vocational coal mine electrical and mechanical equipment management professional textbook serieschinese edition
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vocational coal mine electrical and mechanical equipment management professional textbook serieschinese editionThe current custom error settings for this application prevent the details of the application error from being viewed remotely (for security reasons). It could, however, be viewed by browsers running on the local server machine. The current custom error settings for this application prevent the details of the application error from being viewed remotely (for security reasons). It could, however, be viewed by browsers running on the local server machine. Learn More. This article has been cited by other articles in PMC. Abstract Cholesterol transport between intracellular compartments proceeds by both energy- and non-energy-dependent processes. Energy-dependent vesicular traffic partly contributes to cholesterol flux between endoplasmic reticulum, plasma membrane, and endocytic vesicles. Membrane contact sites and lipid transfer proteins are involved in nonvesicular lipid traffic. The dissociation of partially exposed cholesterol molecules in water determines the rate of passive aqueous diffusion of cholesterol out of plasma membrane. ATP hydrolysis with concomitant conformational transition is required to cholesterol efflux by ABCA1 and ABCG1 transporters. Besides, scavenger receptor SR-B1 is involved also in cholesterol efflux by facilitated diffusion via hydrophobic tunnel within the molecule. Direct interaction of ABCA1 with apolipoprotein A-I (apoA-I) or apoA-I binding to high capacity binding sites in plasma membrane is important in cholesterol escape to free apoA-I. ABCG1-mediated efflux to fully lipidated apoA-I within high density lipoprotein particle proceeds more likely through the increase of “active” cholesterol level. Putative cholesterol-binding linear motifs within the structure of all three proteins ABCA1, ABCG1, and SR-B1 are suggested to contribute to the binding and transfer of cholesterol molecules from cytoplasmic to outer leaflets of lipid bilayer.http://comitatoamiantovelodromo.org/userfiles/bt-freestyle-2200-trio-manual.xml
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Together, plasma membrane events and intracellular cholesterol metabolism and traffic determine the capacity of the cell for cholesterol efflux. 1. Introduction Cholesterol homeostasis is a well-coordinated machinery of de novo cholesterol synthesis in endoplasmic reticulum and uptake of cholesterol-containing low-density lipoproteins (LDL). Cholesterol turnover is normally balanced by cholesteryl ester formation at cholesterol excess and cellular cholesterol efflux by both passive and active transport. Eukaryotic cells maintain a gradient in sterol concentration between plasma membrane (PM) and the membranes of cell organelles such as endoplasmic reticulum (ER) by both vesicular and nonvesicular mechanisms involving lipid transport proteins. Such a drastic difference in cholesterol pools in the PM and ER is due to much higher cholesterol concentration in PM compared to ER and other intracellular membranes. All other intracellular membranes have smaller cholesterol concentration than the PM. Despite the large size of PM cholesterol pool, efflux of just a small fraction of PM cholesterol can be significantly affected by intracellular events. The goal of this review is to describe the complex processes of cholesterol metabolism and cholesterol traffic inside the cell and the effect of these processes on the cholesterol efflux from the cells. The mechanisms of cholesterol transfer between cell membranes and underlying reason of gradient of cholesterol concentration between intracellular and plasma membranes will be discussed. The contribution of different pools of cholesterol and types of acceptor will be also considered. 2. Lipid Rafts and Cholesterol Pools in Lipid Bilayer and Cell Membranes 2.1. Membrane Lipid Composition and Two Kinetic Pools of PM Cholesterol The distribution of lipids between membrane leaflets is not even.http://areicon.com/images/bt-freestyle-350-user-manual.xml Dependent on the membrane composition, cholesterol can be associated with other lipids in more or less tight and stable complexes that affect its activity. The ability to form a complex and its stoichiometry depends on the lipid structure, such as the saturation and length of the acyl chains and the size of the polar head. Under certain conditions, the addition of cholesterol to phospholipids leads to phase separation: phosphatidylcholine and especially sphingomyelin concentrate in the ordered and condensed cholesterol-rich phase, while the remaining phospholipids are displaced into the liquid phase. The pressure-composition phase diagram for cholesterol-phospholipid mixtures is characterized by an initial increase in pressure at low cholesterol content caused by the formation of ordered regions in the liquid phase. As cholesterol content increases, the pressure decreases due to the formation of a stoichiometric complex. Cholesterol, not associated in complexes with other lipids, is more available for reactions and more active at the escape from the membrane, probably due to disruption of its orientation in the bilayer. In the membrane, cholesterol pools with different activity can simultaneously be present ( Figure 1 ). It was suggested that cholesterol distribution in membranes of various organelles depends on the composition of these membranes and corresponds to the stoichiometry of the cholesterol complexes. Cholesterol level in endoplasmic reticulum does not exceed 5 and there is no complex with 19:1 stoichiometry; the complex formation is discarded for such phospholipid as 1-stearoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine. Alternatively, the diminished cholesterol content may originate from the presence in ER of any substances that exclude cholesterol from the complex. Open in a separate window Figure 1 Cholesterol distribution and movement between major compartments.https://www.thebiketube.com/acros-bosch-miter-saw-3915-manual Solid arrows indicate nonvesicular cholesterol transport (including transport via membrane contact sites and lipid transfer proteins); dashed arrows indicate vesicular transport and transport of cholesterol mediated by organelles. Three pools of cholesterols with different accessibility to water phase are known in PM. PFO-accessible cholesterol is the most available pool for the interactions with reagents in aqueous phase, such as PFO (Perfringolysin O), cholesterol oxidase, and cyclodextrin. This pool with variable size is considered as a putative “active” cholesterol. The size of this pool is very small at cholesterol depletion, while at the increase of its size in PM cholesterol moves to the ER. PFO-accessible pool in ER appears at much smaller mol of cholesterol. PM (plasma membrane), ER (endoplasmic reticulum), LD (lipid droplets), TGN (trans-Golgi network), LDL (low-density lipoprotein), and SM (sphingomyelin). Cholesterol level is tightly maintained in cell membrane due to complex formation. Normally, the cholesterol content of PM of fibroblasts and CHO cells is about 40-50 of total PM lipids. This cholesterol pool disappeared when cells are cholesterol-depleted. It is an essential pool, and the depletion of this cholesterol results in the rounding of the cells and their detachment to the medium. The binding of ER cholesterol with PFO occurs at cholesterol level over 5. Two pools of cholesterol are observed in the kinetics of cholesterol efflux to cyclodextrin in Fu5AH hepatoma cells, mouse fibroblasts L-cells, human skin fibroblasts, and CHO-K1 cells. The fast pool is 20-60 (the highest is for the Fu5AH cells) of cell cholesterol and the efflux half time is about 15-23 sec. The cholesterol efflux to HDL 3 in CHO-K1 cells similarly to the efflux to cyclodextrin shows fast and slow pools. However, the sizes of both pools for the efflux to HDL3 are much smaller than if the cholesterol acceptor is cyclodextrin.http://curabona.com/images/brinks-home-security-control-panel-manual.pdf Slow and fast pools exchange cholesterol with a half time 20-30 min. Energy poisons do not significantly affect the fast pool of cholesterol. The data on the effect of energy poisons on the parameters of slow cholesterol pool are controversial. Sphingomyelins (SMs) are known as lipids that can be associated with cholesterol in membranes. It can be assumed that many processes that depend on individual cholesterol molecules, such as cholesterol diffusion and cholesterol-protein interaction, similarly depend on the concentration of the accessible “active” cholesterol, but not the total cholesterol. On the contrary, the “active” cholesterol inhibits the activity of ER-associated enzyme HMG-CoA reductase. A model was proposed that explains sterol gradient between ER and PM and the ability of the sterol-poor ER to respond to the small changes in sterol content in the sterol-rich PM. It suggests that PM rafts contain the most of PM sterols, which is not “free” (or “active”) and does not participate in the exchange with ER cholesterol. “Free” (not raft-associated) cholesterol is transferred between ER and PM by nonvesicular mechanism. Thus, the gradient of cholesterol concentration between the PM and ER might be thermodynamically stable. 3. Intracellular Cholesterol Turnover A number of intracellular proteins affect cholesterol efflux to extracellular acceptors of cholesterol ( Table 1 ) with activator and inhibitor properties toward cholesterol synthesis and uptake, cholesterol distribution in the membrane, intracellular vesicular and nonvesicular trafficking, cytoskeletal organization, and cholesterol escape. It can be assumed that proper cholesterol homeostasis and fully functional intracellular cholesterol transport are required for normal level of cholesterol efflux. The central processes that maintain cholesterol balance and are common for the most of the cells are described below.https://www.adler-leitishofen.de/wp-content/plugins/formcraft/file-upload/server/content/files/16288d6d4d8696---Canon-220ex-instruction-manual.pdf Table 1 Genes that participate in the intracellular cholesterol traffic and cholesterol homeostasis and affect the efflux of cholesterol to extracellular acceptors. Gene Description Cell (a) Acceptor Reference In particular, rate-limiting enzyme in cholesterol synthesis 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) is located in the ER. Low-density lipoproteins are internalized by LDL receptor (LDLR) in clathrin-coated vesicles. The vesicle is transported to sorting endosome, where LDL dissociates from the LDL receptor and the latter is recycled back to the plasma membrane via the endocytic recycling compartment (ERC). Niemann-Pick type C proteins NPC1 and NPC2 are critically important for unloading of cholesterol from LE. One of the routes of cholesterol transport from LE to ER is vesicular transport through trans-Golgi network (TGN) and requires NPC1 and v-SNARE vesicle-associated membrane protein 4. Peritoneal macrophages from NPC1 knockout mouse show less efficient cholesterol efflux compared to the normal peritoneal macrophages ( Table 1 ). While cholesterol content of ER is much lower than of PM, it plays essential role in maintaining cholesterol homeostasis as a site of sensing cholesterol level that regulates expression of LDLR and HMGCR and a site of cholesterol synthesis if required and esterification for storage when cholesterol is in excess. Loading of fibroblasts with cholesterol using hydroxypropyl-beta-cyclodextrin-cholesterol complex that increases total cell cholesterol by 50 results in 10-fold increase in cholesterol level in the ER from 0.5 to 5 of total cell cholesterol. An excess of some intermediates of cholesterol synthesis results in HMGCR degradation. Both the biosynthesis and uptake of cholesterol are transcriptionally regulated by sterol regulatory element-binding protein family of SREBP-1a, SREBP-1c, and SREBP-2. The function of SREBPs is dependent on proper protein trafficking from ER to Golgi.AYBAR-GALLERY.COM/userfiles/files/boss-59-bassman-manual.pdf When cell does not require a supply of cholesterol, SREBPs are anchored to ER. At low cholesterol condition, sterol-sensing domain (SSD) of SREBP cleavage-activating protein (SCAP) loses cholesterol, and SCAP initiates COPII-mediated incorporation of SREBPs into budding vesicles and transport them from the ER to the Golgi, where SREBPs are cleaved by Site-1 and Site-2 proteases. N-termini of SREBPs release into cytoplasm and move to nucleus escorted by importin-beta, where they induce expression of LDLR, HMGCR, Insulin induced gene 1 ( Insig-1 ), and other SREBP target genes. In addition, SREBPs suppress expression of ABCA1 that removes cholesterol to extracellular acceptors. A large number of CE-rich LDs is an indicator of macrophage transformation to foam cell because of excessive uptake of cholesterol. Lipid droplets are organelles that store sterol esters, triglycerides, and some other neutral lipids. The neutral lipid core is surrounded by a monolayer of phospholipids that contains a number of proteins that participate in LD metabolism. LDs are formed in ER because of synthesis of neutral lipids, such as CE that is synthesized from newly synthesized or LDL-derived cholesterol and fatty acyl-CoA by ACAT-1 or sterol O-acyltransferase 1. As the concentration of neutral lipids increases, they cannot be dissolved anymore in the ER membrane, and supposedly, a “lens” of neutral lipids between ER membrane leaflets appears that grows to a “drop” being still attached to the ER membrane. An integral membrane protein Seipin is detected in the LD-ER contact site. It is not fully clear whether fully formed LD stays attached to the ER or separated from the ER. Nevertheless the proteins of COPI vesicle coats are found on the LD surface. That “futile cycle” is a LD-based mechanism that can help to maintain the normal cholesterol concentration.https://www.optionassurance.ca/wp-content/plugins/formcraft/file-upload/server/content/files/16288d6e346f47---canon-220ex-manual.pdf Beside the cytoplasmic lipolysis, LD can release cholesterol by LD lysosomal degradation in an autophagy route when CE is hydrolyzed by lysosomal acid lipase. In foam cells, the LD incorporates into autophagosome that fuses with lysosome and releases cholesterol for efflux from the cells. Anterograde COPII (coat protein complex II) vesicles traverse from the ER to Golgi, and retrograde COPI vesicles traverse from Golgi to the ER. Golgi along with trans-Golgi network is structurally highly dynamic organelle and intra-Golgi vesicle transport is not clearly understood. The Golgi routes the vesicle to PM and endosomal compartments. Intracellular traffic between compartments depends on various mechanisms. These mechanisms can be roughly described as energy-dependent and cytoskeleton-dependent. For instance, vesicle transport requires both energy and functional cytoskeleton. Despite the hypothetical possibility of vesicular traffic to transport significant amount of cholesterol, this route plays just a minor role in the cholesterol transfer from the site of the synthesis (ER) to PM. The PM cholesterol is constantly transported back to ER by not energy-dependent mechanism. Considering the hypothesis of some “active” cholesterol in membranes, the half time is even faster. Unlike creating a cholesterol gradient between PM and ER, its maintaining does not depend on energy. However, recent data of the same group suggest rather different mechanism of bidirectional sterol movement. Membranes of virtually any organelle are interconnected through membrane contact sites (MCSs). MCSs connect ER with PM, Golgi, endosomes, lysosomes, mitochondria, and peroxisomes. The MCSs are organized as protein complexes that link the membranes and hold them in the distance about 10-50nm apart and serve as sites for lipid transfer protein- (LTP-) assisted nonvesicle lipid transport. Several LTPs are known to transfer cholesterol between the organelles.https://www.lavalledesign.com/wp-content/plugins/formcraft/file-upload/server/content/files/16288d6e990e1e---Canon-2220i-user-manual.pdf OSBP is predominately cytosolic protein with minor fraction bound to ER. Overexpression of OSBP in HeLa cells suppresses sterols incorporation into lipid droplets, while the mutant OSBP protein, which is assumed to lose PI4P binding ability, does not interfere with sterols accumulation in LDs. In vivo and in vitro experiments suggest that OSBP is a PI4P-dependent cholesterol transporter. According to the proposed model, ER-anchored VAP-A at the ER-trans-Golgi MCS binds OSBP, which starts to transfer cholesterol from ER to trans-Golgi, and PI4P in the opposite direction. Thus, this mechanism requires ATP to maintain PI4P gradient. Similarly, Osh4p transfers ergosterol between ER and trans-Golgi in yeast. A contribution of ORP6 was investigated in THP-1 macrophages and HepG2 hepatocytes. ORP6 localizes in early endosomes, lysosomes, and the endoplasmic reticulum. Loading of THP-1 cells with cholesterol by acetylated low-density lipoprotein (acLDL) induces ORP6 expression. At the same time ORP6 knockdown inhibits cholesterol efflux to apoA-I and HDL in THP-1 macrophages and inhibits cholesterol efflux to apoA-I in HepG2 hepatocytes. Thus, ORP6-dependent cholesterol supply from the intracellular sources significantly affects cholesterol efflux. StAR (or STARD1) is the founder protein of the STARD family. It transfers cholesterol from the outer mitochondrial membrane to the inner mitochondrial membrane in steroidogenic tissues for hormone synthesis. StAR overexpression stimulates cholesterol efflux by activating LXR and stimulation of ABCA1 expression. STARD3 protein is anchored to late endosomes and together with ER-anchored vesicle-associated membrane protein-associated proteins A and B STARD3 contributes to formation of MCSs between endosomes and ER. Overexpression of STARD3 in HeLa cells, which express STARD3 at very low level, promotes accumulation of cholesterol in LE, while not changing the total cell cholesterol level.avtomix.com/upload/files/boss-550-manual.pdf Cholesterol depletion of the cells does not prevent cholesterol accumulation in endosomes, while inhibitor of cholesterol synthesis mevinolin prevents the endosomal cholesterol accumulation that indicates on the ER-synthesized cholesterol transport by STARD3. All together, it suggests that STARD3 mediates cholesterol traffic from ER to endosomes, and this route competes with ER to PM traffic. In HepG2 hepatocytes expression of STARD4 is induced when cells are incubated in cholesterol-poor conditions. The overall effect of knockdown of the STARD4 on the cell cholesterol level and intracellular distribution depends on the cell type. Sterol carrier protein 2 (SCP-2) binds cholesterol and phospholipids with high affinity. It is localized in peroxisomes and in cytoplasm and involved in cholesterol and phospholipid intracellular transfer. The study of SCP-2-deficient fibroblasts from patients with Zellweger syndrome revealed that roughly 50 of ER to PM transport of newly synthesized cholesterol is cytoskeleton- and Golgi-dependent, in contrast to the transport in normal fibroblasts, which does not depend on the cytoskeleton and Golgi. Overexpression of SCP-2 in McA-RH7777 rat hepatoma cells sharply increases the rate of the transfer of newly synthesized cholesterol from ER to PM and the amount of newly synthesized cholesterol in the secreted HDL. The overexpression also decreases the rate of CE synthesis without affecting the acyl-CoA:cholesterol acyltransferase and neutral cholesterol ester hydrolase activities measured in vitro. Possible clue to explanation of negative effect of SCP-2 on cholesterol efflux is the inverse relationship between the expression of SCP-2 and liver fatty acid-binding protein (L-FABP aka FABP1). L-FABP is a hepatic cytosolic protein that binds long-chain fatty acids and other hydrophobic molecules including cholesterol. Thus, overexpression of SCP-2 might possibly repress the expression of L-FABP and inhibit the efflux. Besides cytoplasmic localization, SCP-2 and L-FABP are found on the PM in close proximity to SR-BI. In fibroblasts, at least 70 of cholesterol from LDL is quickly transported to caveolae domains of PM by a Golgi-dependent pathway. This path does not depend on the functional cytoskeleton. The rest of cholesterol from LDL is transported from lysosomes to the ER. In yeast, contrary, newly synthesized ergosterol, the major yeast sterol, first appears mostly in non-raft fraction of PM. Caveolae formations start with expression of integral membrane proteins caveolin-1 or caveolin -2 in ER followed by their oligomerization (7-14 molecules of caveolin) and COPII-dependent transportation to the Golgi. The oligomer size in the Golgi increases to 18-25 molecules of caveolin and the oligomer-associated membrane saturates with cholesterol molecules. Then the cholesterol-rich complex is transported from trans-Golgi network to PM by four phosphate-adapter protein (FAPP1, FAPP2) secretory vesicles. Caveolin family consists of three genes. Contrary to stimulatory effect of caveolin-1 on cholesterol efflux observed in the most other cell cultures, mouse embryonic fibroblasts from caveolin-1 knockout mouse have an increased efflux to apoA-I compared to the cells from wild type animal. Induction of ABCA1 gene expression by LXR agonist increases this difference. Caveolin-1 disruption partly prevents apoA-I from its internalization into the cells and degradation. All the proteins mediating efflux from PM to extracellular acceptor are also involved in the intracellular cholesterol traffic and cholesterol distribution between various intracellular pools. The aqueous diffusion occurs for any cells; however, its contribution to the total cholesterol efflux for most of the type of cells is relatively small. All three proteins interact with other proteins at cholesterol efflux and the most significant pairs are given on Figure 2. Open in a separate window Figure 2 Protein-protein interactions involved in cholesterol efflux by cholesterol transporters. Data for human ABCA1 (a), ABCG1 (b), and SR-B1 (SCARB1) (c) molecules were imported from STRING database with Cytoscape STRING plugin. Table 2 The contribution of specific pathways in cholesterol efflux. The estimations are from the tables, texts, and graphs in the cited papers. Some values do not give a total of 100, probably because of the rounding of the data in the tables. Efflux values are given as a percentage of total cell cholesterol and the contribution of pathways in the original studies was estimated using inhibitors of ABCA1 and SR-BI (probucol and BLT-1), if other is not mentioned.The serum was from healthy nonsmokers; efflux for 4 hours. The efficiency of nondirectional diffusional transfer of cholesterol is determined by the cholesterol capacity of the membrane and the kinetic factors—the rate of desorption and the concentration gradient. When measuring the rate of intermembrane cholesterol transfer, the following deviations from the diffusion mechanism were observed: (1) the rate of cholesterol transfer from erythrocytes to acceptors was inversely related to the size of the acceptor; (2) the rate of cholesterol transfer from erythrocytes to the erythrocyte ghosts increased with the addition of plasma, while the opposite effect could be expected due to competition between ghosts and plasma components that act as cholesterol acceptors; (3) the rate of transfer decreased upon the dilution of the mixture of erythrocytes and ghosts but did not obey the second-order kinetics; (4) cholesterol in the membranes of the bovine retina rod cells is not in equilibrium with the cholesterol of the plasma and its content increased after incubation with plasma; (5) the deviation of transfer kinetics from the diffusion model can not be explained by the presence of a non-stirred layer, since the transfer rate of lysolecithin was three orders of magnitude higher. However, the transfer of cholesterol between vesicles and reconstituted HDL (rHDL) was not consistent with aqueous diffusion or collision mechanisms. It was suggested that apoA-I of rHDL interacts with vesicles, which facilitates the transfer of cholesterol, and the interaction depends on the conformation of the apolipoprotein. Opposite, the collision mechanism at cholesterol exchange between vesicles and rHDL (apoA-I-containing nanodiscs) was discarded in the work of Matsuzaki et al. The authors postulated the importance of the diffusion mechanism with cholesterol dissociation from the vesicles as a rate-limiting step of the cholesterol transfer. The authors suggested that it might be explained by denser bilayer packing in rHDL. Another reason may be the appearance of “active” cholesterol in the nanodiscs due to the heterogeneity of the distribution of cholesterol in discoidal lipoproteins. Another study demonstrated that ABCA1 participates in the cholesterol traffic from PM to ER. This PM to ER flow is mediated by ABCA1 by about 50 in mouse embryonic fibroblasts. ATP hydrolysis in two hydrophilic domains of ABCA1 results in a change in the protein conformation accompanied by the transfer of the transported molecule to the outer part of the membrane. ABCA1 molecules undergo palmitoylation of cysteine residues 3, 23, 1110, and 1111. In the absence of these modifications, the transporter molecules remain inside the cell. Cholesterol efflux mediated by ABCA1 results in the formation of discoidal HDL, containing two, three, or four molecules of apoA-I per particle. Nascent HDLs are heterogeneous in size and composition and contain the main classes of lipids present in plasma membrane. The nature of the molecular interaction between various cholesterol acceptors and ABCA1 is controversial, and two alternative models suggesting a direct protein-protein interaction or indirect association have been proposed. Both models recognize the significant contribution of the interaction of apoA-I and membrane lipids in the ABCA1-mediated cholesterol efflux. ABCA1 translocates phospholipids to the exofacial leaflet of the plasma membrane bilayer that creates membrane tension. The alternative model questions the exclusiveness of the direct interaction of apoA-I and ABCA1. Experiments on human fibroblasts have shown that most (90) of the apoA-I molecules bind to the HCBS (high capacity binding site), and not to ABCA1. Interestingly, HCBS is not a part of the lipid rafts. There is some inconsistency in the data on ABCG1 localization. In a recent study in CHO and HeLa cell lines that were transfected to stably express ABCG1 fused with Myc tag or green fluorescent protein (GFP), the transporter was distributed between PM and ER pools. ABCG1 is palmitoylated at positions 26, 150, 311, 390, and 402. Interestingly, ABCG1, in addition to cholesterol, transports sphingomyelin, and different structural motifs are responsible for binding of these lipids. There is no specific binding of the transporter to the lipoprotein in ABCG1-mediated efflux of cholesterol. For SUV, LDL, and rHDL discs as cholesterol acceptors, the kinetics of the ABCG1-mediated efflux corresponds to the aqueous diffusion mechanism, and ABCG1 increases the pool of active cholesterol available for efflux. The kinetics of efflux with HDL 2 and HDL 3 deviates from the kinetics for diffusion, presumably due to the shielding by apolipoproteins of cholesterol-accepting phospholipid patches. In experiments with BHK cells, the size of the pool of cholesterol available for efflux on HDL 3 as an acceptor was about 20 of total cell cholesterol. Neufeld et al. also observed the increase of the pool of active cholesterol available for efflux. Both PM- and late endosome-localized ABCG1 contributed to the stimulation of cholesterol efflux. Nevertheless, HDL binding to SR-B1 is about 150-fold lower than the binding of LDL to LDL receptor. The weaker binding and the faster dissociation of HDL from SR-B1 can explain why HDL does not undergo endocytosis. The isotherm of binding of HDL to SR-B1 on the cell surface most corresponds to the presence in SR-B1 of one high affinity and one low-affinity binding sites. The rate of cholesterol transfer from HDL increases proportionally with their CE content. This mechanism can be viewed as a facilitated diffusion. It is assumed that the transfer of cholesterol similarly occurs through the hydrophobic channel. Perhaps the cholesterol-binding motifs predicted by us in the structure of SR-B1 (Dergunov et al., 2018 submitted ) are responsible for the redistribution of cholesterol in the membrane.