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Diana Cardoso, Esperanza Perucha; Cholesterol metabolism: a new molecular switch to control inflammation. Clin Sci Lond 11 June ; 11 : — The immune system protects the body against harm by inducing inflammation. During the immune response, cells of the immune system get activated, divided and differentiated in order to eliminate the danger signal. This process relies on the metabolic reprogramming of both catabolic and anabolic pathways not only to produce energy in the form of ATP but also to generate metabolites that exert key functions in controlling the response.
Equally important to mounting an appropriate effector response is the process of immune resolution, as uncontrolled inflammation is implicated in the pathogenesis of many human diseases, including allergy, chronic inflammation and cancer. In this review, we aim to introduce the reader to the field of cholesterol immunometabolism and discuss how both metabolites arising from the pathway and cholesterol homeostasis are able to impact innate and adaptive immune cells, staging cholesterol homeostasis at the centre of an adequate immune response.
We also review evidence that demonstrates the clear impact that cholesterol metabolism has in both the induction and the resolution of the inflammatory response. Cholesterol metabolism is generally associated with an unhealthy diet and atherosclerosis.
However, it entitles a much more complicated and fascinating metabolic route, where its metabolites and regulatory circuits have profound effects at the cellular and whole organism level.
Among these effects, cholesterol metabolism affects the immune response and the capability of organisms to clear infection and tumour cells, while maintaining homeostasis and health. In this work, we aim to summarise some of the fundamental roles of cholesterol metabolism in controlling the fate of both innate and adaptive immune cells.
First, we will briefly introduce both the immune response and basic concepts of cholesterol metabolism. We will then address some of the molecular mechanisms that link immune function with cholesterol metabolites and regulatory elements.
We will conclude with some relevant examples of how this knowledge is being harnessed to understand human disease, to develop new therapeutic targets and to repurpose current treatments. It is mainly mediated and controlled by the immune system, a complex network of cells and molecules distributed throughout the body.
The immune system detects and eliminates danger in the form of pathogens, dead cells or stress signals by eliciting an immune response. In brief, upon recognition of antigen, the immune system activates innate immune cells such as monocytes and neutrophils that respond rapidly to the challenge. They secrete soluble mediators like cytokines, complement molecules and prostaglandins, that drive the inflammatory cascade and promote effector functions such as phagocytosis.
Innate immune cells recognise pathogen- or danger-associated molecular patterns through specific receptors, such as toll-like receptors TLRs [ 1 ]. Once activated, Th cells will differentiate into Th1, Th2 and Th17 subsets according to the signals they receive upon activation.
Once the concentration of antigen decreases, the majority of the immune cells will undergo apoptosis, while some will survive to form the memory pool and ready to respond to the next challenge. The generation of immunological memory can be considered as a long-term event arisen from an inflammatory response [ 2 ]. As important as driving inflammation to eliminate pathogens is the resolution of the process in order to return to homeostasis. Unresolved inflammation causes tissue damage, chronic inflammation and infection, which contribute to the pathogenesis of many diseases such as cancer, rheumatoid arthritis and asthma.
But it is also an active and tightly regulated process where anti-inflammatory mediators and immune-regulatory pathways and cells play a key role. These include cytokines such as IL, lipid metabolites steroids, eicosanoids and immune cells, like T regulatory Treg and B regulatory Breg cells [ 2 , 3 ]. Immune cells need to react rapidly upon encounter with antigen by dividing very actively and acquiring effector function.
To do so, immune cells require nutrients to fulfil the anabolic and catabolic processes driving the effector programme, making the immune response a highly energetically demanding process.
Hence, we now know that there is a critical link between immunity and metabolism at the cellular, tissue and whole organism level [ 4 , 5 ]. In contrast, upon antigenic recognition, activated immune cells undergo metabolic reprograming, switching towards aerobic glycolysis as main source of energy.
Lipid metabolism also plays an important part in this metabolic switch, by up-regulating cholesterol and fatty acid biosynthesis, as we will describe in detail in the following sections. Perturbations in lipid metabolism reprogramming, i. This highlights the key role of cholesterol metabolism in controlling and driving metabolic reprogramming in immune cells.
As both metabolic and immune responses are linked, it is not surprising to observe that dysregulation in these processes are common features of the most prevalent human diseases in First World countries [ 7 ]. These include conditions that have chronic inflammation as a feature, either in low grade such as obesity, type 2 diabetes or high grade such as rheumatoid arthritis, inflammatory bowel disease or sepsis.
Therefore, immune dysfunction can be targeted by modifying cell metabolism. However, while great progress has been made in the field of immunometabolism describing the molecular and cellular pathways that fuel the immune response, more work is expected to come from the use of this knowledge to manipulate the immune response.
Unlike other metabolites, cholesterol cannot be catabolised to generate ATP, and it is toxic in excess. Therefore, at the cellular level, cholesterol content has to be tightly monitored and regulated [ 8 ]. In this section, we will cover basic concepts of cholesterol metabolism that are important in immune cells, including cholesterol uptake and efflux, the cholesterol biosynthesis pathway as well as the machinery that senses cholesterol inside the cell, driving a tight regulatory circuit Figure 1.
The cholesterol biosynthesis pathway and its branches: the mevalonate pathway, the isoprenylation pathway and the sterol pathway. Some important functions in immune cells are highlighted in purple; 3. Excess cholesterol can be transformed into cholesterol esters or exported through HDL; 4.
Myeloid cells can also internalise modified lipoproteins through scavenger receptors like CD36 or lectin-like oxidized low-density lipoprotein receptor-1 [ 13 ]. Cholesterol itself can also be synthesised by the cell via the cholesterol biosynthesis pathway CBP that provides not only a metabolic route that generates cholesterol but also various metabolites that either directly or indirectly have important functions in immune cells. The CBP can be divided in sub-pathways Figure 1.
The first one, the mevalonate pathway, starts with acetyl-CoA and the subsequent formation of 3-hydroxymethylglutaryl-coenzyme A HMG-CoA followed by mevalonic acid synthesis, in a reaction catalysed HMG-CoA reductase HMGCR , a key regulatory step in the pathway and the target of pharmacological inhibition by statins [ 14 ].
Downstream is the formation of farnesyl pyrophosphate FPP , a metabolite that sits at the junction between the sterol pathway and the isoprenylation pathway.
FPP is the precursor of geranylgeranyl pyrophosphate GGPP and together they serve as substrates for donation of prenyl groups, via farnesylation and geranylgeranylation, to small GTPases like Rho and Ras families [ 15 ]. The prenylation enhances hydrophobicity and facilitates membrane anchoring, which is required for correct positioning and signal transduction.
FPP is also the substrate for the synthesis of squalene, which metabolises into 2,3-epoxysqualene via squalene monooxygenase, another crucial regulatory step in the CBP. This step precedes the synthesis of lanosterol, the beginning of the sterol branch of the CBP, which finishes with the synthesis of cholesterol [ 15 , 16 ]. Cholesterol itself is the substrate for the synthesis of important downstream metabolites such as steroid hormones or bile acids, but more relevant in the context of immune cells is the biosynthesis of oxysterols, including hydroxycholesterol HC.
As the Ch25h-deficient mouse has no metabolic phenotype, the physiological role of HC in systemic cholesterol metabolism is unclear, although its function in regulating the immune response is becoming more apparent and it will be discussed later [ 17 ].
Nonvesicular transport is also important for cholesterol distribution between cellular structures [ 20 ] and to monitor cholesterol content between organelles [ 21 ]. Once distributed, excess cholesterol needs to be disposed of to avoid toxicity, either through storage in the form of cholesterol esters through the actions of the acyl coenzyme A: cholesterol acyltransferase ACAT enzymes [ 22 ] or exported outside the cell [ 23 ].
The tight regulation of cholesterol homeostasis occurs through a complex interplay at the transcriptional and post-transcriptional level, allowing fast adaptation to cellular requirements [ 19 ] Figure 1.
Intracellular cholesterol is sensed in the endoplasmic reticulum ER , where levels are regulated through the action of sterol sensors, like sensor response element binding protein 2 SREBP-2 and the more recently described nuclear erythroid 2 related factor 1 NRF1 [ 24 ]. Of note, SREBP-2 transcription can be activated through the mechanistic target of rapamycin mTOR [ 27 ], linking two important metabolic sensors in immune cells.
The transcriptional function of LXR, a nuclear receptor, is engaged in the presence of increased levels of cholesterol within the cell [ 32 ]. Both SREBP-2 and LXR have important functions in controlling the differentiation and effector function of immune cells, sometimes even independently of their role in regulating cholesterol metabolism, as we will discuss in detail.
Despite the central role of cholesterol metabolism in cellular biology, our understanding of how it is linked with the innate and adaptive immune responses is just beginning to emerge.
Traditionally, the pathway has been associated with cholesterol production within the cell and its role in maintaining membrane fluidity [ 33 ] and lipid raft formation. We refer the reader to excellent reviews in this topic [ 34 , 35 ], as in this review we will focus on less well known functions of cholesterol in cells of the immune system. However, cholesterol metabolism also provides metabolites that have specific functions in immune cells, and different than other cells of the body, in a similar way to other metabolic pathways [ 36 ].
For instance, we know that signalling downstream antigen recognition i. Moreover, systemic immunotherapy with IFN has been known to induce hypercholesterolaemia [ 37 ], highlighting the connection between immunity and cholesterol metabolism at both cellular and systemic levels. In this section, we will discuss some of the roles that cholesterol metabolism fulfils in different aspects of the immune response, with a main focus on mechanisms influencing inflammation and resolution.
As a consequence, host cells down-regulate their lipid metabolism upon microbial sensing to protect the body from infection. Pathogens are sensed by TLR, that together with engagement of type I IFN receptors, have a general outcome to downregulate cholesterol metabolism in order to deplete energy reserves that might be used by the pathogen for propagation [ 41—45 ].
Perhaps the best studied example is the formation of foam cells in the atherosclerotic plaque, where excess circulating cholesterol promotes macrophage lipid reprogramming and triggers inflammation. This extensive topic is outside the scope of this review, so we refer the reader to excellent reviews in this field [ 46 , 47 ]. Macrophages are at the centre of the innate immune response, and the downstream events involving lipid metabolism and inflammation have been mostly studied in these cells upon TLR4 stimulation.
Of note, TLR4 is not only a receptor for endotoxin or certain viral proteins but can also elicit sterile inflammation [ 48 ]. Upon TLR4 stimulation and induction of the type I IFN response, both human and mouse macrophages undergo lipid metabolic reprogramming.
This includes alterations in sterol content, such as increases in lanosterol and desmosterol content. Moreover, high lanosterol levels improved anti-microbial capacity by increasing membrane fluidity and reactive oxygen species ROS production [ 49 ]. Similarly, desmosterol accumulation integrates the transcriptional regulation of cholesterol metabolism in foam cells, dampening the inflammatory cascade [ 50 ].
Equally important is the requirement of isoprenylation mediators that regulate effector functions such as ROS production, migration and phagocytosis [ 51 ] and have been traditionally thought to be pro-inflammatory. Furthermore, inhibition of Geranylgeranyl transferase GGTase I has been considered as a therapeutic strategy to treat chronic inflammatory diseases [ 52 ]. However, mice with selective GGTase I deficiency in macrophages have increased pro-inflammatory secretion upon stimulation and develop chronic inflammatory arthritis [ 53 ].
The reasons behind these conflicting studies are still unknown, but more recent data suggest that GTP-loading of specifically Rac1 and not other Rho family proteins is involved in the inflammatory response [ 54 ], demonstrating the complexity in the regulation network of these GTPases.
Not only metabolites but also metabolic flux through the mevalonate pathway is important. In addition to this, a striking role for mevalonate itself has been described in driving the epigenetic reprogramming required for the acquisition of trained immunity, via activation of insulin-like growth factor 1 receptor IGFR-1 and mTOR [ 56 , 57 ]. Cholesterol levels in cellular organelles can also regulate macrophage effector response, with excess ER cholesterol content being an activator of NLR family pyrin domain containing NLRP 3 inflammasome [ 58 ], while in mitochondria it can reduce respiratory capacity, resulting in organelle damage and the release of mitochondrial DNA into the cytosol.
The generated HC is a natural agonist of LXR, and drives an overall anti-inflammatory programme [ 60 ]. In agreement with this model, activation of LXR with pharmacological agonists represses the expression of inflammatory genes by blocking NF-kB activity, inhibiting the production of nitric oxide, cyclooxygenase-2 and IL-6, both in vitro and in vivo [ 28 , 61 ].
The molecular mechanism of this blockade is still not fully understood, but LXR SUMOylation [ 62 ], its role in inducing ABCA1 expression and TLR signalling suppression as a consequence [ 63 ] and its capacity to up-regulate IRF8, driving arginase transcription and the anti-inflammatory macrophage programme [ 64 ] have all been implicated.
On the other hand, LXR signalling deficiency specifically in macrophages shows defects in phagocytosis of apoptotic cells, eliciting a breakdown of self-tolerance [ 65 ].
Apoptotic cells are able to activate LXR, delivering a positive cycle that supresses the inflammatory cascade and drives a tolerogenic programme, thus providing another insight into the role of LXR in preventing inflammation and promoting tolerance. Finally, mice deficient in LXR signalling are more susceptible to infection by intracellular pathogens [ 66 ], while treatment of mice with LXR agonists can ameliorate inflammatory conditions such as lupus-like autoimmunity [ 65 ] and generate protective immune responses against pathogens [ 67 ].
Of interest, not all the studies agree with an anti-inflammatory effect of LXR signalling. Of note, an LXR-responsive element has been reported in the human TLR4 promoter [ 69 ], which might explain some of the pro-inflammatory roles ascribed to LXR activation. Ch25h catabolises the formation of HC from cholesterol and its expression is tightly regulated due to the potent effects of HC in both cholesterol metabolism and immune function.
Interestingly, Ch25h is not an interferon responsive gene in human cells [ 71 ]. In addition to this, it can exert very potent immunomodulatory roles independently of LXR regulation, via mechanisms that are still poorly understood and somewhat controversial, with both anti- and pro-inflammatory roles described [ 17 , 43 ]. In a landmark study, Reboldi et al. Accordingly, Ch25h deficient mice exhibit increased susceptibility to septic shock [ 43 ], while HC exerts protective effects in an in vivo model of LPS induced-acute lung injury, where systemic levels of pro-inflammatory cytokines were found to be decreased [ 77 ].
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MYC sustains non-stop proliferation by altering metabolic machinery to support growth of cell mass. As part of the metabolic transformation MYC promotes lipid, nucleotide and protein synthesis by hijacking citric acid cycle to serve biosynthetic processes, which simultaneously exhausts ATP production. Cells with normal growth control can stop cell proliferation machinery to replenish ATP reservoirs whereas MYC prevents such break by blocking the cell cycle exit. Here we first review the role of anabolic MYC and catabolic AMPK pathways in context of cancer and then discuss how the concomitant activity of both pathways in tumor cells may result in targetable synthetic lethal vulnerabilities. The classical view of oncogenic MYC expression being a cell cycle reprogrammer has recently broadened in the light of new genome-scale promoter and transcriptomic studies, which have exposed MYC's widespread transcriptional impact across the genome and especially on the genes orchestrating anabolic metabolism Eilers and Eisenman, ; Dang, ; Kress et al.
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Common Searches How do I apply? When is Open House? How much is tuition? How do I get to campus? Would you like to contact us? In addition, operational amplifier characteristics and models are used in the analysis of open loop and closed loop amplifiers. Adders, subtractors, active filters, comparators, differentiators, integrators, and the Schmitt trigger are also studied.
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Puberty is a complex developmental event, controlled by sophisticated regulatory networks that integrate peripheral and internal cues and impinge at the brain centers driving the reproductive axis. The tempo of puberty is genetically determined but is also sensitive to numerous modifiers, from metabolic and sex steroid signals to environmental factors. Recent epidemiological evidence suggests that the onset of puberty is advancing in humans, through as yet unknown mechanisms.
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