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Circulation Jan 2023Cross-talk between sterol metabolism and inflammatory pathways has been demonstrated to significantly affect the development of atherosclerosis. Cholesterol biosynthetic...
BACKGROUND
Cross-talk between sterol metabolism and inflammatory pathways has been demonstrated to significantly affect the development of atherosclerosis. Cholesterol biosynthetic intermediates and derivatives are increasingly recognized as key immune regulators of macrophages in response to innate immune activation and lipid overloading. 25-Hydroxycholesterol (25-HC) is produced as an oxidation product of cholesterol by the enzyme cholesterol 25-hydroxylase (CH25H) and belongs to a family of bioactive cholesterol derivatives produced by cells in response to fluctuating cholesterol levels and immune activation. Despite the major role of 25-HC as a mediator of innate and adaptive immune responses, its contribution during the progression of atherosclerosis remains unclear.
METHODS
The levels of 25-HC were analyzed by liquid chromatography-mass spectrometry, and the expression of in different macrophage populations of human or mouse atherosclerotic plaques, respectively. The effect of CH25H on atherosclerosis progression was analyzed by bone marrow adoptive transfer of cells from wild-type or mice to lethally irradiated mice, followed by a Western diet feeding for 12 weeks. Lipidomic, transcriptomic analysis and effects on macrophage function and signaling were analyzed in vitro from lipid-loaded macrophage isolated from or . The contribution of secreted 25-HC to fibrous cap formation was analyzed using a smooth muscle cell lineage-tracing mouse model, , adoptively transferred with wild-type or mice bone marrow followed by 12 weeks of Western diet feeding.
RESULTS
We found that 25-HC accumulated in human coronary atherosclerotic lesions and that macrophage-derived 25-HC accelerated atherosclerosis progression, promoting plaque instability through autocrine and paracrine actions. 25-HC amplified the inflammatory response of lipid-loaded macrophages and inhibited the migration of smooth muscle cells within the plaque. 25-HC intensified inflammatory responses of lipid-laden macrophages by modifying the pool of accessible cholesterol in the plasma membrane, which altered Toll-like receptor 4 signaling, promoted nuclear factor-κB-mediated proinflammatory gene expression, and increased apoptosis susceptibility. These effects were independent of 25-HC-mediated modulation of liver X receptor or SREBP (sterol regulatory element-binding protein) transcriptional activity.
CONCLUSIONS
Production of 25-HC by activated macrophages amplifies their inflammatory phenotype, thus promoting atherogenesis.
Topics: Humans; Mice; Animals; Atherosclerosis; Hydroxycholesterols; Plaque, Atherosclerotic; Macrophages; Cholesterol; Inflammation; Mice, Knockout
PubMed: 36416142
DOI: 10.1161/CIRCULATIONAHA.122.059062 -
Science (New York, N.Y.) Nov 2013Hypercholesterolemia is a risk factor for estrogen receptor (ER)-positive breast cancers and is associated with a decreased response of tumors to endocrine therapies....
Hypercholesterolemia is a risk factor for estrogen receptor (ER)-positive breast cancers and is associated with a decreased response of tumors to endocrine therapies. Here, we show that 27-hydroxycholesterol (27HC), a primary metabolite of cholesterol and an ER and liver X receptor (LXR) ligand, increases ER-dependent growth and LXR-dependent metastasis in mouse models of breast cancer. The effects of cholesterol on tumor pathology required its conversion to 27HC by the cytochrome P450 oxidase CYP27A1 and were attenuated by treatment with CYP27A1 inhibitors. In human breast cancer specimens, CYP27A1 expression levels correlated with tumor grade. In high-grade tumors, both tumor cells and tumor-associated macrophages exhibited high expression levels of the enzyme. Thus, lowering circulating cholesterol levels or interfering with its conversion to 27HC may be a useful strategy to prevent and/or treat breast cancer.
Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Cholestanetriol 26-Monooxygenase; Disease Models, Animal; Female; Humans; Hydroxycholesterols; Hypercholesterolemia; Lung Neoplasms; Mice; Tumor Cells, Cultured
PubMed: 24288332
DOI: 10.1126/science.1241908 -
Journal of Controlled Release :... Jul 2022Delivery of nucleic acids, such as mRNA, to immune cells has become a major focus in the past decade with ionizable lipid nanoparticles (LNPs) emerging as a...
Delivery of nucleic acids, such as mRNA, to immune cells has become a major focus in the past decade with ionizable lipid nanoparticles (LNPs) emerging as a clinically-validated delivery platform. LNPs-typically composed of ionizable lipids, cholesterol, phospholipids, and polyethylene glycol lipids -have been designed and optimized for a variety of applications including cancer therapies, vaccines, and gene editing. However, LNPs have only recently been investigated for delivery to T cells, which has various therapeutic applications including the engineering of T cell immunotherapies. While several LNP formulations have been evaluated for mRNA delivery, recent work has demonstrated that the utilization of cholesterol analogs may enhance mRNA delivery. Other studies have shown that cholesterols modified with hydroxyl groups can alter endocytic recycling mechanisms. Here, we engineered a library of LNPs incorporating hydroxycholesterols to evaluate their impact on mRNA delivery to T cells by leveraging endosomal trafficking mechanisms. Substitution of 25% and 50% 7α-hydroxycholesterol for cholesterol in LNPs enhanced mRNA delivery to primary human T cells ex vivo by 1.8-fold and 2.0-fold, respectively. Investigation of endosomal trafficking revealed that these modifications also increase late endosome production and reduce the presence of recycling endosomes. These results suggest that hydroxyl modification of cholesterol molecules incorporated into LNP formulations provides a mechanism for improving delivery of nucleic acid cargo to T cells for a range of immunotherapy applications.
Topics: Cholesterol; Humans; Hydroxycholesterols; Lipids; Liposomes; Nanoparticles; RNA, Messenger; T-Lymphocytes
PubMed: 35569584
DOI: 10.1016/j.jconrel.2022.05.020 -
Immunity Oct 2021Diets high in cholesterol alter intestinal immunity. Here, we examined how the cholesterol metabolite 25-hydroxycholesterol (25-HC) impacts the intestinal B cell...
Diets high in cholesterol alter intestinal immunity. Here, we examined how the cholesterol metabolite 25-hydroxycholesterol (25-HC) impacts the intestinal B cell response. Mice lacking cholesterol 25-hydroxylase (CH25H), the enzyme generating 25-HC, had higher frequencies of immunoglobulin A (IgA)-secreting antigen-specific B cells upon immunization or infection. 25-HC did not affect class-switch recombination but rather restrained plasma cell (PC) differentiation. 25-HC was produced by follicular dendritic cells and increased in response to dietary cholesterol. Mechanistically, 25-HC restricted activation of the sterol-sensing transcription factor SREBP2, thereby regulating B cell cholesterol biosynthesis. Ectopic expression of SREBP2 in germinal center B cells induced rapid PC differentiation, whereas SREBP2 deficiency reduced PC output in vitro and in vivo. High-cholesterol diet impaired, whereas Ch25h deficiency enhanced, the IgA response against Salmonella and the resulting protection from systemic bacterial dissemination. Thus, a 25-HC-SREBP2 axis shapes the humoral response at the intestinal barrier, providing insight into the effect of high dietary cholesterol in intestinal immunity.
Topics: Animals; Cell Differentiation; Cholesterol, Dietary; Hydroxycholesterols; Immunoglobulin A; Intestinal Mucosa; Mice; Peyer's Patches; Plasma Cells; Sterol Regulatory Element Binding Protein 2
PubMed: 34644558
DOI: 10.1016/j.immuni.2021.09.004 -
Biochemistry. Biokhimiia Jun 2022Cholesterol is an essential component of plasma membrane and precursor of biological active compounds, including hydroxycholesterols (HCs). HCs regulate cellular... (Review)
Review
Cholesterol is an essential component of plasma membrane and precursor of biological active compounds, including hydroxycholesterols (HCs). HCs regulate cellular homeostasis of cholesterol; they can pass across the membrane and vascular barriers and act distantly as para- and endocrine agents. A small amount of 25-hydroxycholesterol (25-HC) is produced in the endoplasmic reticulum of most cells, where it serves as a potent regulator of the synthesis, intracellular transport, and storage of cholesterol. Production of 25-HC is strongly increased in the macrophages, dendrite cells, and microglia at the inflammatory response. The synthesis of 25-HC can be also upregulated in some neurological disorders, such as Alzheimer's disease, amyotrophic lateral sclerosis, spastic paraplegia type 5, and X-linked adrenoleukodystrophy. However, it is unclear whether 25-HC aggravates these pathologies or has the protective properties. The molecular targets for 25-HC are transcriptional factors (LX receptors, SREBP2, ROR), G protein-coupled receptor (GPR183), ion channels (NMDA receptors, SLO1), adhesive molecules (α5β1 and ανβ3 integrins), and oxysterol-binding proteins. The diversity of 25-HC-binding proteins points to the ability of HC to affect many physiological and pathological processes. In this review, we focused on the regulation of 25-HC production and its universal role in the control of cellular cholesterol homeostasis, as well as the effects of 25-HC as a signaling molecule mediating the influence of inflammation on the processes in the neuromuscular system and brain. Based on the evidence collected, it can be suggested that 25-HC prevents accumulation of cellular cholesterol and serves as a potent modulator of neuroinflammation, synaptic transmission, and myelinization. An increased production of 25-HC in response to a various type of damage can have a protective role and reduce neuronal loss. At the same time, an excess of 25-HC may exert the neurotoxic effects.
Topics: Brain; Cholesterol; Hydroxycholesterols; Signal Transduction
PubMed: 35790411
DOI: 10.1134/S0006297922060049 -
Redox Biology Feb 2022More and more attention is nowadays given to the possible translational application of a great number of biochemical and biological findings with the involved molecules.... (Review)
Review
More and more attention is nowadays given to the possible translational application of a great number of biochemical and biological findings with the involved molecules. This is also the case of cholesterol oxidation products, redox molecules over the last years deeply investigated for their implication in human pathophysiology. Oxysterols of non-enzymatic origin, the excessive increase of which in biological fluids and tissues is of toxicological relevance for their marked pro-oxidant and pro-inflammatory properties, are increasingly applied in clinical biochemistry as molecular markers in the diagnosis and monitoring of several human and veterinary diseases. Conversely, oxysterols of enzymatic origin, the production of which is commonly under physiological regulation, could be considered and tested as promising pharmaceutical agents because of their antiviral, pro-osteogenic and antiadipogenic properties of some of them. Very recently, the quantification of oxysterols of non-enzymatic origin has been adopted in a systematic way to evaluate, monitor and improve the quality of cholesterol-based food ingredients, that are prone to auto-oxidation, as well as their industrial processing and the packaging and the shelf life of the finished food products. The growing translational value of oxysterols is here reviewed in its present and upcoming applications in various industrial fields.
Topics: Biomarkers; Cholesterol; Humans; Hydroxycholesterols; Oxidation-Reduction; Oxysterols
PubMed: 34968886
DOI: 10.1016/j.redox.2021.102220 -
Journal of Lipid Research Jan 2024Cholesterol is an essential structural component of all membranes of mammalian cells where it plays a fundamental role not only in cellular architecture, but also, for... (Review)
Review
Cholesterol is an essential structural component of all membranes of mammalian cells where it plays a fundamental role not only in cellular architecture, but also, for example, in signaling pathway transduction, endocytosis process, receptor functioning and recycling, or cytoskeleton remodeling. Consequently, intracellular cholesterol concentrations are tightly regulated by complex processes, including cholesterol synthesis, uptake from circulating lipoproteins, lipid transfer to these lipoproteins, esterification, and metabolization into oxysterols that are intermediates for bile acids. Oxysterols have been considered for long time as sterol waste products, but a large body of evidence has clearly demonstrated that they play key roles in central nervous system functioning, immune cell response, cell death, or migration and are involved in age-related diseases, cancers, autoimmunity, or neurological disorders. Among all the existing oxysterols, this review summarizes basic as well as recent knowledge on 25-hydroxycholesterol which is mainly produced during inflammatory or infectious situations and that in turn contributes to immune response, central nervous system disorders, atherosclerosis, macular degeneration, or cancer development. Effects of its metabolite 7α,25-dihydroxycholesterol are also presented and discussed.
Topics: Animals; Hydroxycholesterols; Cholesterol; Oxysterols; Biological Transport; Lipoproteins; Mammals
PubMed: 38104944
DOI: 10.1016/j.jlr.2023.100486 -
American Journal of Respiratory Cell... Dec 2023Oxysterols (i.e., oxidized cholesterol species) have complex roles in biology. 25-Hydroxycholesterol (25HC), a product of the activity of cholesterol-25-hydroxylase...
Oxysterols (i.e., oxidized cholesterol species) have complex roles in biology. 25-Hydroxycholesterol (25HC), a product of the activity of cholesterol-25-hydroxylase (CH25H) on cholesterol, has recently been shown to be broadly antiviral, suggesting therapeutic potential against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, 25HC can also amplify inflammation and be converted by CYP7B1 (cytochrome P450 family 7 subfamily B member 1) to 7α,25-dihydroxycholesterol, a lipid with chemoattractant activity, via the G protein-coupled receptor EBI2 (Epstein-Barr virus-induced gene 2)/GPR183 (G protein-coupled receptor 183). Here, using studies and two different murine models of SARS-CoV-2 infection, we investigate the effects of these two oxysterols on SARS-CoV-2 pneumonia. We show that although 25HC and enantiomeric-25HC are antiviral against human endemic coronavirus-229E, they did not inhibit SARS-CoV-2; nor did supplemental 25HC reduce pulmonary SARS-CoV-2 titers in the K18-human ACE2 (angiotensin-converting enzyme 2) mouse model . Treatment with 25HC also did not alter immune cell influx into the airway, airspace cytokines, lung pathology, weight loss, symptoms, or survival but was associated with increased airspace albumin, an indicator of microvascular injury, and increased plasma proinflammatory cytokines. Conversely, mice treated with the EBI2/GPR183 inhibitor NIBR189 displayed a modest increase in lung viral load only at late time points but no change in weight loss. Consistent with these findings, although and 25HC were upregulated in the lungs of SARS-CoV-2-infected wild-type mice, lung viral titers and weight loss in and mice infected with the β variant were similar to those in control animals. Taken together, endogenous 25HCs do not significantly regulate early SARS-CoV-2 replication or pathogenesis, and supplemental 25HC may have proinjury rather than therapeutic effects in SARS-CoV-2 pneumonia.
Topics: Humans; Animals; Mice; SARS-CoV-2; Epstein-Barr Virus Infections; COVID-19; Herpesvirus 4, Human; Hydroxycholesterols; Cholesterol; Receptors, G-Protein-Coupled; Antiviral Agents; Cytokines; Weight Loss
PubMed: 37578898
DOI: 10.1165/rcmb.2023-0007OC -
International Journal of Molecular... Jul 2020Obesity is currently affecting more than 40% of the Americans, and if it progresses with this rate, soon one out of two Americans will be obese. Obesity is an important... (Review)
Review
Obesity is currently affecting more than 40% of the Americans, and if it progresses with this rate, soon one out of two Americans will be obese. Obesity is an important risk factor for several disorders including cardiovascular disease, the first cause of death in the United States. Cancer follows as the second deadliest disease, and a link between obesity and cancer has been suggested. However, it is very hard to establish an exact connection between obesity and cancers due to the multifactorial nature of obesity. Hypercholesterolemia is a comorbidity of obesity and also linked to several cancers. Recently a cholesterol metabolite 27-hydroxycholesterol (27HC) was found to be an endogenous selective estrogen receptor modulator (SERM), which opened new doors toward several interesting studies on the role of this molecule in biological disorders. It is speculated that 27HC might be the missing link in the obesity and cancer chain. Here, we explored the effects of 27-hydroxycholesterol on obesity and cancers with a focus on the SERM capacity of 27HC.
Topics: Animals; Estrogen Receptor Modulators; Humans; Hydroxycholesterols; Hypercholesterolemia; Neoplasms; Obesity
PubMed: 32650428
DOI: 10.3390/ijms21144822 -
Maturitas Oct 2017Estrogen receptors (ERs) mediate the actions of the steroidal estrogens, and are important for the regulation of several physiological and pathophysiological processes,... (Review)
Review
Estrogen receptors (ERs) mediate the actions of the steroidal estrogens, and are important for the regulation of several physiological and pathophysiological processes, including reproduction, bone physiology, cardiovascular physiology and breast cancer. The unique pharmacology of the ERs allows for certain ligands, such as tamoxifen, to elicit tissue- and context-specific responses, ligands now referred to as selective estrogen receptor modulators (SERMs). Recently, the cholesterol metabolite 27-hydroxychoelsterol (27HC) has been defined as an endogenous SERM, with activities in atherosclerosis, osteoporosis, breast and prostate cancers, and neural degenerative diseases. Since 27HC concentrations closely mirror those of cholesterol, it is possible that 27HC mediates many of the biological effects of cholesterol. This paper provides an overview of ER pharmacology and summarizes the work to date implicating 27HC in various diseases. Wherever possible, we highlight clinical data in support of a role for 27HC in the diseases discussed.
Topics: Animals; Atherosclerosis; Breast Neoplasms; Cognitive Dysfunction; Female; Humans; Hydroxycholesterols; Male; Osteoporosis; Prostatic Neoplasms; Receptors, Estrogen; Selective Estrogen Receptor Modulators
PubMed: 28923174
DOI: 10.1016/j.maturitas.2017.07.014