Is Cholesterol Only Found In Animal Cells
Int J Mol Sci. 2022 January; 23(1): 533.
Cholesterol in the Cell Membrane—An Emerging Player in Atherogenesis
Karel Paukner
oneLaboratory for Atherosclerosis Research, Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, 140 21 Prague, Czech Republic; zc.meki@akvi (I.K.50.); zc.meki@opur (R.P.)
2Department of Physiology, Kinesthesia of Scientific discipline, Charles University, 128 44 Prague, Czech Republic
3Faculty of Veterinary Medicine, University of Veterinary Sciences Brno, Small Animate being Clinic, 612 00 Brno, Czechia
Ivana Králová Lesná
1Laboratory for Atherosclerosis Enquiry, Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 140 21 Prague, Czech Commonwealth; zc.meki@akvi (I.K.L.); zc.meki@opur (R.P.)
4Department of Anesthesia and Intensive Medicine, Offset Faculty of Medicine, Charles Academy and Academy War machine Hospital, 128 08 Prague, Czech Democracy
Rudolf Poledne
1Laboratory for Atherosclerosis Research, Eye for Experimental Medicine, Plant for Clinical and Experimental Medicine, 140 21 Prague, Czechia; zc.meki@akvi (I.One thousand.L.); zc.meki@opur (R.P.)
Evgeny East. Bezsonov, Academic Editor
Received 2021 Dec 14; Accepted 2021 Dec xxx.
Abstract
Membrane cholesterol is essential for jail cell membrane backdrop, simply every bit serum cholesterol is important for the transport of molecules between organs. This review focuses on cholesterol transport between lipoproteins and lipid rafts on the surface of macrophages. Recent studies exploring this machinery and recognition of the central dogma—the cardinal role of macrophages in cardiovascular illness—have led to the notion that this transport mechanism plays a major role in the pathogenesis of atherosclerosis. The exact molecular mechanism of this transport remains unclear. Future research will ameliorate our agreement of the molecular and cellular bases of lipid raft-associated cholesterol transport.
Keywords: cholesterol, macrophages, cell membrane
1. Introduction
A century of cholesterol enquiry has revealed, step by step, the dietary cholesterol event in experimental atherosclerosis [1], the human relationship betwixt atherosclerosis and dietary fat consumption [ii], and cholesterol physiological synthesis [3]. Furthermore, low-density lipoprotein (LDL) has been identified every bit a carrier of cholesterol in the apportionment [4], and high LDL levels as a key risk factor of atherosclerosis and myocardial infarction [five]. More recently, the importance of the function of a specific LDL receptor in the regulation of claret cholesterol levels has been described (reviewed in [6]). Lately, the increased use of statins to lower the levels of LDL-cholesterol [seven] and the proprotein convertase subtilisin-kexin type 9 inhibitor (iPCSK9) disruptor blockade arroyo have been described.
Cholesterol and the phospholipid components of the cell membrane are important for normal jail cell function, and erratic lipid distribution or metabolism tin can have serious consequences for cells and the body. The membrane has a number of most important functions, such every bit serving as a permeability barrier and signaling through phosphoinositides. Numerous authors accept shown that the biophysical characteristics of the membrane bilayer can have major effects on the properties of membrane proteins [eight]. Changes in lipid organization can largely touch various cellular functions, such equally membrane trafficking or signal transduction. These membrane-related effects can cause affliction in living organisms due to genetic alterations, environmental factors (e.g., high dietary intake of saturated fats), or both [9]. The membrane is essential for prison cell existence, with cholesterol being an of import determinant of membrane organization. Cholesterol is obtained mostly from food, and synthesized by nearly all cells [10], but predominantly the liver and intestine. The liver also plays a crucial role in the availability of lipoproteins, the main cholesterol acceptors and carriers.
Its homeostasis is maintained through diverse mechanisms. The recommended total serum cholesterol level is nether v mmol/L. Hypercholesterolemia has been successfully managed by statins over decades. However, recent information also suggest that the anti-inflammatory consequence of statins direct impacts the macrophage phenotype, and the proportion of macrophage subpopulations in adipose tissue. The rates of cholesterol influx versus efflux through the cell membrane tin can bear upon the cholesterol content of lipid rafts in the prison cell membrane and may influence macrophage polarization and their inflammatory condition. The office of the cell membrane in reverse cholesterol ship (RCT) (meet below) is yet to exist clarified. Cholesterol dysfunctionality may lead to structural and functional modifications, resulting in proatherogenic weather and plaque progression up to the development of overt atherosclerosis. In this review, we volition briefly summarize cholesterol trafficking and its influence on membrane organisation and macrophage functions.
ii. Cholesterol Homeostasis
The mammals take developed sophisticated and complex mechanisms to maintain plasma cholesterol levels, as well every bit cell membrane cholesterol levels, inside a narrow physiological range [11]. In humans, 1 of the well-nigh significant factors affecting cell membrane functions and structure is the dietary intake of various fatty acids and cholesterol, which are later on delivered to cells throughout the body by lipoproteins. Cholesterol levels in the cell must be maintained within a homeostatic range; when these homeostatic mechanisms are weakened, such as in the after stages of atherosclerosis evolution, the consequences can be serious. Cholesterol imbalance leads to changes in membrane lipid arrangement, to symptoms of affliction and, in the case of atherosclerosis, for case, to plaque progression [ix].
Despite the important office of cholesterol in various cellular functions, regular plasma cholesterol levels in the populations of industrialized countries significantly exceed the physiological requirements. The influence of excess cholesterol intake on macrophage properties was demonstrated in an experimental model, where atherosclerosis-decumbent apolipoprotein E-scarce mice were fed the Western pattern diet. Within several days, circulating murine monocytes crossed the endothelium and increased their influx to the intima [12]. In humans, the complex coaction betwixt the genotype and the phenotype was documented in a long-term analysis of the lifespan of a large Dutch family with a monogenic disease called familial hypercholesterolemia (FH). This written report was possible thanks to the complete registry of all births and deaths, as well every bit marriages, since the mid-19th century. All three selected subjects had an identical disorder of the LDL receptor; they were heterozygous for the V408M mutation, and their family tree consisted of seven generations. Results revealed a variable lifespan over time from the mid-19th century until contempo times. Quite surprisingly, the average lifespan of FH individuals was longer compared with that of the average Dutch population in the 19th century. A change came around 1920 when nutrient availability and animal fatty consumption increased, whereas the lifespan of FH individuals (with increased LDL cholesterol levels) shrunk. This was true until the 1960s when the awareness of the run a risk of cholesterol increased and, currently, at that place is no difference in the lifespan between FH individuals and controls. 1 can speculate that, in the 19th century, mortality from factors other than atherosclerosis-related causes, mainly infectious diseases, was so loftier that people died before they were able to develop cardiovascular illness. Hence, hypercholesterolemia and induced macrophage phagocytic activity may have conferred a survival advantage when communicable diseases was prevalent [13,xiv,15].
Given the in a higher place, information technology may have been the consequence of the nutrition high in cholesterol after the Second Earth War which caused the increase in bloodshed in FH individuals. The recurrence of backlog bloodshed close to the mean age was probably related to handling with statins [13]. This hypothesis was supported by experiments with genetically modified mice with loftier cholesterol levels, documenting increased protection confronting Gram-negative infections [xvi]. Together with the accelerated migration of allowed cells into the arterial wall, elevated levels of LDL cholesterol particles and low levels of loftier-density lipoprotein (HDL) particles are believed to exist among the major risk factors for the development of atherosclerosis [17]. Recently, the synergistic issue of monocyte properties and their cholesterol intracellular content was reported [18]. Loftier-sensitivity C-reactive poly peptide (hsCRP) is a common mark of inflammation. Data from Ridker's studies suggest the key part of inflammation in the development of atherosclerosis and cardiovascular events. One of the studies demonstrated that the rate of death from ischemic eye disease (IHD) of individuals with low hsCRP levels (<1 mg/100 mL) was significantly lower, whereas those with high hsCRP levels (>3 mg/100 mL) showed a higher IHD prevalence [nineteen,xx]. This finding documented the synergy of high intravasal cholesterol levels and the pro-inflammatory status of the torso. In fact, all patients with low hsCRP levels afterward statin therapy were reported to have more favorable clinical outcomes than those with higher hsCRP levels, despite significant reductions in LDL-cholesterol levels [21]. This "residual inflammatory risk" seems to be a suitable target for pharmacological treatment [22]. In add-on, hsCRP levels provide significant prognostic data on one'southward first cardiovascular event [19,twenty]. In a recent clinical study (CANTOS), handling with interleukin 1β monoclonal antibodies (canakinumab) led to the effective reduction of not only hsCRP levels, but likewise, myocardial infarction-related mortality rates [23]. It is necessary to stress that although the recent utilise of hsCRP as an inflammation marking is of import for epidemiological and clinical research, it is not informative in individual cases.
Not only do high atherogenic lipoprotein particles influence macrophage changes in both adipose tissue and the arterial wall [24], simply the acute-phase response downregulates RCT [25,26]. Information technology is at present well established that the atherosclerotic plaque contains both pro-inflammatory (M1) and anti-inflammatory (M2) macrophages. The primal role of macrophages in the pathophysiology of atherosclerosis has fatigued attending to their properties in plaque initiation and progression, also equally regression. Data reported to date have demonstrated that the nutrition-induced disadvantage of elevated intravascular cholesterol levels acts in synergy with pro-inflammatory macrophage polarization by increasing cholesterol influx into the arterial wall [27].
three. Cholesterol Ship
Cholesterol accumulation within the cell is the consequence of an imbalance between the delivery to and removal of cholesterol from cells past lipoproteins. Commitment of cholesterol occurs past frontwards cholesterol transport, with apoB-containing lipoproteins, mainly native or modified LDL [28], playing a key role in the delivery of cholesterol esters to cells by receptor-mediated endocytosis. The removal of cholesterol from cells occurs via RCT, whereby the gratuitous cholesterol is transferred from cells to apolipoprotein A-ane (apoA-I), the major constituent protein in HDL. Cholesterol is later on esterified and exchanged within circulating lipoproteins, and transported to the liver and intestine for excretion. In this way, HDL particles (probably their small subfraction) play a pivotal role in the maintenance of cellular cholesterol homeostasis and, hence, in preventing the development of hypercholesterolemia and atherosclerosis. The fact that most of the cholesterol in our body is transported every bit cholesterol esters with plasma lipoproteins, serving every bit the principal vehicle for cholesterol transport, are considered the ii key elements of this current epitome [29]. Still, several recent studies take suggested that the transport of free cholesterol between its various pools within the trunk is much faster, and may be quantitatively more of import than the transport of esterified cholesterol to be excreted via the liver [30] and intestine [31,32]. In addition, plasma lipoproteins are in constant directly contact with blood cells and endothelial cells of the vascular wall, which contain considerable amounts of costless cholesterol, and may therefore significantly impact plasma cholesterol transport [29].
Recently, it was hypothesized that erythrocytes may besides participate in RCT [33]. A study using cholesterol efflux capacity assays, the procedure that mediates the removal of excess cholesterol from cream cells to apoA-I or HDL, demonstrated that erythrocytes can exchange cholesterol with HDL in a bidirectional manner. However, simply one-directional exchanges from erythrocytes towards apoA-I accept been documented to date. In this study, specifically, erythrocytes, HDL and apoA-I, were obtained from homo blood samples. Cell culture was prepared from the THP-ane monocyte line after loading with 3H-labeled cholesterol to imitate foam cells. These parts of the experiment together suggested that erythrocytes may play a significant role in RCT-mediated cholesterol efflux, as a temporary cholesterol store [34]. Another recent study [29] using erythrocytes indicated an active office of erythrocytes in RCT. In this report, erythrocytes were incubated with autologous plasma and the net movement of cholesterol from erythrocytes to plasma lipoproteins was demonstrated. A detailed analysis of cholesterol distribution among lipoprotein fractions revealed the net movement of cholesterol from erythrocytes to HDL and net move of cholesterol from LDL to erythrocytes. In addition, in experiments with isolated lipoproteins, cholesterol motion was minimal after erythrocyte incubation with phosphate-buffered saline (PBS), very low-density lipoprotein (VLDL), or lipoprotein-depleted plasma [29]. The movement was unrelated to cholesterol esterification in the plasma: it was rapid, unaffected past the inhibition of lecithin–cholesterol acyltransferase (LCAT), with its plasma levels being the rate-limiting gene. The movement of cholesterol from erythrocytes to HDL and from LDL to erythrocytes suggested that this cholesterol flux could be part of contrary, rather than frontward, cholesterol transport. Information technology would also, therefore, seem unlikely that the cholesterol flux was the result of the disengagement of cholesterol from the plasma membrane, or the secretion of exosomes from the erythrocytes. Thus, erythrocytes may take up free cholesterol from LDL and, presumably, from modified LDL besides, mayhap lowering the amount of cholesterol which would be delivered to cells in the vessel wall. Erythrocytes may too transport cholesterol direct, by feeding the transport pathway to the intestine or liver for excretion, or conversion to bile acids. Erythrocytes are non-nucleated cells, and the half-life of virtually cholesterol transporters is much shorter than that of erythrocytes [29]. Still, the dynamics and mechanism of cholesterol transport between erythrocytes and plasma lipoproteins have not been fully elucidated yet.
4. The Macrophage–Lipoprotein Interaction in Atherogenesis
The central function of monocytes and macrophages in atherogenesis was first described in the pioneering work of Goldstein and Brown, scientists who detailed the regulation of plasma cholesterol by specific apoB receptors [35]. They explained the function of scavenger receptors for apoB-containing particles on the surface of macrophages [36]. Macrophages with this receptor clean the subendothelial space of big and medium-sized arteries of abundant LDL particles. Macrophages, therefore, are able to maintain the physiological rest of the arterial wall between the current need for cholesterol molecules on the i hand, and adequate or inadequate influx of LDL-carrying particles in hypercholesterolemia on the other [37]. In susceptible areas of medium-sized arteries that are prone to the permeation and subendothelial retention of LDL and remnant lipoproteins, atherosclerotic plaques may form [38]. Moreover, obese adipose tissue affects the adhesion of monocytes to endothelial cells, and their migration to the arterial wall. Adipokines produced in adipose tissue stimulate the production of adhesion molecules, and after increment the adhesion of monocytes to the endothelium [39,40], followed by entry of monocytes into the subendothelial space [41,42]. Macrophage-trapping in the subendothelial space of the vessel wall is also influenced past proteins produced by the macrophages themselves (such as the macrophage colony-stimulating factor, MCSF and macrophage chemotactic gene, MCF).
The differentiation of monocytes into macrophages and, next, into resident macrophages in the subendothelial space of arteries is a about important process in atherogenesis. The development of macrophages into cream cells is always associated with LDL phagocytic activity then, understandably, the product of foam cells is greatly potentiated by abundant LDL particles within the arterial wall. Likewise, atherogenesis is enhanced by a subtract in RCT activeness [43], and an increment in the intravascular levels of triglycerides and their accumulation in macrophages of the arterial wall, whereby remnants of very-depression-density lipoprotein (VLDL) particles enter the arterial wall and become trapped in macrophages [44]. The recruitment of foamy monocytes to the inflamed endothelium-expressing vascular cell adhesion molecule-one (VCAM-1) contributes to plaque formation during atherogenesis. Lipid uptake and CD11c activation are early and critical events in signaling the agglutinative office of very late antigen-4 (VLA-4) on foamy monocytes, which can recruit monocytes through VCAM-i on the inflamed arterial endothelium [12]. Lipoprotein inflow promotes the intracellular aggregating of lipid droplets in the cytoplasm to grade foam cells, and the inflammatory cellular response. The process continues over a long menstruation of time, up to many years, and may be amplified through the further promotion of lipoprotein retention, and the attraction of more white blood cells [38].
Differentiation of monocytes into residential macrophages is regulated by several transcription factors [45,46,47]. One of the significant differentiation factors is caveolin (a structural protein of intracellular caveolae), which stimulates the transcription of several pro-inflammatory mediators and surface receptors of macrophages [48]. Caveolin promotes the synthesis of CD36 (fat acid translocase) on the macrophage surface [49,50]. This transmembrane protein mediates the caveolar endocytosis or phagocytosis of oxLDL in macrophages. Moreover, caveolin, CD36, and CD14 were cofractionated in the lipid raft [26,50,51,52]. In this way, CD36 could contribute to the retention of macrophages in atherosclerotic lesions and their subsequent conversion into foam cells [53,54]. One may also speculate on the role of the macrophage-producing poly peptide netrin-1, a neuroimmune guidance cue, which is likewise abundantly expressed by macrophage foam cells in atherosclerotic plaques, where its expression promotes the accumulation of macrophages and affliction progression [55]. The expression of netrin-1 is stimulated intracellularly by the result of saturated fatty acids (SAFAs) such as palmitate [56]. This may indicate an atherogenic upshot of SAFAs in addition to their well-known effect on hypercholesterolemia. In add-on to the transcription factors, the non-coding RNAs represent yet some other form of regulation of monocyte differentiation [57].
Another regulatory gene leading to the differentiation of monocytes into residential macrophages is the modification of circulating lipoproteins, with the modification of LDL cholesterol, namely desialylation (cleavage of sialic acid from native LDL), seemingly being the nearly fundamental [58]. Sialic acid represents the terminal saccharide of biantennary sugar chains in apolipoprotein B. In this pace, LDL becomes smaller and denser than native LDL [59,lx]. Desialylated LDL is more sensitive to oxidation [61] and self-association [62]. Modified LDL is more prone to be deposited in the vessel wall compared with the native LDL; these clusters are also more than probable to be phagocytosed [63]. All of these events help in the evolution of an inflammatory condition and, ultimately, the development of atherosclerosis.
5. Cholesterol in Cell Membrane and Rafts
Equally described above, cholesterol is a major lipid in the plasma membrane of mammalian cells, and plays various structural and functional roles. Cellular unesterified cholesterol is primarily (upwardly to 90%) localized in the plasma membrane [64] and is essential for its physical integrity. Cholesterol has been implicated in the structural and functional modulation of integral membrane proteins and in the germination of cholesterol-rich membrane domains called membrane (lipid) rafts (Figure 1). It affects the physiological features of the jail cell membrane by decision-making its fluidity, and regulating the negative membrane curvature through interaction with phospholipid acyl chains [65]. Another essential interaction is hydrogen bond formation between cholesterol and sphingomyelin. Lateral interactions of cholesterol with SAFAs or glycosylated lipid species divide the membrane into two singled-out liquid phases. These interactions are essential for creating liquid-ordered membrane microdomains [66]. First, cholesterol in the inner leaflet of the plasma membrane may regulate diverse prison cell signaling pathways by specifically interacting with cytosolic scaffold proteins in a stimulus-dependent manner [67]. Second, the inner leaflet cholesterol levels were shown to modulate neurotransmitter receptor trafficking [68], the cytoskeleton and motion [68] and the intercellular behavior of cells [69]. Collectively, these studies betoken to a potential link between the inner leaflet cholesterol levels and diverse cellular processes, and suggest the importance of the transbilayer asymmetry of plasma membrane cholesterol. The asymmetry is maintained by the agile ship of cholesterol from the inner leaflet to the outer one, and its chemical retention in the outer leaflet. Finally, the increase in cholesterol levels in the inner leaflet is triggered in a stimulus-specific manner, with cholesterol serving as a signaling lipid. The transbilayer disproportion of plasma membrane cholesterol and the stimulus-induced plasma membrane cholesterol redistribution are crucial for tight regulation of the cellular processes nether physiological weather [70]. Despite recent information, the concept of the transbilayer distribution of cholesterol in the plasma membrane of mammalian cells is notwithstanding considered controversial, partly because the assumed lipid rafts have not been visualized in the living cell yet. Analysis using radiometric cholesterol sensors have shown that the bachelor cholesterol levels in the inner leaflet of the plasma membrane were low in unstimulated cells, and increased in a stimulus-specific manner to trigger cell signaling events. These differences support the hypothesis that cholesterol in the inner leaflet is kept low in unstimulated cells. The basal inner leaflet cholesterol levels vary significantly among cells [71]. The virtually recent data accept demonstrated that the asymmetric distribution is maintained by ABCA1 (ATP-binding cassette transporter ABCA1) and ABCG1 (ATP-bounden cassette sub-family G member 1) and their ATP-dependent cholesterol flopase activity, and past the ability of sphingomyelin in the outer leaflet to deter the reverse translocation of cholesterol to the inner leaflet [71].
Schematic phospholipid bilayer cell membrane with cholesterol molecule (red symbol) and location of transmembrane receptor. Cholesterol asymmetry represents unlike proportions of cholesterol in the outer and inner phospholipid layers. Ship of cholesterol to the surface raft from plasma lipoproteins and possible contrary efflux.
Despite the above controversy, there is general agreement that unstable nanoscale assemblies within the membrane, primarily oligomeric protein–cholesterol–lipid complexes, associate into larger liquid-ordered functional nanodomains, also known as lipid (membrane) rafts. Lipid rafts are defined equally small-scale (10–200 nm) heterogeneous, highly dynamic cholesterol-, sphingolipid- and protein-enriched domains that compartmentalize cellular processes [72]. Lipid rafts are dynamic assemblies of both proteins and lipids, which contain various receptors and regulatory molecules, and act equally a indicate transduction platform. The rafts float freely within a liquid-matted bilayer of cellular membranes and tin cluster to class larger ordered domains. Several singled-out classes of proteins are commonly incorporated—true resident proteins (glycosylphosphatidylinositol-linked proteins, caveolin, flotillin), signaling proteins (doubly acylated proteins similar Src family kinases), G-protein-coupled receptor (GPCR) proteins, cholesterol linked and palmitoylated and myristoylated proteins [73]. Proteomic analyses of membrane lipid raft limerick take shown that, in improver to the dominant presence of sphingolipids (generally sphingomyelin), cholesterol, and glycolipids, and other phospholipids, including some species of phosphatidyl serine and phosphatidyl ethanolamine (PE), with by and large fully saturated or monounsaturated acyl bondage, are also present [74,75].
Two types of lipid rafts are by and large described: planar lipid rafts (also known as non-caveolar) and caveolae. Planar rafts grade continuous non-invaginated membrane domains lacking any distinguishing morphological features, while caveolae are flask-shaped invaginated membrane structures formed past caveolin protein polymerization. Caveolins are transmembrane palmitoylated proteins forming a hairpin-like construction that binds tightly to cholesterol [76]. Three isoforms (caveolin-1, -2 and -iii) transcribed from dissimilar genes have been identified. Of the iii caveolins, caveolin-ane is known to modulate inflammatory responses [77]. Signal transduction is of particular importance in white blood cells, and upstream in the signaling pathway, many membrane receptors are functional simply as complexes that assemble with specific lipid species [78].
The lipid rafts serve equally a platform for betoken transduction, particularly in the immune and inflammatory responses; for instance, the T-prison cell antigen receptor (TCR) is a multisubunit allowed recognition receptor, crucial for the adaptive allowed response involved in signaling and engaging the lipid rafts in the process. T-cell antigen receptor activation changes the properties of the TCR complex and linked cytoplasmic raft-associated proteins, with the assembly becoming detergent-resistant upon TCR activation. Cholesterol depletion by methyl-beta-cyclodextrin dissociates these proteins from the lipid rafts, and inactivates the TCR signaling cascade. Moreover, the lipid rafts too part to concentrate major histocompatibility circuitous (MHC) grade Ii molecules, loaded with specific peptides on the surface of antigen-presenting cells [73]. Given the lipid raft interest in immune cell signaling, it is not surprising that lipid raft alterations are commonly found to be associated with the pathogenesis of various man diseases [79]. Knockdown of the caveoline-one protein in an fauna model was shown to lead to innate immunity defects, with affected mice condign more susceptible to infection [77]. A study analyzing adipose tissue macrophages from living human being kidney donors revealed the pro-inflammatory event of palmitic and palmitoleic acids [eighty]. The proportion of pro-inflammatory CD14 + CD16 + CD36high adipose tissue macrophages increases in visceral adipose tissue with the rising proportions of palmitic and palmitoleic acids in the phospholipids of the cell membrane [75]. Also, the proportion of these pro-inflammatory macrophages in adipose tissue increases with the major cardiovascular risk factors [81]. In our contempo review, we suggested that pro-inflammatory macrophages participate in synergy with higher LDL-cholesterol levels in atherogenesis [82]. Cost-like receptors (TLRs) are part of the innate immune system that acts as the master sensor of pathogens, and inquiry has demonstrated that the integrity of lipid rafts is crucial for normal TLR signaling. Tsai et al. broadly showed that caveolin-one regulates not only TL4 signaling, but also CD14, CD36 and MyD88 protein expression in macrophages and their response to bacterial infection [50]. Using cyclodextrin (for cholesterol depletion), Molfetta et al. reported that lipid raft integrity is essential for receptor ubiquitination and endocytosis, which is further involved in downstream signaling [83]. Cytokine signaling is altered by the disruption of cellular lipid rafts, attenuating the cytokine response. Decreased interferon gamma (INFγ) signaling was observed in Leishmania donovani-infected macrophages of Kala-azar patients. 50. donovani increases membrane fluidity and perturbs the INFγ receptor (IFNGR1 and INFGR2) subunit assembly of the receptor occurring in normal macrophage lipid rafts. The depletion of macrophage membrane cholesterol by exogenous liposomal commitment restores INFγ signaling in infected macrophages [84].
Due to the lipid rafts' increased cholesterol content, raft domains exhibit lower fluidity than the surrounding membrane [74]. The cell membranes of solid tumors, such as breast cancer, incorporate college levels of cholesterol compared with normal jail cell membranes, with the implication being that larger raft domains can class in those membranes. This may stimulate signaling pathways to promote tumor growth and progression. An emerging area of research indicates a part of membrane rafts in neoplastic or tumor cell growth and invasiveness [74]. In accordance with this, an elevated level of blood cholesterol has been shown to increase the membrane raft content, promote tumor growth, and reduce apoptosis in prostate cancer [85]. Experiments with cholesterol depletion accept largely improved our understanding of the effect of membrane raft disorganization on cellular activity. Since hypercholesterolemia and low-form inflammation are key elements of atherogenesis, it is conceivable that the cholesterol (and its oxidized forms) content of lipid rafts probable influences the inflammatory signaling pathways, thereby modulating, among other things, the development of atherosclerosis. Indeed, the involvement of lipid rafts in several key steps in atherogenesis, such equally the oxysterol-mediated apoptosis of vascular cells, attenuated the ability of HDL to exert anti-inflammatory effects and increased secretion of pro-inflammatory cytokines past white blood cells, has been documented [86].
6. Conclusions
In conclusion, is at that place any robust evidence that an increase in raft cholesterol of monocytes and macrophages is a significant histrion in general immune signaling? Although the relationship of a drib in LDL-cholesterol to pro-inflammatory parameters in a big clinical written report was demonstrated more than than a decade ago [87], its mechanism is nevertheless unclear. Nosotros already know that there is an intensive cholesterol molecule exchange on the cell surface [29,33,34] and that the plasma cholesterol levels increase the proportion of pro-inflammatory macrophages in human adipose tissue. On the other paw, stimulation of RCT past an HDL subfraction seems to accept an opposite effect [88,89]. Unfortunately, any evidence of the presence of lipid rafts on the surface of a living cell is yet to be plant. Further research is warranted to evaluate the mechanism and identify the role played by lipid raft cholesterol in atherogenesis.
Abbreviations
| apoA-I | apolipoprotein A-1 |
| apoB | apolipoprotein B |
| FH | familial hypercholesterolemia |
| HDL | high-density lipoprotein |
| hsCRP | loftier-sensitivity C-reactive protein |
| IHD | ischemic heart illness |
| LDL | low-density lipoprotein |
| MHC | major histocompatibility complex |
| oxLDL | oxidized depression-density lipoprotein |
| RCT | reverse cholesterol transport |
| SAFAs | saturated fat acids |
| TLRs | toll-like receptors |
| VLDL | very-low-density lipoprotein |
Author Contributions
All authors writing—review and editing. All authors accept read and agreed to the published version of the manuscript.
Funding
This projection was supported by the Ministry building of Health of the Czechia, grant no. NU20-01-00022.
Conflicts of Interest
The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Footnotes
Publisher's Notation: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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