Pandzic E, Gelissen Cholesterol regulation benefits, Ebnefits R, Barter PJ, Sviridov D, Cholesterol regulation benefits K, et venefits. Thus, we proposed that IFNs Choleesterol a robust but highly Regulatkon cholesterol redistribution Cholssterol that moves cholesterol targeted by Integrative health practices out Cholesterol regulation benefits the PM, redistributes it to the ER, and subsequently stores esterified cholesterol if needed. Mevalonate is finally converted to isopentenyl pyrophosphate IPP through two phosphorylation steps and one decarboxylation step that requires ATP. Monitoring and modulating intracellular cholesterol trafficking using ALOD4, a cholesterol-binding protein. Sixth memoir. Consistent with the above findings, the administration of mevalonate was shown to enhance tumor growth in mice carrying tumor xenograft Duncan et al. This molecule is then reduced to mevalonate by the enzyme HMG-CoA reductase.

Cholesterol regulation benefits -

To get around this problem, the body packages cholesterol and other lipids into minuscule protein-covered particles that mix easily with blood. These tiny particles, called lipoproteins lipid plus protein , move cholesterol and other fats throughout the body.

Cholesterol and other lipids circulate in the bloodstream in several different forms. Of these, the one that gets the most attention is low-density lipoprotein— better known as LDL, or "bad" cholesterol. But lipoproteins come in a range of shapes and sizes, and each type has its own tasks. They also morph from one form into another.

The capacity of 25HC to specifically decrease the accessible cholesterol pool is thought to increase cholesterol esterification, decrease cholesterol biosynthesis, and activate the LXR pathway [ 10 , 34 , 46 ].

This observation further highlights the exquisite specificity by which IFNs can remap the cellular cholesterol landscape and indicates that shifting specific cholesterol pools of the cell is an important component of host defense against viruses and aspects of microbial infections.

In contrast to IFN signaling, MyDdependent PRRs, such as Toll-like receptor TLR -2, TLR-7, and TLR-9, lead to an overall increase in cholesterol biosynthesis and total cholesterol in macrophages [ 21 ]. This increase in cholesterol is dependent on the upregulation of the SREBP transcriptional axis.

Due to increased cholesterol synthesis, MyDdependent PRRs expand the accessible cholesterol pool in the plasma membrane [ 21 ].

Despite this increase in total and membrane cholesterol levels, MyDdependent PRRs do not significantly increase the levels of cholesterol esters.

The conserved use of cholesterol in mammalian cells likely underlies cholesterol targeting by microbes and viruses to facilitate their lifecycle and pathogenicity. These strategies have been described in several reviews, and we direct the reader to the literature to gain a greater appreciation of the specifics of the different classes or types of pathogens [ 47 , 48 ].

In this brief review, we restrict our discussion to some interesting aspects of cholesterol metabolism in bacterial pathogenesis, followed by a more detailed discussion of cholesterol-dependent cytolysins CDCs , a family of pore-forming toxins that rely on cholesterol for their effector functions.

One well-characterized example of the interplay between cholesterol metabolism and microbial pathogenesis can be found in Mycobacteria infections. One hallmark of M. tuberculosis M. tb infection of cells is the marked accumulation of intracellular lipids resulting in foam cell formation [ 49 ]. It has been shown that M.

tb has the ability to degrade cholesterol for use in bacterial metabolism and that this cholesterol catabolism may be a mechanism by which M. tb persists in IFN-activated macrophages [ 50 ]. Similarly, M. leprae uses the oxidation of cholesterol to facilitate energetics and cell wall biosynthesis [ 51 ].

Importantly, interfering with the ability of these bacteria to use cholesterol decreases intracellular survival in host cells.

Thus, cholesterol is a requisite host metabolite that is used as a nutrient source by Mycobacteria for persistence and pathogenicity. In other instances, obligate intracellular bacteria use cholesterol to facilitate entry into host cells. The hydrophobic nature of cholesterol means that this lipid is primarily embedded in cellular membranes.

Some intracellular microbes specifically target the pool of cholesterol in cholesterol-rich microdomains in the PM for their entry [ 48 ]. Microbe-induced alterations in cholesterol metabolism have also been shown to perturb cellular phagolysosome function and intracellular organelle trafficking [ 48 , 52 ].

Pharmacologic or genetic disruptions of lipid microdomains or intracellular cholesterol trafficking pathways decreases the efficiency of microbe entry and intracellular pathogen persistence [ 48 , 53 ].

While these are just a few examples of how microbes exploit host cholesterol metabolism for their pathogenesis, they support the concept that reprogramming cholesterol homeostasis through inflammation is an innate immune mechanism used in host defense.

These observations also support the idea that pharmacologically targeting cellular cholesterol metabolism could be an adjunctive therapeutic approach to facilitate the clearance of microbes. As discussed previously, microbial proteins can target lipids in membrane to facilitate pathogenesis.

One well-defined group of virulence factors that target host cholesterol are cholesterol-dependent cytolysins CDCs. CDCs are pore-forming toxins that are secreted as soluble monomers and subsequently oligomerize on host membranes to form pores [ 40 ]. Approximately thirty distinct gram-positive bacteria have been identified that produce CDCs, including several species that mediate severe diseases in humans e.

CDCs contain four domains. Domains 1—3 primarily play structural roles that facilitate oligomerization into a prepore intermediate once cholesterol recognition occurs. Domain 4 contains a tryptophan-rich region s that is involved in cholesterol recognition and membrane binding. Once Domain 4 successfully binds to cholesterol in the membrane, the CDC monomers oligomerize into a prepore intermediate, which then becomes inserted into the membrane [ 56 ].

The cellular consequences of CDCs vary depending on the CDC dosage, duration, and cell type. Pores also allow the influx of water into cells, which leads to blebbing and apoptosis due to osmotic shock. The mechanisms underlying CDC-mediated cell lysis have been characterized in erythrocytes because these cells have a minimal capacity to repair membrane damage.

Repair processes induced by CDC pore formation include patch repair, clogging, and microvesicle shedding [ 56 , 57 ]. Whether changes in cholesterol metabolism induced by microbes or host inflammation alter the efficiency of membrane repair is largely unknown and should be investigated.

However, it is easy to hypothesize that the dramatic alterations in lipid homeostasis observed in response to proinflammatory signals will have some impact on host membrane repair systems. The specific dependency of CDCs on membrane cholesterol to execute their effector function led to the hypothesis that alterations in membrane cholesterol homeostasis could provide some form of resistance to CDC-mediated cellular damage.

Indeed, induced cholesterol efflux through pharmacologic activation of the LXR transcriptional pathway or genetic manipulation of cholesterol metabolism provides some measure of protection against CDC-mediated cellular toxicity [ 21 , 46 ].

However, it is unclear whether physiological signals in the context of inflammatory responses to infections would have similar protective effects. Leveraging previous work that showed that PRR and cytokine signaling influence macrophage cholesterol homeostasis, we explored whether activating macrophages might intrinsically induce resistance to CDCs.

Working from the hypothesis that the recognition of gram-positive bacteria by PRRs would be required for such a mechanism, we set out to determine whether activating macrophages with TLR2 agonists could influence CDC-mediated loss of membrane integrity. However, we found that this supposition was incorrect and that the opposite appeared to be true.

We observed that activating macrophages via TLR2 and other MyDdependent TLRs resulted in a modest but highly reproducible increase in sensitivity to CDC-mediated cellular toxicity. Thus, TLR2-mediated recognition of gram-positive bacteria by macrophages does not appear to induce resistance to CDCs.

Rather, this signal primes heightened CDC sensitivity. The increased sensitivity to CDCs is dependent on the ability of TLR2 to drive cholesterol biosynthesis, and inhibiting this pathway ameliorates the increase in CDC toxicity. Whether this circuit of TLR2 agonism, heightened cholesterol synthesis and increased sensitivity to CDCs is important for microbial pathogenesis remains to be tested [ 21 ].

In our studies on PRRs, we were surprised to find that TLR3 activation rendered macrophages very resistant to CDC-mediated cytotoxicity. Indeed, subsequent gain- and loss-of-function studies showed a critical and essential role for type I IFN signaling in this protective mechanism [ 21 ].

The activation of PRRs that lead to type I interferon production [ 58 ] e. Importantly, delivery of either type I IFN or type II IFN-γ in trans resulted in protection, expanding the impact of this immunometabolic reprogramming event. We observed that IFN-stimulated macrophages retained functionality, even when challenged with CDCs, as evidenced by their ability to phagocytose microbes or apoptotic cells.

We also found that the protective effect of IFNs could be observed in freshly isolated neutrophils, indicating that a generalized cellular mechanism, at least for phagocytes, underlie this response [ 21 ].

Whether this effect is also true for nonimmune cells stimulated with IFNs has not been determined. The molecular mechanism of IFN-mediated protection against CDCs also lies in the ability of IFNs to alter cholesterol synthesis in macrophages.

Isotope labeling studies showed that IFN signaling decreases cholesterol synthesis and that this decrease in cholesterol synthesis was dependent on the upregulation of CH25H and the subsequent production of 25HC [ 21 ]. The generation of 25HC by macrophages results in inhibition of the SREBP2 transcriptional axis and the direct degradation of HMGCR [ 20 , 59 , 60 ].

Consistent with this finding, genetic ablation of CH25H rendered naïve macrophages highly sensitive to CDCs and abrogated the ability of IFNs to protect against CDC-mediated pore formation.

Ch25h -deficient mice also developed severe erythema and larger ulcerative skin lesions when intradermally challenged with streptolysin O SLO , a CDC secreted by S. Conversely, pharmacologic addition of 25HC provided a marked level of protection against CDC challenge, solidifying the role of CH25H in this interesting immune-metabolic response.

Consistent with a role for oxysterols in mediating protection to CDCs, both 25HC and 27HC protect endometrial cells from the CDC pyolysin, which is produced by Trueperella pyogenes [ 46 ]. Interestingly, this effect was partially dependent on the ability of these oxysterols to activate LXRs and reduce accessible cholesterol, likely through cholesterol efflux.

The molecular events mediating the ability of IFNs to protect against CDCs remain incompletely defined, but we have been able to gain some understanding of the pathways required for this effect. Using fluorescently labeled ALO-D4 the D4 domain of the CDC Anthrolysin O [ 39 ], we were able to show that IFNs decreased ALO-D4 binding to the membrane.

These data suggest that the cholesterol levels in the plasma membrane dropped below those required for effective CDC binding and oligomerization [ 21 ]. Reprogramming cholesterol synthesis appears to be important for altering CDC binding to the plasma membrane, but how these changes in cholesterol synthesis directly translate into protection at the PM remains less clear.

One possibility is that inhibiting cholesterol biosynthesis globally reduces cholesterol levels in the PMs of cells. However, mass spectrometry data showed that cholesterol levels in the PM were largely maintained in IFN-stimulated macrophages, and we observed decreases in ALO-D4 binding as little as two hours after IFN treatment.

Likewise, a brief minute treatment of macrophages with sphingomyelinase, which effectively liberated cholesterol associated with sphingomyelin, quickly restored CDC binding and sensitivity to CDC-mediated toxicity.

Thus, we concluded that a small and difficult-to-quantify cholesterol pool in the PM must be rapidly decreased in response to IFN signaling to mediate protection [ 21 ].

These data also suggest that the production of, microbial sphingomyelinases [ 61 ] in the context of polymicrobial infections will sensitize host cells to the harmful effects of CDCs and quickly overcome the protective effects induced by IFNs. It has also been shown that IFN signaling, downstream of TLR4, results in the accumulation of lanosterol, a sterol intermediate of the cholesterol biosynthetic pathway, in the PMs of macrophages [ 62 ].

This increase in lanosterol levels alters membrane fluidity, which potentiates phagocytosis by macrophages and the killing of E. coli [ 62 ]. Therefore, it remains possible that the accumulation of lanosterol or other sterol intermediates in the PM in response to IFN signaling contributes to this protective effect, perhaps through the dilution of the accessible cholesterol pool.

However, this hypothesis needs to be formally tested. It also remains unclear where the cholesterol targeted by CDCs is moved in response to IFN signaling. One possibility is that cholesterol moves into another cholesterol pool within the plasma membrane.

We measured sphingomyelin-associated cholesterol by imaging macrophages with the mushroom toxin protein, ostreolysin OlyA , to test this possibility. In contrast to ALO-D4 staining, imaging macrophages with recombinant OlyA protein revealed little difference in staining between the IFN and control groups [ 21 ].

Thus, it does not appear that cholesterol from the CDC-targeted pool flows into the sphingomyelin-associated pool in response to IFNs. We were unable to test whether cholesterol moves into the essential pool since we cannot define this pool in macrophages.

Additional biochemical studies on membrane fractions will be required to determine whether the lateral movement of cholesterol occurs in response to IFN and mediates protection of the PM to CDCs.

An alternative explanation is that the cholesterol required for CDC recognition is rapidly moved into another subcellular location. In support of this concept, we observed that IFNs upregulated several genes involved in intracellular cholesterol movement e.

Moreover, we found that IFNs induced the accumulation of a small amount of cholesterol esters in macrophages. Inhibiting ACAT enzymes increased the sensitivity of macrophages to CDCs, even in the absence of CH25H. Thus, we proposed that IFNs induce a robust but highly selective cholesterol redistribution program that moves cholesterol targeted by CDCs out of the PM, redistributes it to the ER, and subsequently stores esterified cholesterol if needed.

Inhibiting cholesterol synthesis with 25HC is necessary to prevent this small but highly labile pool from refilling and resensitizing macrophages to CDC toxins. A working model of how IFN-mediated reprogramming of cholesterol homeostasis promotes resistance to CDCs is shown in Fig.

A In a quiescent state, CDCs target metabolically active or accessible cholesterol in the plasma membrane of macrophages, resulting in pore formation and the subsequent loss of membrane integrity. B IFN stimulation markedly decreases the size of the accessible cholesterol pool, resulting in reduced CDC binding and pore formation on the plasma membrane.

Alterations in the accessible cholesterol pool in the plasma membrane are driven by a reduction in cholesterol biosynthesis and heightened cholesterol esterification.

The inhibition of cholesterol synthesis and esterification is dependent, in part, on the upregulation of the interferon-stimulated gene, Ch25h , and the production of oxysterol 25HC. A recent complementary study showed that IFN-mediated production of 25HC increased cellular immunity to L.

monocytogenes and Shigella flexneri by inhibiting cell—cell spreading [ 34 ]. This study found that 25HC interfered with the ability of these microbes to traverse the plasma membrane of infected cells and enter uninfected neighboring cells through double plasma membrane structures.

The molecular mechanism is also under investigation but appears to be dependent on rapid internalization of the accessible cholesterol pool via the activation of ACATs and subsequent storage of this cholesterol as esters in a process that is highly analogous to that seen in macrophages [ 34 ]. However, it is important to note that 25HC was not effective at blocking L.

monocytogenes escape from the phagocytic vacuole, which is a process that requires listeriolysin O LLO , a CDC produced by these microbes. Therefore, the mechanism by which IFN-induced changes in the accessible cholesterol pool alter CDC sensitivity may only be relevant to the plasma membrane.

Based on these new concepts in membrane cholesterol homeostasis, it will be interesting to revisit whether other intracellular microbes that exploit cellular cholesterol for their lifecycle depend on the accessible cholesterol pool. Given that both type I and type II IFNs regulate the size of the metabolically active cholesterol pool, we suspect that this small pool of cholesterol will also be necessary for viruses that rely on cholesterol for entry.

Necrotizing fasciitis NF , also known as flesh-eating disease, is a subset of an aggressive skin and soft tissue infection consisting of liquefying necrosis of dermal and subcutaneous tissues [ 64 ]. NF is mediated by select gram-positive microbes that secrete toxins, including CDCs and hemolytic toxins into infected and surrounding tissues [ 65 ].

The observation that metabolic reprogramming of cholesterol metabolism attenuates CDC-mediated cytotoxicity and tissue damage in the skin is striking. It is tantalizing to hypothesize that the dysregulation of tissue lipid homeostasis could influence the extent of tissue damage associated with necrotizing soft tissue infection.

However, it is worth noting that comorbidities associated with the development of NF include metabolic diseases, such as obesity and diabetes [ 66 , 67 ]. Thus, it is possible that the dysregulation of lipid metabolism, in particular cholesterol homeostasis, sensitizes individuals to the deleterious effects of CDCs and other toxins that drive the pathogenesis of NF.

It will be necessary for the field to test these interesting but nascent ideas. Likewise, it will be exciting to determine whether targeting lipid metabolism in infected tissues attenuates the development of NF, particularly in individuals who have pre-existing lipid metabolic dysregulation.

If proven true, this concept will open new avenues for developing adjunctive therapies to attenuate these rare but highly pathogenic skin and soft tissue infections.

It is now clear that reshaping lipid composition is an integral and essential part of myeloid cell differentiation and function. In the absence of proper lipid metabolic reprogramming, macrophages exhibit dysregulated inflammatory responses and altered immune functions.

These observations suggest that environmental or metabolic signals that interfere with the metabolic reprogramming of lipid composition will result in phagocyte dysfunction. An additional layer of complexity lies in the observation that macrophages do not converge on a single lipidome irrespective of the activating signal.

Instead, distinct proinflammatory stimuli drive the acquisition of different lipidomes [ 17 ]. These data indicate considerable specificity in the lipidome that macrophages acquire during different inflammatory responses.

Moreover, these specific changes in lipid composition appear to impart information to the cell that ultimately regulates distinct effector functions and immunity. We expect that there will be instances in which reprogramming of lipid composition will be beneficial for some forms of immunity but harmful to other forms of immunity.

For example, reprogramming of cholesterol metabolism may benefit antiviral immune responses but interfere with antimicrobial responses.

This additional layer of complexity also suggests that a context-specific approach to correcting the metabolism of macrophages and other immune cells will be necessary if one hopes to normalize function. Of course, there remain many important and unresolved questions about lipid metabolic reprogramming that the field of immunometabolism should address.

One crucial issue is to determine the extent to which activation signals reshape lipid composition in the context of infections. Much of our knowledge about lipid metabolic reprogramming is predicated on knowledge gained using highly reductionist systems.

The intrinsic complexity of infections will undoubtedly muddy the water of our current working models.

We predict that there will be instances in which pathogens misdirect macrophages to acquire the wrong lipidome, ostensibly interfering with requisite effector functions to clear infections. It will be exciting for the field to generate comprehensive pathogen-based immune metabolic studies to guide our thinking and shape models.

Another series of questions for the field to address center around the issues of durability and plasticity. The approaches we and others have taken reasonably focus on short-lived inflammatory macrophages.

It remains unclear how durable these changes in lipid composition are and whether macrophages can undergo secondary reshaping of their lipidome in response to newly received information. For example, we envision that exposure to different cytokines throughout an immune response will continually reshape the lipidome to match required effector functions.

Alternatively, it is possible that initial exposure to a specific proinflammatory cytokine i. Macrophages have variable lifespans, and resident tissue macrophages are long-lived with some self-renewal capabilities [ 3 ].

It will be important to determine whether inflammation-driven metabolic reprogramming of lipid metabolism indelibly imprints on long-lived macrophages, their progeny in tissues, or myeloid stem cells. If such an observation was found to be true, this could be critical for understanding pathogenic circuits that link metabolic disease e.

This type of indelible programming could also help to explain aspects of innate immune memory or the capacity of innate immune cells to generate preferential immunity to pathogens upon subsequent exposures. Tackling these exciting and important questions will undoubtedly advance our mechanistic understanding of immunometabolism.

We also believe that continued research into the crosstalk between lipid metabolism and the function of macrophages will provide essential insights for developing new therapeutic approaches to control unwanted inflammation, infections, and metabolic diseases.

Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu Rev Immunol. Article CAS PubMed Google Scholar. Ozinsky A, Underhill DM, Fontenot JD, Hajjar AM, Smith KD, Wilson CB, et al.

The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between Toll-like receptors. Proc Natl Acad Sci. Article CAS PubMed PubMed Central Google Scholar.

Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Hubler MJ, Kennedy AJ. Role of lipids in the metabolism and activation of immune cells.

J Nutr Biochem. Russell DG, Huang L, VanderVen BC. Immunometabolism at the interface between macrophages and pathogens. Nat Rev Immunol. Kominsky DJ, Campbell EL, Colgan SP. Metabolic shifts in immunity and inflammation.

J Immunol. Lange Y, Swaisgood MH, Ramos BV, Steck TL. J Biol Chem. Ikonen E. Cellular cholesterol trafficking and compartmentalization. Nat Rev Mol Cell Biol. van Meer G, Voelker DR, Feigenson GW. Membrane lipids: where they are and how they behave. Article PubMed PubMed Central Google Scholar.

Luo J, Yang H, Song BL. Mechanisms and regulation of cholesterol homeostasis. Guo H, Callaway JB, Ting JP.

Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med. Tall AR, Yvan-Charvet L. Cholesterol, inflammation and innate immunity. Brown MS, Goldstein JL. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor.

Madison BB. Srebp2: A master regulator of sterol and fatty acid synthesis. J Lipid Res. Lee SH, Lee J-H, Im S-S. The cellular function of SCAP in metabolic signaling.

Exp Mol Med. Chatterjee S, Szustakowski JD, Nanguneri NR, Mickanin C, Labow MA, Nohturfft A, et al. Identification of novel genes and pathways regulating SREBP transcriptional activity. PLoS ONE. This is called peripheral arterial disease PAD. Lowered production of thyroid hormone hypothyroidism leads to an increase in total and LDL cholesterol.

Excess thyroid hormone hyperthyroidism has the opposite effect. Androgen deprivation therapy, which reduces levels of male hormones to stop prostate cancer growth, can raise LDL cholesterol levels.

A deficiency of growth hormone can also raise LDL cholesterol levels. Cholesterol is an essential component of the human brain. This fat is essential for the development and protection of nerve cells, which enable the brain to communicate with the rest of the body.

While you need some cholesterol for your brain to function optimally, too much of it can be damaging. Excess cholesterol in the arteries can lead to strokes — a disruption in blood flow that can damage parts of the brain, leading to loss of memory, movement, difficulty with swallowing and speech and other functions.

High blood cholesterol on its own has also been implicated in the loss of memory and mental function. In the digestive system, cholesterol is essential for the production of bile — a substance that helps your body break down foods and absorb nutrients in your intestines.

But if you have too much cholesterol in your bile, the excess forms into crystals and then hard stones in your gallbladder. Gallstones can be very painful.

Keeping an eye on your cholesterol level with recommended blood tests and lowering your risk for heart disease will help improve your overall quality of life. Our experts continually monitor the health and wellness space, and we update our articles when new information becomes available.

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