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The cholesterol metabolite 27-hydroxycholesterol inhibits SARS-CoV-2 and is markedly decreased in COVID-19 patients.

ABSTRACT: There is an urgent need to identify antivirals against the coronavirus SARS-CoV-2 in the current COVID-19 pandemic and to contain future similar emergencies early on. Specific side-chain cholesterol oxidation products of the oxysterols family have been shown to inhibit a large variety of both enveloped and non-enveloped human viral pathogens. Here we report on the in vitro inhibitory activity of the redox active oxysterol 27-hydroxycholesterol against SARS-CoV-2 and against one of the common cold agents HCoV-OC43 human coronavirus without significant cytotoxicity. Interestingly, physiological serum levels of 27-hydroxycholesterol in SARS-CoV-2 positive subjects were significantly decreased compared to the matched control group, reaching a marked 50% reduction in severe COVID-19 cases. Moreover, no correlation at all was observed between 24-hydroxycholesterol and 25-hydroxycholesterol serum levels and the severity of the disease. Opposite to that of 27-hydroxycholesterol was the behaviour of two recognized markers of redox imbalance, i.e. 7-ketocholesterol and 7β-hydroxycholesterol, whose serum levels were significantly increased especially in severe COVID-19. The exogenous administration of 27-hydroxycholesterol may represent in the near future a valid antiviral strategy in the worsening of diseases caused by present and emerging coronaviruses.

SUBMITTER: Marcello A

PROVIDER: S-EPMC7416714 | biostudies-literature |

REPOSITORIES: biostudies-literature

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The cholesterol metabolite 27-hydroxycholesterol promotes atherosclerosis via proinflammatory processes mediated by estrogen receptor alpha.

Project description:Oxysterols are cholesterol metabolites that serve multiple functions in lipid metabolism, including as liver X receptor (LXR) ligands. 27-hydroxycholesterol (27HC) is an abundant oxysterol metabolized by CYP7B1. How 27HC impacts vascular health is unknown. We show that elevations in 27HC via cyp7b1 deletion promote atherosclerosis in apoe(-/-) mice without altering lipid status; furthermore, estrogen-related atheroprotection is attenuated. In wild-type mice, leukocyte-endothelial cell adhesion is increased by 27HC via estrogen receptor (ER)-dependent processes. In monocytes/macrophages, 27HC upregulates proinflammatory genes and increases adhesion via ER?. In endothelial cells, 27HC is also proadhesive via ER?, and in contrast to estrogen, which blunts NF-?B activation, 27HC stimulates NF-?B activation via Erk1,2 and JNK-dependent I?B? degradation. Whereas 27HC administration to apoe(-/-) mice increases atherosclerosis, apoe(-/-);er?(-/-) are unaffected. Thus, 27HC promotes atherosclerosis via proinflammatory processes mediated by ER?, and it attenuates estrogen-related atheroprotection. Strategies to lower 27HC may complement approaches targeting cholesterol to prevent vascular disease.

| S-EPMC4098728 | biostudies-literature

Cholesterol and 27-hydroxycholesterol promote thyroid carcinoma aggressiveness.

Project description:Cholesterol mediates its proliferative and metastatic effects via the metabolite 27-hydroxycholesterol (27-HC), at least in breast and endometrial cancer. We determined the serum lipoprotein profile, intratumoral cholesterol and 27-HC levels in a cohort of patients with well-differentiated papillary thyroid carcinoma (PTC; low/intermediate and high risk), advanced thyroid cancers (poorly differentiated, PDTC and anaplastic thyroid carcinoma, ATC) and benign thyroid tumors, as well as the expression of genes involved in cholesterol metabolism. We investigated the gene expression profile, cellular proliferation, and migration in Nthy-ori 3.1 and CAL-62 cell lines loaded with human low-density lipoprotein (LDL). Patients with more aggressive tumors (high-risk PTC and PDTC/ATC) showed a decrease in blood LDL cholesterol and apolipoprotein B. These changes were associated with an increase in the expression of the thyroid's LDL receptor, whereas 3-hydroxy-3-methylglutaryl-CoA reductase and 25-hydroxycholesterol 7-alpha-hydroxylase were downregulated, with an intratumoral increase of the 27-HC metabolite. Furthermore, LDL promoted proliferation in both the Nthy-ori 3.1 and CAL-62 thyroid cellular models, but only in ATC cells was its cellular migration increased significantly. We conclude that cholesterol and intratumoral accumulation of 27-HC promote the aggressive behavior process of PTC. Targeting cholesterol metabolism could be a new therapeutic strategy in thyroid tumors with poor prognosis.

| S-EPMC6635382 | biostudies-literature

The cholesterol metabolite 27 hydroxycholesterol facilitates breast cancer metastasis through its actions on immune cells.

Project description:Obesity and elevated circulating cholesterol are risk factors for breast cancer recurrence, while the use of statins, cholesterol biosynthesis inhibitors widely used for treating hypercholesterolemia, is associated with improved disease-free survival. Here, we show that cholesterol mediates the metastatic effects of a high-fat diet via its oxysterol metabolite, 27-hydroxycholesterol. Ablation or inhibition of CYP27A1, the enzyme responsible for the rate-limiting step in 27-hydroxycholesterol biosynthesis, significantly reduces metastasis in relevant animal models of cancer. The robust effects of 27-hydroxycholesterol on metastasis requires myeloid immune cell function, and it was found that this oxysterol increases the number of polymorphonuclear-neutrophils and ??-T cells at distal metastatic sites. The pro-metastatic actions of 27-hydroxycholesterol requires both polymorphonuclear-neutrophils and ??-T cells, and 27-hydroxycholesterol treatment results in a decreased number of cytotoxic CD8+T lymphocytes. Therefore, through its actions on ??-T cells and polymorphonuclear-neutrophils, 27-hydroxycholesterol functions as a biochemical mediator of the metastatic effects of hypercholesterolemia.High cholesterol is a risk factor for breast cancer recurrence. Here the authors show that cholesterol promotes breast cancer metastasis via its metabolite 27-hydroxycholesterol (27HC) that acts on immune myeloid cells residing at the distal metastatic sites, thus promoting an immune suppressive environment.

| S-EPMC5636879 | biostudies-other

27-Hydroxycholesterol links cholesterol and breast cancer pathophysiology.

Project description:The cholesterol metabolite and SERM, 27HC, is the signaling molecule that links cholesterol to breast cancer pathophysiology Hypercholesterolemia is a risk factor for breast cancer, and patients taking statins demonstrate lower breast cancer incidence and decreased breast cancer recurrence, data that highlights the potential importance of the recent finding that 27-Hydroxycholesterol (27HC), a primary metabolite of cholesterol, acts as a selective estrogen receptor modulator (SERM). The goal of this study was to evaluate the impact of 27HC on breast cancer pathophysiology. Elevation of 27HC in murine models increased tumor growth in an estrogen receptor dependent manner. Importantly, a high cholesterol diet decreased the time to tumor onset and increased tumor growth, and this response required presence of CYP27A1. Within human breast cancer samples, CYP27A1 expression increasesd with grade, in addition to being highly expressed in tumor associated macrophages. Finally 27HC increases metastasis to the lung. The findings herein strongly support a role for 27HC in breast cancer pathophysiology, providing support for the exploration of potential chemopreventative benefits of lower cholesterol diets, and pharmacological inhibitors of HMG-CoA reductase or CYP27A1. MCF-7 cells were treated as indicated in the presence of E2 or vehicle; RNA was isolated and used for preparation of label for 3' expression analysis.

2013-08-01 | E-GEOD-46924 | biostudies-arrayexpress

Cholesterol 25-Hydroxylase inhibits SARS-CoV-2 and coronaviruses by depleting membrane cholesterol

Project description:Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2 and has spread across the globe. SARS-CoV-2 is a highly infectious virus with no vaccine or antiviral therapy available to control the pandemic, therefore, it is crucial to understand the mechanisms of viral pathogenesis and the host immune responses to SARS-CoV-2. SARS-CoV-2 is a new member of the betacoronavirus genus like other closely related viruses including SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). Here, we report that one of the interferon-stimulated genes (ISGs), cholesterol 25-hydroxylase (CH25H), is induced by SARS-CoV-2 infection in vitro and in COVID-19 patients. CH25H converts cholesterol to 25-hydrocholesterol (25HC) and 25HC shows broad anti-coronavirus activity by blocking membrane fusion. 25HC inhibits SARS-CoV-2 infection in lung epithelial cells and viral entry in human lung organoids. Mechanistically, 25HC inhibits viral membrane fusion by activating the ER-localized ACAT which leads to the depletion of accessible cholesterol from the plasma membrane. Altogether, our results shed light on a potentially broad antiviral mechanism by 25HC through depleting accessible cholesterol on the plasma membrane to suppress virus-cell fusion.

| S-SCDT-EMBOJ-2020-106057 | biostudies-other

The cholesterol metabolite 27-hydroxycholesterol increases the secretion of extracellular vesicles which promote breast cancer progression

Project description:Mice bearing Met1 tumors were treated with extracellular vessicles (EVs) isolated from neutrophils treated with vehicle (DMSO) or 27-hydroxycholesterol. RNAseq was performed on harvested tumors.

2021-06-16 | GSE171949 | GEO

27-Hydroxycholesterol links cholesterol and breast cancer pathophysiology

| S-ECPF-GEOD-46924 | biostudies-other

27-Hydroxycholesterol links cholesterol and breast cancer pathophysiology.

2013-08-01 | GSE46924 | GEO

Modulation of cell proteome by 25-hydroxycholesterol and 27-hydroxycholesterol: A link between cholesterol metabolism and antiviral defense.

Project description:Physiological cholesterol metabolism implies the generation of a series of oxidized derivatives, whose oxysterols are by far the most investigated ones for their potential multifaceted involvement in human pathophysiology. In this regard, noteworthy is the broad antiviral activity displayed by defined side chain oxysterols, in particular 25-hydroxycholesterol (25HC) and 27-hydroxycholesterol (27HC). Although their antiviral mechanism(s) may vary depending on virus/host interaction, these oxysterols share the common feature to hamper viral replication by interacting with cellular proteins. Here reported is the first analysis of the modulation of a cell proteome by these two oxysterols, that, besides yielding additional clues about their potential involvement in the regulation of sterol metabolism, provides novelinsights about the mechanism underlying the inhibition of virus entry and trafficking within infected cells. We show here that both 25HC and 27HC can down-regulate the junction adhesion molecule-A (JAM-A) and the cation independent isoform of mannose-6-phosphate receptor (MPRci), two crucial molecules for the replication of all those viruses that exploit adhesion molecules and the endosomal pathway to enter and diffuse within target cells.

| S-EPMC7126780 | biostudies-literature

Cholesterol, 24-Hydroxycholesterol, and 27-Hydroxycholesterol as Surrogate Biomarkers in Cerebrospinal Fluid in Mild Cognitive Impairment and Alzheimer's Disease: A Meta-Analysis.

Project description:Abnormal cholesterol metabolism is an established feature of Alzheimer's disease (AD). Cerebrospinal fluid (CSF) is the fluid surrounding the central nervous system, and the protein and lipid content alterations in the CSF could be biomarkers for degenerative changes in the brain. The laboratory diagnosis of AD is limited to the analysis of three biomarkers in CSF: A?42, total tau, and phospho-tau. The purpose of this analysis is to systematically analyze the available data describing the biomarkers of cholesterol and its metabolites in the CSF of subjects with AD. MEDLINE, EMBASE, and the Cochrane Central database were systematically queried to collect studies that have evaluated the markers of cholesterol and its metabolites in the CSF of subjects with mild cognitive impairment (MCI) or AD and age-matched controls. Analysis of the published data shows that the levels of cholesterol are increased in MCI subjects; 24-hydroxycholesterol and 27-hydroxycholesterol are elevated in AD and MCI subjects compared to controls. There is a significant dysfunction of cholesterol metabolism in the CSF of AD subjects. This analysis indicates that in addition to the available biomarkers in the CSF, such as A?42, total tau, and phospho-tau, 24-hydroxycholesterol, 27-hydroxycholesterol, and cholesterol appear to be sensitive biomarkers for the evaluation of MCI and AD.

| S-EPMC6110663 | biostudies-literature

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