cholesterol homeostasis
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Processes ◽  
2022 ◽  
Vol 10 (1) ◽  
pp. 155
Author(s):  
Fangyuan Zhang ◽  
Brittany Macshane ◽  
Ryan Searcy ◽  
Zuyi Huang

Cholesterol is an essential component of eukaryotic cellular membranes. It is also an important precursor for making other molecules needed by the body. Cholesterol homeostasis plays an essential role in human health. Having high cholesterol can increase the chances of getting heart disease. As a result of the risks associated with high cholesterol, it is imperative that studies are conducted to determine the best course of action to reduce whole body cholesterol levels. Mathematical models can provide direction on this. By examining existing models, the suitable reactions or processes for drug targeting to lower whole-body cholesterol can be determined. This paper examines existing models in the literature that, in total, cover most of the processes involving cholesterol metabolism and transport, including: the absorption of cholesterol in the intestine; the cholesterol biosynthesis in the liver; the storage and transport of cholesterol between the intestine, the liver, blood vessels, and peripheral cells. The findings presented in these models will be discussed for potential combination to form a comprehensive model of cholesterol within the entire body, which is then taken as an in-silico patient for identifying drug targets, screening drugs, and designing intervention strategies to regulate cholesterol levels in the human body.


Author(s):  
Min-Sub Lee ◽  
Steven J. Bensinger

AbstractCholesterol is a critical lipid for all mammalian cells, ensuring proper membrane integrity, fluidity, and biochemical function. Accumulating evidence indicates that macrophages rapidly and profoundly reprogram their cholesterol metabolism in response to activation signals to support host defense processes. However, our understanding of the molecular details underlying how and why cholesterol homeostasis is specifically reshaped during immune responses remains less well understood. This review discusses our current knowledge of cellular cholesterol homeostatic machinery and introduces emerging concepts regarding how plasma membrane cholesterol is partitioned into distinct pools. We then discuss how proinflammatory signals can markedly reshape the cholesterol metabolism of macrophages, with a focus on the differences between MyD88-dependent pattern recognition receptors and the interferon signaling pathway. We also discuss recent work investigating the capacity of these proinflammatory signals to selectively reshape plasma membrane cholesterol homeostasis. We examine how these changes in plasma membrane cholesterol metabolism influence sensitivity to a set of microbial pore-forming toxins known as cholesterol-dependent cytolysins that specifically target cholesterol for their effector functions. We also discuss whether lipid metabolic reprogramming can be leveraged for therapy to mitigate tissue damage mediated by cholesterol-dependent cytolysins in necrotizing fasciitis and other related infections. We expect that advancing our understanding of the crosstalk between metabolism and innate immunity will help explain how inflammation underlies metabolic diseases and highlight pathways that could be targeted to normalize metabolic homeostasis in disease states.


Cells ◽  
2022 ◽  
Vol 11 (2) ◽  
pp. 201
Author(s):  
Cheng Xiang Foo ◽  
Stacey Bartlett ◽  
Katharina Ronacher

Oxidized cholesterols, the so-called oxysterols, are widely known to regulate cholesterol homeostasis. However, more recently oxysterols have emerged as important lipid mediators in the response to both bacterial and viral infections. This review summarizes our current knowledge of selected oxysterols and their receptors in the control of intracellular bacterial growth as well as viral entry into the host cell and viral replication. Lastly, we briefly discuss the potential of oxysterols and their receptors as drug targets for infectious and inflammatory diseases.


2022 ◽  
pp. 1-27
Author(s):  
Lydia Qian ◽  
Amanda B. Chai ◽  
Ingrid C. Gelissen ◽  
Andrew J. Brown

The cholesterol is a vital component of cell membranes and myelin sheaths, and a precursor for essential molecules such as steroid hormones. In humans, cholesterol is partially obtained through the diet, while the majority is synthesized in the body, primarily in the liver. However, the limited exchange between the central nervous system and peripheral circulation, due to the presence of the blood-brain barrier, necessitates cholesterol in the brain to be exclusively acquired from local de novo synthesis. This cholesterol is reutilized efficiently, rendering a much slower overall turnover of the compound in the brain as compared with the periphery. Furthermore, brain cholesterol is regulated independently from peripheral cholesterol. Numerous enzymes, proteins, and other factors are involved in cholesterol synthesis and metabolism in the brain. Understanding the unique mechanisms and pathways involved in the maintenance of cholesterol homeostasis in the brain is critical, considering perturbations to these processes are implicated in numerous neurodegenerative diseases. This review focuses on the developing understanding of cholesterol metabolism in the brain, discussing the sites and processes involved in its synthesis and regulation, as well as the mechanisms involved in its distribution throughout, and elimination from, the brain.


2022 ◽  
Vol 5 (3) ◽  
pp. e202101256
Author(s):  
Sampath Katakam ◽  
Santosh Anand ◽  
Patricia Martin ◽  
Nicolo Riggi ◽  
Ivan Stamenkovic

Malignant tumors commonly display necrosis, which invariably triggers an inflammatory response that supports tumor growth. However, the effect on tumor cells of necrotic debris, or damage-associated molecular patterns (DAMPs) released by dying cells is unknown. Here, we addressed the effect of DAMPs on primary Ewing sarcoma (EwS) cells and cell lines grown in 3D (spheroids) and 2D culture. We show that DAMPs promote the growth of EwS spheroids but not 2D cultures and that the underlying mechanism implicates an increase in cholesterol load in spheroids. In contrast, stimulation of the nucleic acid sensor signaling platform STING by its ligand cyclic GMP-AMP decreases the tumor cell cholesterol load and reduces their tumor initiating ability. Overexpression of STING or stimulation with cyclic GMP-AMP opposes the growth stimulatory effect of DAMPs and synergizes with the cholesterol synthesis inhibitor simvastatin to inhibit tumor growth. Our observations show that modulation of cholesterol homeostasis is a major effect of necrotic cell debris and STING and suggest that combining STING agonists with statins may help control tumor growth.


2021 ◽  
Vol 9 (3) ◽  
pp. 712-721
Author(s):  
Vasanth Konda Mohan ◽  
Melvin George

Coronary artery disease (CAD) has a high prevalence and one of the principal drivers of mortality worldwide. Therefore, there is a requirement to develop sensitive diagnostic biomarkers, disease progression control and therapeutic stratification in order to keep a check on the disease rate. Atherosclerosis is a systemic disease, the main cause of heart disease, is associated with hyperlipidemia and lipid oxidation and has always been a common single leading cause of death in well-developed countries. In the attempts to study CAD and the causative agents for the disease, a metabolite circulating in the plasma termed trimethylamine-N-oxide (TMAO) has been found out to be an independent risk factor that increases CAD risk. The use of a metabolomic approach has proven useful in the recent past, as it can aid in the identification and quantification of several metabolites that play a crucial role for diagnosis and exploring therapeutic targets. TMAO is majorly synthesized by a process which involves the bioconversion of gut microbiota and hepatic flavin monooxygenases (FMOs) from nutrient-containing dietary trimethylamine (TMA). TMA is synthesized by gut bacterial fermentation from the components present in meat such as phosphatidylcholine (PC), betaine, choline, and L-carnitine. It can accentuate the process of atherosclerosis through the novel meta-organismal metabolic pathway. TMAO leads to atherogenesis by increasing vascular inflammation, reducing vascular functions and disrupting cholesterol homeostasis at various levels. This review article attempts to summarize the pool of evidence collected on the microbiota-dependent TMAO and its association with atherosclerosis. We performed literature search with Medline, PubMed, and Google Scholar, on “TMAO in CAD”, “metabolites in CAD” and “TMAO in other diseases” from the year 1990 to 2020. Although the circulatory TMAO has been identified as an independent marker for CAD, there is still no conclusive evidence to justify its role as a routine marker for CAD diagnosis. Future research must clarify the mechanisms which underpin these complex associations to determine if there is a causal link exists between TMAO and CAD.


2021 ◽  
Author(s):  
Tandrila Das ◽  
Xinglin Yang ◽  
Hwayoung Lee ◽  
Emma Garst ◽  
Estefania Valencia ◽  
...  

Abstract Interferon-induced transmembrane proteins (IFITM1, 2 and 3) are important antiviral proteins that are active against many viruses, including influenza A virus (IAV), dengue virus (DENV), Ebola virus (EBOV), Zika virus (ZIKV) and severe acute respiratory syndrome coronavirus (SARS-CoV). IFITMs exhibit isoform-specific activity, but their distinct mechanisms of action and regulation are unclear. Since S-palmitoylation and cholesterol homeostasis are crucial for viral infections, we investigated IFITM interactions with cholesterol by molecular dynamic stimulations, nuclear magnetic resonance analysis in vitro and photoaffinity crosslinking in mammalian cells. These studies suggest that cholesterol can alter the conformation of IFITMs in membrane bilayers and directly interact with S-palmitoylated IFITMs in cells. Notably, we discovered that the S-palmitoylation levels regulate differential IFITM isoform interactions with cholesterol in mammalian cells and specificity of antiviral activity towards IAV, SARS-CoV-2 and EBOV. Our studies suggest that modulation of IFITM S-palmitoylation levels and cholesterol interaction may influence host susceptibility to different viruses.


2021 ◽  
pp. 1-12
Author(s):  
T. Adimulam ◽  
N.S. Abdul ◽  
A.A. Chuturgoon

Fumonisin B1 (FB1) contributes to mycotoxicosis in animals and has been associated with the incidence of some cancers in humans. The effect of FB1 on lipidomic profiles, sphingolipids and cholesterol levels have been demonstrated in experimental models, however, the events leading to altered cholesterol levels are unclear. This study investigates the molecular mechanisms that regulate the effect of FB1 on cholesterol homeostasis in galactose supplemented HepG2 liver cells. Galactose supplementation is a proven method utilised to circumvent the Crabtree effect exhibited by cancer cells, which forces cancer cells to activate the mitochondria. HepG2 cells were cultured in galactose supplemented media and treated with FB1 (IC50 = 25 μM) for 6 h. Cell viability was determined using the MTT assay. Metabolic status was evaluated using ATP luciferase assay, and cholesterol regulatory transcription factors (SIRT1, SREBP-1C, LXR, LDLR, PCSK9, and ABCA1) were investigated using western blotting and qPCR. FB1 in galactose supplemented HepG2 cells increased gene expression of SIRT1 (P<0.05), SREBP-1C, LXR, and LDLR; however, PCSK9 (P<0.05) was decreased. Furthermore, protein expression of SIRT1, LXR, and LDLR was elevated upon FB1 treatment, while SREBP-1C and PCSK9 were reduced. The data provides evidence that SIRT1 reduced the expression of PCSK9 and deacetylated LXR to prevent degradation of LDLR. This could result in a dysregulated cholesterol flux, which may contribute to FB1 mediated toxicity.


2021 ◽  
Author(s):  
Feiliang Zhong ◽  
Tingting Chen ◽  
Jia Liu ◽  
Ying Wang ◽  
Mingdong Yao ◽  
...  

Abstract Background: Melanoma is the most serious skin cancer with gradually increased incidence and poor prognosis mainly as the result of cancer stem cell (CSC) expansion and drug resistance. Some studies have suggested that dysregulated cholesterol homeostasis increasing tumorigenicity and metastasis in cancers. In the present study, our objective was to elucidate the contribution of 24-Dehydrocholesterol reductase (DHCR24) towards melanoma progression and drug resistance.Methods: Immunohistochemistry and HE staining were performed for determing the expression of DHCR24 in melanoma patients, lentivirus perturbation and functional assays were used to evaluate the ability of turmorigenesis of DHCR24 altered melanoma cells and melanoma stem-like cells. RNA sequencing (RNA-seq) and targeted metabolomics were carried out for identifying metabolites which contributes melanoma stem-like cell expansion and vemurafenib treatment resistance.Results: DHCR24 was over-expressed in melanoma patients while knockdown of DHCR24 blocked melanoma cells in S phase and lead to significant inhibition in proliferation and migration. Meanwhile, forced expression of DHCR24 promotes the growth of melanoma cells in xenograft mice. We further demonstrated that DHCR24 promotes the proliferation of melanoma stem-like cell populations by activating Rap1/AKT signaling and result in accumulation of cellular 27-Hydroxycholesterol (27-HC) contents. Next, we validated that both CYP27A1 and 27-HC administration contributed to melanoma stem-like cells formation and vemurafenib resistance through AKT-308/309 phosphorylation. Conclusions: Our data confirmed the oncogenic role of DHCR24 in melanoma stem-like cells proliferation and vemurafenib resistance by regulating 27-HC. These findings established the basis of targeting DHCR24 as a potential therapeutic target for advanced melanoma.


Author(s):  
Sara Awan ◽  
Magalie Lambert ◽  
Ali Imtiaz ◽  
Fabien Alpy ◽  
Catherine Tomasetto ◽  
...  

Background: Impairment of cellular cholesterol trafficking is at the heart of atherosclerotic lesions formation. This involves egress of cholesterol from the lysosomes and two lysosomal proteins, the Niemann-Pick C1 (NPC1) and NPC2 that promotes cholesterol trafficking. However, movement of cholesterol out the lysosome and how disrupted cholesterol trafficking leads to atherosclerosis is unclear. As the Wnt ligand, Wnt5a inhibits the intracellular accumulation of cholesterol in multiple cell types, we tested whether Wnt5a interacts with the lysosomal cholesterol export machinery and studied its role in atherosclerotic lesions formation. Methods: We generated mice deleted for the Wnt5a gene in vascular smooth muscle cells (VSMCs). To establish whether Wnt5a also protects against cholesterol accumulation in human VSMCs, we used a CRISPR/Cas9 guided nuclease approach to generate human VSMCs knockout for Wnt5a. Results: We show that Wnt5a is a crucial component of the lysosomal cholesterol export machinery. By increasing lysosomal acid lipase expression, decreasing metabolic signaling by the mTORC1 kinase, and through binding to NPC1 and NPC2, Wnt5a senses changes in dietary cholesterol supply and promotes lysosomal cholesterol egress to the endoplasmic reticulum (ER). Consequently, loss of Wnt5a decoupled mTORC1 from variations in lysosomal sterol levels, disrupted lysosomal function, decreased cholesterol content in the ER, and promoted atherosclerosis. Conclusions: These results reveal an unexpected function of the Wnt5a pathway as essential for maintaining cholesterol homeostasis in vivo.


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