterol regulatory element binding protein system Citation2, Citation3. On the other hand, release of cholesterol from somatic cells is equally important for cholesterol homeostasis both for cells and whole body, but understanding of this part has been substantially behind. However, knowledge has rapidly accumulated in this field in the last several years, and significant progress has been made for understanding the mechanism for cellular cholesterol release.
Release of cellular cholesterol and its transport to the liver are both mediated by high‐density lipoprotein (HDL). This pathway is under kinetic control and in a steady state with assembly and clearance of plasma lipoproteins and with extracellular cholesterol metabolism by lecithin: cholesterol acyltransferase (LCAT), cholesteryl ester transfer protein (CETP), and other active molecules Citation4. However, the most critical step for this pathway is the release of cholesterol from the cells, and it is also one of the key components of cellular cholesterol homeostasis. This pathway is often referred to as the concept of ‘reverse cholesterol transport’ and an anti‐atherosclerosis nature of HDL, based on the two lines of evidence that plasma HDL level is negatively correlated to the risk of atherosclerotic vascular disease Citation5 and that incubation of the cells with HDL results in reduction of cellular cholesterol in vitroCitation6. Two major mechanisms are proposed for the cellular cholesterol release step Citation7–9: non‐specific diffusion‐mediated cell cholesterol ‘efflux’, and apolipoprotein/ATP‐binding cassette transporter (ABC) A1‐mediated biogenesis of HDL particles from cellular lipids.
Non‐specific release of cell cholesterol
Non‐specific cholesterol efflux from the cellular surface by physicochemical cholesterol exchange between the cell membrane and extracellular ‘acceptors’ is perhaps mediated by its diffusion in an aqueous phase. Net release of cellular cholesterol is driven by extracellular acyl‐esterification of cholesterol by LCAT in this pathway. This concept was first proposed by Glomest in 1968 Citation10 as HDL is a major cholesterol acceptor in this reaction because of its capacity for cholesterol accommodation and because it provides a major and optimum site for the LCAT reaction. This is under kinetic control and the net release of cell cholesterol is in fact demonstrated only when outflow diffusion of cell cholesterol is not a rate‐limiting factor Citation11, Citation12 (Figure ). Scavenger receptor B1 seems to expedite cholesterol exchange rate between cell membrane and HDL, perhaps through a specific mode of binding to HDL Citation13–16. ABCG1/ABCG4 alters intracellular cholesterol distribution to the direction to increase its release by this pathway Citation17.
Figure 1 LCAT‐mediated net cholesterol release from erythrocytes Citation12. Pig erythrocytes that lack apolipoprotein‐mediated cell cholesterol release were used for increasing the cellular cholesterol pool in order to provide a high off‐diffusion rate of cellular cholesterol and to make LCAT reaction a rate‐limiting factor for net cholesterol efflux. Panel A shows cell cholesterol efflux to HDL in the medium in the absence and presence of LCAT measured by pre‐labelling cell cholesterol. Cholesterol esterification by LCAT results in just as much increase of cell cholesterol efflux (an upward arrow). In contrast, influx of HDL cholesterol into erythrocytes measured by pre‐labelling HDL cholesterol. Cholesterol influx was reduced in the presence of cholesterol esterification on HDL (a downward arrow). FC, free cholesterol; CE, cholesteryl ester. Panel B shows the net cholesterol efflux calculated from the results in the panel A. There is no net flux between erythrocytes and HDL without LCAT, and LCAT generates the net outflow of cell cholesterol to HDL (an upward arrow). Overall results indicated that acyl esterification of cholesterol on HDL is the driving force for its net release from cells by its diffusion between HDL and cell surface (Panel C).
Key messages
Cholesterol in extrahepatic cells, except for steroidogenic cells, must be released and transported to the liver for its conversion to bile acids mainly mediated by high‐density lipoprotein (HDL), as its major catabolic pathway both for cellular and whole body levels.
Cell cholesterol release is mediated by two independent mechanisms: a physicochemical diffusion‐mediated pathway in which one of the driving forces for the net release is lecithin: cholesterol acyltransferase (LCAT) reaction on HDL, and an HDL biogenesis by the interaction of helical apolipoprotein and cellular lipid mediated by ATP‐binding cassette transporter (ABC) A1.
Helical apolipoprotein, represented by apoA‐I, must be in a free form to interact with ABCA1‐expressing cells to generate HDL, and it either dissociates from HDL or is secreted as a free form before the interaction for HDL biogenesis.
Cholesterol enrichment of HDL in the ABCA1‐mediated HDL biogenesis is independent of assembly of HDL particles with cellular phospholipid, and cholesterol‐rich and cholesterol‐poor HDL are generated by apoA‐I in the presence of transfected‐and‐expressed ABCA1 and ABCA7, respectively.
Apolipoprotein‐mediated HDL assembly
The other important mechanism is an assembly of new HDL particles with cellular phospholipid and cholesterol upon the direct interaction of helical apolipoproteins of HDL with cells. Many specific cellular functions are required for this reaction, including a cellular interaction site for apolipoprotein and specific intracellular cholesterol trafficking for the HDL assembly. This reaction seems to be a major source of plasma HDL, and ABCA1 is a key cellular factor.
The first finding of HDL assembly by cellular lipid and extracellular helical apolipoproteins was our observation that apolipoproteins of HDL, such as apoA‐I, A‐II, and E, remove phospholipid and cholesterol from mouse peritoneal macrophages and generate new HDL particles Citation18 (Figure ). The lipoprotein thus generated meets the criteria of preβ‐HDL with respect to physical and chemical properties Citation18 (Figure ), morphological appearance Citation19, Citation20, and biochemical characteristics such as reactivity to LCAT Citation11, Citation21 (Figure ). Cholesterol in the cells reciprocally decreased mainly in the compartment accumulated as cholesteryl ester Citation18. The reaction can be carried out by various helical apolipoproteins having amphiphilic helices composed of some 20–22 amino acid residues, so that apoA‐I, A‐II, A‐IV, E, and insect apoIII all generate HDL Citation18, Citation22, Citation23, and so do synthetic amphiphilic peptides as far as they meet such criteria Citation23, Citation24. More recently the peptides were shown to be active whether composed of D‐ or L‐amino acids Citation25. It seems that certain numbers of the helical segment are required to carry out the reaction.
Figure 2 HDL biogenesis by apolipoproteins and cellular lipid. Panels A and B show the results of incubation of mouse peritoneal macrophages with apoA‐I or apoA‐II. The medium was analysed by ultracentrifugation (Panel A) and agarose gel electrophoresis (Panel B, bands of fast and slow mobility in each gel indicate HDL and LDL, respectively) Citation18. Panel C demonstrates the reactivity to LCAT (activity was standardized for plasma LCAT activity) of the HDL generated by human fibroblasts and apoA‐I or apoA‐II Citation11.
The physiological relevance of this reaction became evident by the finding that the cells from patients with Tangier disease, familiar HDL deficiency, lack the interaction with apolipoprotein and the HDL assembly Citation26, Citation27. Mutations were identified in the gene of ATP‐binding cassette transporter A1 (ABCA1) in patients with this disease Citation28–33, and disruption of this gene resulted in the HDL deficiency in mice. Thus, ABCA1 was shown to be essential for production of plasma HDL Citation34, Citation35. While apolipoproteins do not interact with the Tangier cells and generate no HDL Citation26, Citation27, the cells are intact for the non‐specific diffusion‐based cholesterol release Citation26. This means that ABCA1 may act as or create a direct interaction site for apolipoproteins to generate HDL. To support this idea, induction of the HDL assembly reaction in RAW264 cells by cAMP is accompanied by induction of apoA‐I binding and expression of ABCA1 Citation36, Citation37. Thus, ABCA1 essentially functions as a mediator for apolipoprotein‐cell binding and for subsequent assembly of nascent HDL particles from apolipoprotein and cellular phospholipid/cholesterol.
Helical apolipoproteins are in equilibrium between a lipid‐bound form and a dissociated form from the lipid surface presumably free in solution. Although the dissociation constants of apolipoproteins are not known directly for the HDL surface, the constants measured for the LDL‐size lipid particles are all in the order of 10−7 M, which may not be irrelevant to be extrapolated for the HDL surface Citation38, Citation39. Assuming that the dissociation constant of apoA‐I is in this range, and binding capacity of HDL is just enough to accommodate the total plasma apoA‐I, a few percent of plasma apoA‐I can be lipid‐free in the aqueous phase in equilibrium. It should be noted that the Km for the HDL assembly reaction is less than 1% of plasma apoA‐I concentration Citation18 so that this protein in a free form can carry out the reaction at the Vmax. Also, there are several reactions that reportedly liberate helical apolipoproteins from the HDL surface in plasma, such as CETP in the presence of free fatty acids Citation40–42. Phospholipid transfer protein (PLTP) Citation43 by itself also releases apolipoprotein from HDL, and transfer of cellular phospholipid and cholesterol to HDL was indeed enhanced by PLTP Citation44. Apolipoproteins can be transferred from HDL to the cell surface simply due to the higher affinity of free apolipoproteins for the cells than for lipid surface Citation45.
We investigated the ABCA1‐dependent interaction of HDL particles with cells Citation46 (Figure ). ABCA1 mediates the interaction only of the protein moiety of HDL but not its lipid (Figure ). It was also shown that a monoclonal antibody specific for lipid‐free apoA‐I selectively inhibited the ABCA1‐dependent part of cell cholesterol release to HDL Citation46 (Figure ). These findings were magnified when apoA‐I was displaced by apoA‐II to increase lipid‐free apoA‐I. In that paper, kinetic analysis of the data indicated that apoA‐I has an affinity for HDL as high as that for cellular surface, and apoA‐I could still be transferred from HDL to cell surface. It is thus not irrelevant to speculate that apolipoproteins dissociate from HDL and interact with the cells in their lipid‐free form to generate new HDL particles.
Figure 3 Binding of HDL components to RAW264 cells when ABCA1 expression is induced by cAMPCitation46. Panel A shows reconstituted HDL of apoA‐I (proapoA‐I), cholesteryl oleate and egg phospholipid. Panel B shows the results of binding of the particles labelled with uniformly labelled proapoA‐I with 3H and 14C‐cholesteryl oleate. An upward red arrow between open and closed circles indicates the increase of proapoA‐I binding by induction of ABCA1 expression by cAMP. Red lines between open and closed squares indicate change of cholesteryl oleate (CO) binding by inducing ABCA1 expression. Binding takes places only with protein of HDL. Panels C and D demonstrate inhibition of the ABCA1/apoA‐I‐mediated cholesterol release by the monoclonal antibody specific for lipid‐free apoA‐I, 725‐1E2. Panel C‐a shows specificity of the antibody against lipid‐free apoA‐I, and Panel C‐b shows inhibition by the antibody of the apoA‐I‐ and HDL‐mediated cell cholesterol release induced by cAMP. ApoA‐I‐mediated cholesterol release was inhibited by 75% of the cAMP‐induced increment, and the increment of the HDL‐mediated cholesterol release by cAMP was inhibited to the same extent as the apoA‐I‐mediated release was inhibited. Panel C shows the results of the similar experiments performed in the presence of apoA‐II. ApoA‐II displaces apoA‐I from the HDL surface to make it a free form (Panel D‐a and D‐b), and therefore the increment of cell cholesterol release was larger in this condition (Panel D‐c). The antibody inhibited so much as the apoA‐I‐mediated cholesterol release (Panel D‐c).
Major sites for synthesis of helical apolipoproteins, especially for the main apolipoprotein of HDL, apoA‐I, are believed to be the liver and intestine. In contrast to apoB‐containing lipoproteins, however, no HDL particles, not even premature HDL, have been identified in the secretory pathways such as the endoplasmic reticulum and the Golgi apparatus in the cells of these organs. Nevertheless, HDL particles are found in the culture media of the hepatocytes Citation47, Citation48 or in the perfusate of the liver Citation49, Citation50, mostly as a so‐called nascent HDL that is composed mostly of surface lipids, phospholipid, and cholesterol, not containing much core lipid, and consequently in a disc‐like shape. The question then becomes how and where these particles are formed. If the apolipoprotein‐cell interaction is a major mechanism for production of HDL, it is possible that HDL is assembled by an autocrine mechanism, such that apoA‐I or E are first secreted by the cells and then interact with the cell surface to generate HDL Citation51, Citation52. This hypothesis has more directly been supported by using an ABCA1 inhibitor, probucol, and the above‐mentioned antibody specific to lipid‐free apoA‐I to inhibit ABCA1‐dependent HDL assembly by hepatocytes Citation53. When HepG2 cells were treated with probucol, apoA‐I otherwise found associated with HDL was secreted all in a free form (Figure ). In the presence of the antibody, generation of HDL was completely inhibited (Figure ) while it did not influence the pre‐produced HDL in the medium.
Figure 4 Biogenesis of HDL by HepG2 cells with endogenous apoA‐I Citation53. Panel A shows the results of apoA‐I secretion when HepG2 cells were treated with an ABCA1 inhibitor, probucol (P), in comparison to control (C). Secretion of apoA‐I into the medium is unchanged by the treatment of the cells with probucol, but apoA‐I was recovered all in a lipid‐free form by the treatment while it was otherwise all bound to HDL. Panel B shows marked decrease of HDL production by HepG2 cells when ABCA1 was inactivated by probucol or the monoclonal antibody specific to lipid‐free apoA‐I, 725‐1E2, was present in the medium, demonstrated as HPLC profiles of the media. Solid lines indicate cholesterol, and dotted lines indicate choline‐phospholipid. Panel C demonstrates the same results shown as quantitative data by using the HPLC analysis data and the ultracentrifugation analysis data.
Thus, lipid‐free apolipoprotein is to be released whether from cells or from HDL particles to interact with cellular ABCA1 for assembly of HDL particles from cellular lipid. Alternatively, apolipoproteins may interact in part with the membrane already somewhere before the secretion through the same mechanism as extracellular apolipoprotein reacts Citation54, Citation55. This view may be consistent with the finding of the abnormal Golgi structure in the hepatocytes of ABCA1 knock‐out mice Citation34 and differential generation of HDL with endogenous apoE and exogenous apoA‐I by rat astrocytes Citation56.
Assembly of HDL particles and cholesterol enrichment
Apolipoprotein recruits primarily phospholipid rather than cholesterol to form stable HDL particles in this HDL assembly pathway Citation57. HDL generated by this reaction contains largely phospholipid and unesterified cholesterol, and the LCAT‐mediated cholesterol esterification on the generated HDL perhaps helps the maturation of this HDL as it generates core cholesteryl ester Citation11, Citation21. However, unlike cholesterol release by non‐specific diffusion‐mediated reaction, cholesterol esterification does not result in further enhancement of cellular cholesterol release when the HDL generated is already cholesterol‐rich Citation11.
HDL‐like particles can be formed in vitro with helical apolipoproteins and phospholipid, with or without core lipid and cholesterol, without specific catalysts except for the requirement of energy for dispersion of the components to homogeneity Citation58. The reaction always yields the particles of certain sizes composed of at least a few hundreds of phospholipid molecules. Therefore, HDL‐like particles are a thermodynamically stable molecular assembly for helical apolipoproteins and phospholipid. The physicochemical nature of apolipoprotein‐phospholipid interaction is that ‘lipidation’ of apolipoprotein takes place primarily with phospholipid in a kind of snap‐in manner rather than ‘gradual growth’. On the other hand, apolipoprotein cannot form a complex with cholesterol alone. When apolipoprotein interacts with cells through ABCA1, the same type of reaction should take place to generate HDL. In fact, disc‐like HDL particles are generated primarily with membrane phospholipid when apoA‐I interacts with the cells in the presence of ABCA1 (Figure ). However, it has not yet been evident whether premature HDL particles found in plasma are produced by this reaction and are direct precursors of plasma HDL, such as preβ‐HDL, γ‐LpE, and LpA‐IV Citation59. It should be noted that Miller and colleagues suggested that preβ‐HDL in human peripheral tissue fluid should be considered substantially produced locally rather than filtered from blood plasma Citation60. This finding may support the view that at least apoA‐I locally dissociates from HDL and produces new preβ‐HDL by removing lipid from peripheral cells.
Figure 5 HDL particles generated by apoA‐I when ABCA1 or ABCA7 are transfected and over‐expressed in HEK293 cells Citation64. Panel A shows electron microgram of the particles isolated from the medium by ultracentrifugation. Scale bars indicate 100 nm. Histograms represent the results of the measurement of diameters. Panel B shows the results of the HPLC analysis. Thick solid lines represent cholesterol, and thin solid lines represent choline‐phospholipid.
It was recently reported that ABCA7 also mediates the HDL assembly in vitro in a similar manner to ABCA1 when transfected and over‐expressed in HEK293 cells Citation61–63. Analysis of the HDL products by size exclusion high‐performance liquid chromatography (HPLC) revealed that ABCA1 generates two different types of HDL, large cholesterol‐rich and small cholesterol‐poor, while ABCA7 produces only small and cholesterol‐poor HDL (Figure ) Citation63, Citation64. Although this reaction may not significantly contribute to the regulation of plasma HDL concentration Citation65 and the expression of the ABCA7 gene is not regulated for the HDL biogenesis Citation66, it is still of interest to examine the difference between the two ABC proteins in order to elucidate the mechanism for ABCA1 to remove cellular cholesterol more efficiently in the HDL biogenesis.
Closing remarks
The finding of the mutation in ABCA1 opened a new gate for studying cellular cholesterol homeostasis with respect to its releasing mechanism. This protein undoubtedly plays an essential role in apolipoprotein‐mediated assembly of HDL. It is, however, still unclear how ABCA1 functions to mediate the interaction of helical apolipoprotein with phospholipid in the cell membrane. In order to maintain cholesterol homeostasis, diffusion‐mediated physicochemical cholesterol release functions as much as the apolipoprotein‐mediated pathway both at the cellular level and for the whole body. Therefore, Tangier patients may not develop general and massive cholesterol accumulation since the diffusion‐mediated system is preserved Citation67. This is the same in LCAT deficiency patients who lack a driving force for the net cholesterol release by the diffusion‐mediated system but not the apolipoprotein‐mediated reaction Citation68. Thus, the two systems back up each other to maintain cellular and body cholesterol homeostasis Citation69.
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