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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.
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Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, , USA. Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA, , USA. You can also search for this author in PubMed Google Scholar. Correspondence to Steven J.
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Subsequently, it is delivered to the proteolytic core of the 20S proteasome for degradation. The extraction process is enhanced by geranylgeraniol, which is a derivative of isoprenoid geranylgeranyl pyrophosphate GGpp.
In the presence of a substrate of GGpp, UBIAD1, which binds with HMGCR and blocks its membrane extraction, is transported to the Golgi and removes the inhibition of HMGCR degradation.
UBIAD1 is a membrane prenyltransferase that can catalyze the transfer of isoprenyl groups to aromatic acceptors and produce ubiquinones, hemes, chlorophylls, vitamin E, and vitamin K.
UBIAD1 knockout in mice is embryonic lethal, and the phenotype can be rescued by knocking in HMGCR, which is a resistant mutant Schumacher et al. Therefore, HMGCR levels can be regulated with nonsterol mevalonate pathway products. Another posttranslational regulation of HMGCR is phosphorylation.
The Ser residue in the C-terminal catalytic domain of HMGCR is phosphorylated by AMPK, and phosphorylation at Ser disrupts HMGCR activity and restricts the flux of the mevalonate pathway rapidly but does not affect sterol-induced ubiquitination and subsequent degradation Clarke and Hardie, SM catalyzes the first oxygenation step in cholesterol synthesis; it introduces an epoxide group to squalene, converts alkene squalene into squalene epoxide, and is proposed to be a rate-limiting step in cholesterol synthesis.
There are three SREs in the SM promoter: two adjacent SREs near the initiation site that partially respond to sterol via SREBP2 and a third SRE that is sterol independent. Other transcriptional cofactors and factors, including NF-Y, Sp1, YY1, c-Myc, and IRF-1, participate in the regulation of SM transcription Chua et al.
Mirb is reported to promote SM mRNA degradation Qin et al. The focus of SM regulation, similar to that of HMGCR, is posttranslational.
SM can be ubiquitinated and degraded under cholesterol abundance. The phenomenon of cholesterol-induced squalene accumulation suggests that SM, similar to HMGCR, is another flux-controlling enzyme Gill et al.
The N-terminal residues of SM contain a cholesterol-sensitive amphipathic helix and a reentrant loop; the amphipathic helix binds membranes with absent cholesterol, the affinity is reduced upon cholesterol addition, and the released helix forms a disordered sequence Chua et al.
MARCH6, an E3 ligase that physically interacts with conformationally changed SM Zelcer et al. In contrast to cholesterol-induced SM degradation, the accumulated substrate squalene binds to the N-terminal residues of SM, altering the recognition of MARCH6, and stabilizing SM on the ER membrane Yoshioka et al.
In addition to ubiquitination, MARCH6 can regulate SREBP2 at the transcriptional level; thus, HMGCR and SM are controlled. During ERAD, SM is truncated by N-terminal degradation, which results in defects in sterol sensing.
Truncated SM has similar abundance and is constitutively active. The distinction of SM and truncated SM function needs further investigation in detail. Cholesterol is distributed unevenly in cellular membranes.
The ER, mitochondria, and lysosomes are characterized by small amounts of cholesterol Maxfield and Wüstner, To achieve compositional heterogeneity, cholesterol needs to be transported in cells in a dedicated manner. The synthesized cholesterol in the ER is transported to organelles immediately, and this cholesterol transport is primarily coupled with the transport and metabolism of phosphoinositide, phosphatidylserine PtdSer , and sphingolipids Holthuis and Menon, Cholesterol trafficking is mediated by vesicular and nonvesicular trafficking systems Prinz, ; Luo et al.
Vesicular transport plays an important role in the response to trafficking of proteins in extracellular and endocytic pathways, and along with protein transport, cholesterol can traffic between organelles in the secretory pathway continuously Holthuis and Menon, However, a number of lines of evidence support that there is an alternative nonvesicular transport response for rapid and bulk cholesterol exchanges in the secretory pathway that do not receive vesicular trafficking.
The nonvesicular transport system includes cholesterol traveling spontaneously between membranes at a low rate of desorption and movement, horizontal movement in continuous membranes, and movement in two leaflets of the membranes.
In vitro investigations have demonstrated that the spontaneous exchange of cholesterol is related to aqueous-phase solubility and membrane curvature. Cholesterol exchanges rapidly from donors of small vesicles that have higher membrane curvature than large vesicles Lev, However, cholesterol interacts with sphingolipid and GPI-anchored proteins to form condensed complexes in the bilayer, and the nanostructure decreases the desorption of cholesterol from membranes.
Lipid transfer proteins LTPs have been identified to accelerate the transport of lipids, including cholesterol Wong et al. Many LTPs are localized to MCSs and undergo conformational changes from open bridges to closed tubes to facilitate the transfer of lipids Figure 3.
To date, at least 27 protein families have been found in lipid trafficking. FIGURE 3. Major molecules in intracellular cholesterol transport. Between the ER and the TGN, OSBP bridges the two membranes, sterols of the ER that bind to the ORD are transferred to the TGN, and the ORD of OSBP transfers PI 4 P of the TGN back to the ER.
The conserved mammalian ortholog of Lam6p is GRAMD1A, which is proposed to interact with the receptor of the mitochondria to transfer sterols. Most newly synthesized cholesterol is transported to the trans-Golgi network TGN , which is a sorting site for lipids, to maintain a low concentration in the ER.
Oxysterol-binding protein OSBP , a bridge between the ER and Golgi membranes, and has been observed to mediate cholesterol transfer. OSBP contains three conserved domains: the N-terminal pH domain, the central FFAT motif, and the C-terminal OSBP-related domain ORD , which recognize PI 4 P and small GTPase ADP-ribosylation factor Arf1 in the Golgi, target the VAP-A protein in the ER, and bind sterols, respectively.
The architecture of OSBP supports cholesterol export Antonny et al. In detail, first, the membranes are tethered between Golgi and ER by the pH domain and FFAT motif of OSBP; second, sterols that bind to the ORD are transferred to the Golgi; third, at the Golgi, the ORD of OSBP transfers PI 4 P, which is synthesized by phosphatidylinositol 4-kinase PI4K IIIβ, back to the ER; and fourth, PI 4 P is dephosphorylated to PI via Sac1, which is an ER-localized phosphatase.
The low ratio of PI 4 P to sterols in the ER makes the phosphorylation and dephosphorylation cycle move continuously to fuel cholesterol export. The exchange between cholesterol in the ER and PI 4 P in the Golgi is maintained by PI4KIIIβ and Sac1 Antonny et al.
Intriguingly, Sac1 also acts in trans on 4-phosphatase on PI 4 P in a manner mediated by FAPP1 when the concentration of PI 4 P is elevated in the TGN Venditti et al. The two modes of Sac1 activity may coexist in cells such that when the concentration of PI 4 P reaches a threshold, the trans-phosphatase activity of Sac1 is enhanced and coordinated with the in cis phosphatase activity to lower PI 4 P levels in the TGN.
Moreover, the in cis activity of Sac1 is required for contact sites between the PM and the ER or the late endosomes LEs and the ER Del Bel and Brill, A recent study found that in cholesterol-fed cells, the ER-anchored cholesterol escort SCAP interacts with the VAP-OSBP complex via Sac1.
Deletion of SCAP inhibits PI 4 P transport and carriers of the Golgi network to the cell surface CARTS Wakana et al. Whether cholesterol perturbation causes disruption of the cycle between PI 4 P and cholesterol is unclear. Mitochondria are important organelles in cells that can synthesize phosphatidylglycerol, cardiolipin, and phosphatidylethanolamine but must import phosphatidylcholine, phosphatidylinositol, PtdSer, and sterols from other organelles to maintain normal function Flis and Daum, ; Horvath and Daum, The ER and mitochondria are physically connected at the mitochondria-associated membrane MAM.
Most cholesterol transfer from the ER to mitochondria takes place on the MCSs of MAMs Giordano, There are three families of LTPs conserved in yeast and mammals as tethers, lipid sensors, or transporters at the MCSs between the ER and mitochondria.
The first is the ORP family; specifically, ORP5 and ORP8 interact with tyrosine phosphatase-interacting protein 51 PTPIP51 at the MCSs and mediate ER-mitochondrial contact as well as at the PM-ER to facilitate sterol transport in mammalian cells Chung et al. The second is the START family, which is responsible for cholesterol transport from the OMM to the IMM under hormonal stimulation, after which the cholesterol in the IMM is transformed into pregnenolone for production of steroids or bile acid in hepatic cells Elustondo et al.
The third is the LAM-GRAM family, which was recently discovered in yeast and includes Lam6 and Lct1, which are ER-anchored proteins located in the ER-mitochondria MCSs that bind with the mitochondrial import receptors Tom70 and Tom71 in yeast Murley et al.
The conserved orthologs in mammals are GRAMD1A and GRAMD1C, which are involved in lipid transfer in the PM Naito et al. Thus, we know little about cholesterol transfer at the ER-mitochondria MCSs in mammals at present. The discovery of new sterol transfer molecules will further illustrate the important roles of cholesterol and MCSs in mitochondria.
Endosomes also have abundant contact sites with the ER, and cholesterol is transferred from the ER to late endosomes LEs and lysosomes LYs via MCSs in cells. StAR-related lipid transfer protein 3 STARD3 , also known as MLN64, contains a conserved FFAT-like motif that interacts with VAPs in the ER membrane, mediates MCS formation between the ER and LE and transfers newly synthesized cholesterol from the ER to endosomes via a sterol-binding domain Wilhelm et al.
Similar to another sterol transfer protein, ORP1L, which responds to cholesterol transfer from endosomes to the ER, STARD3 binds VAP to form a tether between the ER and endosome Ridgway and Zhao, Whether these proteins compete with each other for VAP binding and how the major molecule that binds with VAP is regulated needs further investigation.
Cholesteryl esters CEs carried by low-density lipoprotein LDL are absorbed by LDL receptors LDLRs at the membrane and hydrolyzed by acid lipase in LEs. The released free cholesterol is transferred to other organelles: ER, PM, mitochondria, TGN, and peroxisomes.
Additionally, ORP5 is responsible for the cycling of PS in the ER and PI 4 P in the PM to maintain the low level of PI 4,5 P2 in the PM Ghai et al. Peroxisomes, as sites of lipid metabolism, play an important role in the cholesterol trafficking pathway.
Synaptotagmin VII Syt7 of lysosomes and PI 4, 5 P2 of peroxisomes is located at MCSs that form between the two organelles.
Either Syt7 or PI 4, 5 P2 is essential to the formation of the MCSs and to cholesterol export from LYs Chu et al. Syt7 has been reported to be a potential oncogenic target and to be involved in synaptic transmission as a calcium sensor Turecek et al.
Thus, further side effects need to be studied intensively when targeting Syt7 to cure disease. Cholesterol is an essential lipid that serves as a precursor of steroid hormones, bile acids, and oxysterols in special mammalian tissues. Disturbed cholesterol homeostasis in humans is related to cardiovascular disease, cancer, neurodegenerative disease, and congenital disease.
Thus, the de novo synthesis of cholesterol in cells and regulation, coordination between intracellular syntheses, import of exogenous cholesterol, biological distribution in organelles, transport of cholesterol in and out of cells, trafficking of intracellular cholesterol, and how to coordinate all the above processes precisely need to be researched continuously.
Because of the central role of SREBP2 in cholesterol homeostasis, numerous dysregulations of the gene in certain disease phenotypes are connected to cholesterol homeostasis. Some investigations have revealed that SREBP2 can function independently in addition to regulating cholesterol synthesis.
For example, in circulating melanoma cells, SREBP2 contributes to ferroptosis resistance by inducing transcription of the ion carrier transferrin TF Hong et al. Therefore, SREBP2, as a transcription factor, not only plays a key role in cholesterol homeostasis but also exerts multifunctional effects in pathophysiology.
The additional functions and related mechanisms need further investigation. The newly synthesized cholesterol and the released free cholesterol hydrolyzed from endocytosis LDL-C need to be distributed rapidly to maintain the normal functions of cells.
Although more LTPs are identified and closely connect with MCSs in membranes, the detailed mechanisms by which they facilitate cholesterol transfer, and whether they have other pathophysiological roles and can be inhibited as drug targets, are still not well known.
For example, the well-known function of STARD3 is to tether the ER and endosome and facilitate cholesterol transfer from the ER to the endosome. Recent findings indicate that high STARD3 levels are associated with worse overall survival OS , relapse-free survival RFS , and disease metastasis-free survival MFS.
Thus, STARD1 could be a preclinical marker of AD at early stages. In alcoholic liver disease ALD , STARD1 not only acts as a sterol transporter but also serves as a UPR and ER stress gene, which is stimulated by alcohol and facilitates ALD development Marí et al.
Moreover, STARD1 is expressed in many extra-adrenal and extra-gonadal organs, cells, and malignancies, including brain, eye, liver, vasculature, macrophages, heart, lung, skin cells, and so on.
In addition, in macrophages, STARD1 also facilitated the cholesterol efflux by activate LXRs Taylor et al. The functions of STARD1 in extra-endocrine tissues need more attention in future research. The functional ORD of ORP5 interacts with mTOR1 and participates in cancer cell invasion and tumor progression.
ORP5 depletion impairs mTOR localization to lysosomes, abolishes mTORC1 activity, and inhibits cell proliferation in HeLa cells Du et al. The oncogenic gene KRAS is anchored on PM to maintain biological activity.
The C-terminal of KRAS binds with specificity to PtdSer in the PM. Both ORP5 and ORP8 are responsible for exchanging PtdSer in the ER and phosphatidylphosphate in the PM. Depletion of ORP5 or ORP8 reduces PtdSer in the PM, causes KRAS mislocalization in vitro , and attenuates KRAS signaling in vivo ; in addition, it reduces cell proliferation of KRAS-dependent cancer cells Kattan et al.
GRAMD1A, which facilitates lipid transfer between the mitochondria and the ER, similar to ORP5, promotes HCC self-renewal, tumor growth, and resistance to chemotherapy. The effects of GRAMD1A are mediated by STAT5 Fu et al. In addition, during autophagosome biogenesis, GRAMD1A is bound by autogramins on its StART domain, causing accumulation of GRAMD1A at the sites of autophagosome initiation Laraia et al.
As indicated for the above-mentioned molecules, although alterations in both cholesterol and its related genes are observed in certain pathological conditions simultaneously, the exact functions of the molecules aside from cholesterol regulation need to be further investigated.
The most extensive application of lipid-lowering drugs in the clinic is antiatherogenic to reduce the morbidity and mortality of cardiovascular disease. Aside from cardiovascular disease, increasing evidence indicates that dysregulation of cholesterol homeostasis or some related genes correlates with cancers Kopecka et al.
For example, cholesterol- and lipid-mediated innate immune memory induces COVIDrelated cytokine storms Sohrabi et al. In AD, AD brains retain significantly more cholesterol than age-matched nondementia control ND brains; the APP acts as a lipid-sensing peptide on cholesterol and forms MAMs in the ER, causing extracellular cholesterol internalization in the ER Montesinos et al.
In addition to the antiatherogenic drugs approved by the Food and Drug Administration FDA , several molecules in the mevalonate pathway have emerged as promising drug targets for cancer and AD. For example, SC4MOL and NSDHL inactivation sensitizes tumor cells to EGFR inhibitors Sukhanova et al.
Therefore, further genetic screening of drug targets in the mevalonate pathway and cholesterol homeostasis for cancers and neurodegenerative disease therapy or prevention are essential. Targeting the mevalonate pathway or cholesterol homeostasis combined with medicine used in the clinic may benefit disease therapy.
In recent years, additional traditional Chinese medicines have been observed to have cholesterol-lowering effects, including aloe-emodin Su et al. The mechanisms of some of these medicines involve SREBP2 transcription and maturation processes.
Therefore, it is worth testing additional traditional Chinese medicines based on the present medicinal knowledge. Along with the increasing understanding of cholesterol homeostasis, more regulator molecules have been identified to be involved in pathological conditions.
Targeting of related molecules has been demonstrated to ameliorate certain symptoms; however, more research is needed to assess the side effects. Aside from cholesterol itself, intermediates of the mevalonate pathway, lipid transfer proteins, and metabolites of cholesterol all warrant further research.
QS and JC wrote the manuscript. XZ drew the Figures and edited the review. XT provided thoughts and corrected the review. All authors contributed to the article and approved the submitted manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors, and the reviewers.
Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. We acknowledge the support of Jilin Province science and technology development plan ZP. Antonny, B. The Oxysterol-Binding Protein Cycle: Burning off PI 4 P to Transport Cholesterol.
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