25-Hydroxycholesterol in health and diseases

Journal of Lipid Research, Journal Year: 2023, Volume and Issue: 65(1), P. 100486 - 100486

Published: Dec. 16, 2023

Language: Английский

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A cholesterol-binding bacterial toxin provides a strategy for identifying a specific Scap inhibitor that blocks lipid synthesis in animal cells

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(7)

Published: Feb. 8, 2024

Lipid synthesis is regulated by the actions of Scap, a polytopic membrane protein that binds cholesterol in membranes endoplasmic reticulum (ER). When ER levels are low, Scap activates SREBPs, transcription factors upregulate genes for cholesterol, fatty acids, and triglycerides. rise, sterol to triggering conformational changes prevent activation SREBPs halting lipids. To achieve molecular understanding how regulates Scap/SREBP machine identify therapeutics dysregulated lipid metabolism, cholesterol-mimetic compounds specifically bind inhibit needed. accomplish this goal, we focused on Anthrolysin O (ALO), pore-forming bacterial toxin with specificity sensitivity uncannily similar Scap. We reasoned small molecule would ALO might also High-throughput screening ~300,000-compound library ALO-binding unearthed one molecule, termed UT-59, which Scap’s cholesterol-binding site. Upon binding, UT-59 triggers same conformation as those induced blocks lipogenesis cultured cells. inhibits SREBP mouse liver. Unlike five previously reported inhibitors activation, only acts binding Our approach specific such holds great promise developing therapeutic leads human diseases stemming from elevated liver certain cancers.

Language: Английский

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The role of 25-hydroxycholesterol in the pathophysiology of brain vessel dysfunction associated with infection and cholesterol dysregulation

Disease Models & Mechanisms, Journal Year: 2025, Volume and Issue: 18(9)

Published: May 23, 2025

ABSTRACT The antiviral enzyme cholesterol 25-hydroxylase (CH25H) and its metabolite 25-hydroxycholesterol (25HC), which modulates metabolism during infection, have been associated with vascular pathology. Viral infections linked to intracerebral haemorrhage (ICH) risk, but the molecular mechanisms leading ICH via responses remain unknown. We hypothesised that CH25H/25HC pathway impacts neuroendothelial integrity in context of infection-associated ICH. Using a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein-induced zebrafish model foetal human SARS-CoV-2-associated cortical tissue containing microbleeds, we identified upregulation CH25H cerebral haemorrhage. models brain endothelial cells, asked whether 25HC promotes neurovascular dysfunction by modulating metabolism. found pharmacological inhibition synthesis had an additive effect exacerbate bleeding vitro dysfunction. 25HC-induced was also rescued supplementation vitro. These results demonstrate can dysregulate function remodelling propose plays important role pathophysiology vessel infection dysregulation

Language: Английский

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Visualization of accessible cholesterol using a GRAM domain-based biosensor

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Oct. 25, 2023

Cholesterol is important for membrane integrity and cell signaling, dysregulation of the distribution cellular cholesterol associated with numerous diseases, including neurodegenerative disorders. While regulated transport a specific pool cholesterol, known as "accessible cholesterol", contributes to maintenance homeostasis, tools monitor accessible in live cells remain limited. Here, we engineer highly sensitive biosensor by taking advantage cholesterol-sensing element (the GRAM domain) an evolutionarily conserved lipid transfer protein, GRAMD1b. Using this biosensor, which call GRAM-W, successfully visualize real time many different types, human keratinocytes iPSC-derived neurons, show differential dependencies on biosynthesis uptake maintaining levels cholesterol. Furthermore, combine GRAM-W dimerization-dependent fluorescent protein (ddFP) establish strategy ultrasensitive detection plasma These will allow us obtain insights into molecular mechanisms regulated.

Language: Английский

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Proprotein Convertase Subtilisin/Kexin Type 9 Induction in COVID-19 Is Poorly Associated with Disease Severity and Cholesterol Levels

Infectious Disease Reports, Journal Year: 2024, Volume and Issue: 16(4), P. 593 - 607

Published: July 17, 2024

SARS-CoV-2 infection was shown to induce proprotein convertase subtilisin/kexin type 9 (PCSK9) plasma levels in sepsis. Here, we investigate the association between serum PCSK9 and disease severity. measured of 55 controls, 40 patients with moderate 60 severe COVID-19 disease. Serum elevated compared controls further increased cases. were not associated C-reactive protein, bacterial superinfections, interventions, or survival COVID-19. regulates circulating cholesterol levels, 15 cholesteryl ester (CE) species free (FC) quantified by direct flow injection analysis using a high-resolution hybrid quadrupole-Orbitrap mass spectrometer. Most CE shorter fatty acid chains decreased COVID-19, none correlated Levels all negatively protein patients. Notably, FC induced The FC/CE ratio positively inflammatory markers non-survival. current study suggests that imbalance is severity mortality

Language: Английский

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Mechanisms of lipid homeostasis in the Coxiella Containing Vacuole

Biochemical Society Transactions, Journal Year: 2025, Volume and Issue: 00(00)

Published: Jan. 22, 2025

Coxiella burnetii, the causative agent of human Q fever, is an obligate intracellular bacterial pathogen that replicates in a large, membrane-bound vacuole known as Containing Vacuole (CCV). The CCV unique, phagolysosome-derived with sterol-rich membrane containing host and proteins. itself serves barrier to protect bacteria from host’s innate immune response, lipid protein content directly influence both luminal environment interactions between trafficking pathways. cholesterol critical regulating pH, while phosphatidylinositol phosphate species fusion events dynamics. C. burnetii proteins target metabolism regulate generate source lipids support replication or response. This review provides overview diverse repertoire involved formation maintenance, highlighting pathogen-driven strategies modify homeostasis.

Language: Английский

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Effects of acute pro-inflammatory stimulation and 25-hydroxycholesterol on hippocampal plasticity and learning involve NLRP3 inflammasome and cellular stress responses

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: Feb. 20, 2025

Neuroinflammation is an increasingly important target for therapeutics in neuropsychiatry and contributes to cognitive dysfunction, disability death across a range of illnesses. We previously found that acute effects pro-inflammatory stimulation with lipopolysaccharide (LPS) on hippocampal long-term potentiation (LTP), form synaptic plasticity involved learning memory, requires synthesis the oxysterol, 25-hydroxycholesterol (25HC) exogenous 25HC mimics LPS. However, downstream mechanisms engaged by LPS remain uncertain. Here we use rat slices vivo behavioral studies provide evidence modulation both activation NLRP3 inflammasome, caspase-1 interleukin-1 receptor. Furthermore, engage cellular stress responses including 5α-reduced neurosteroids are prevented modulators these responses. In using one-trial inhibitory avoidance task, inhibition pre-treatment inhibitor NLRP3. The present strong support role as mediator importance inflammasome deleterious inflammation.

Language: Английский

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Aspergillus fumigatus secondary metabolite pyripyropene is important for the dual biofilm formation with Pseudomonas aeruginosa

mBio, Journal Year: 2025, Volume and Issue: unknown

Published: March 17, 2025

ABSTRACT The human pathogenic fungus Aspergillus fumigatus establishes dual biofilm interactions in the lungs with bacterium Pseudomonas aeruginosa . Screening of 21 A null mutants revealed seven (two G protein-coupled receptors, three mitogen-activated protein kinase a Gα protein, and one histidine receptor) reduced formation, specifically presence P. Transcriptional profiling metabolomics analysis secondary metabolites produced by these mutants, Δ gpaB ( encodes protein), showed GpaB controls production several important for interaction, including pyripyropene A, potent inhibitor mammalian acyl-CoA cholesterol acyltransferase. Deletion pyr2 , encoding non-reducing polyketide synthase essential biosynthesis, A. pyr2-P. growth, altered macrophage responses, attenuated mouse virulence chemotherapeutic murine model. We identified as novel player ecology this fungal pathogen. IMPORTANCE are two pathogens. Both organisms establish patients affected chronic lung pulmonary infections, such cystic fibrosis (CF) obstructive disease. Colonization is associated an increased risk colonization CF patients, disease prognosis poor when both pathogens present. Here, we genetic determinants establishment vitro fumigatus-P. interactions. Among them, interaction controlling metabolite pyripyropene. demonstrate that lack decreases between species well model aspergillosis. These results reveal complete role

Language: Английский

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New Directions in Neurosteroid Therapeutics in Neuropsychiatry

Neuroscience & Biobehavioral Reviews, Journal Year: 2025, Volume and Issue: unknown, P. 106119 - 106119

Published: March 1, 2025

Language: Английский

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Crosstalk between metabolites and myeloid cell biology

Elsevier eBooks, Journal Year: 2025, Volume and Issue: unknown, P. 27 - 61

Published: Jan. 1, 2025

Language: Английский

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