A Concerted Mechanism Involving ACAT and SREBPs By which Oxysterols Deplete Accessible Cholesterol To Restrict Microbial Infection DOI Creative Commons
David B. Heisler, Kristen A. Johnson, Maikke B. Ohlson

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: Oct. 11, 2022

Abstract Most of the cholesterol in plasma membranes (PMs) animal cells is sequestered through interactions with phospholipids and transmembrane domains proteins. However, as concentration rises above PM’s sequestration capacity, a new pool cholesterol, called accessible emerges. The transport between PM endoplasmic reticulum (ER) critical to maintain homeostasis. This pathway has also been implicated suppression both bacterial viral pathogens by immunomodulatory oxysterols. Here, we describe mechanism depletion from PMs oxysterol 25-hydroxycholesterol (25HC). We show that 25HC-mediated activation acyl coenzyme A: acyltransferase (ACAT) ER creates an imbalance equilibrium distribution PM. triggers rapid internalization PM, which sustained for long periods time SREBPs. In support physiological role this mechanism, 25HC failed suppress Zika virus human coronavirus infection ACAT-deficient cells, Listeria monocytogenes mice. propose selective triggered ACAT SREBP underpins immunological activities functionally related class

Language: Английский

A concerted mechanism involving ACAT and SREBPs by which oxysterols deplete accessible cholesterol to restrict microbial infection DOI Creative Commons
David B. Heisler, Kristen A. Johnson, Duo Ma

et al.

eLife, Journal Year: 2023, Volume and Issue: 12

Published: Jan. 25, 2023

Most of the cholesterol in plasma membranes (PMs) animal cells is sequestered through interactions with phospholipids and transmembrane domains proteins. However, as concentration rises above PM’s sequestration capacity, a new pool cholesterol, called accessible emerges. The transport between PM endoplasmic reticulum (ER) critical to maintain homeostasis. This pathway has also been implicated suppression both bacterial viral pathogens by immunomodulatory oxysterols. Here, we describe mechanism depletion from PMs oxysterol 25-hydroxycholesterol (25HC). We show that 25HC-mediated activation acyl coenzyme A: acyltransferase (ACAT) ER creates an imbalance equilibrium distribution PM. triggers rapid internalization PM, this sustained for long periods time SREBPs continued ACAT. In support physiological role mechanism, 25HC failed suppress Zika virus human coronavirus infection ACAT-deficient cells, Listeria monocytogenes mice. propose selective triggered ACAT SREBP underpins immunological activities functionally related class

Language: Английский

Citations

25
Regulation of cellular cholesterol distribution via non-vesicular lipid transport at ER-Golgi contact sites DOI Creative Commons
Tomoki Naito, Haoning Yang, Dylan Hong Zheng Koh

et al.

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

Published: Sept. 21, 2023

Abstract Abnormal distribution of cellular cholesterol is associated with numerous diseases, including cardiovascular and neurodegenerative diseases. Regulated transport critical for maintaining its proper in the cell, yet underlying mechanisms remain unclear. Here, we show that lipid transfer proteins, namely ORP9, OSBP, GRAMD1s/Asters (GRAMD1a/GRAMD1b/GRAMD1c), control non-vesicular at points contact between ER trans-Golgi network (TGN), thereby distribution. ORP9 localizes to TGN via interaction tandem α-helices ORP10/ORP11. extracts PI4P from prevent overaccumulation suppresses OSBP-mediated PI4P-driven Golgi. By contrast, GRAMD1s excess Golgi ER, preventing build-up. Cells lacking exhibit accumulation Golgi, which further enhanced by additional depletion major plasma membrane. This accompanied chronic activation SREBP-2 signalling pathway. Our findings reveal importance regulated ER-Golgi contacts homeostasis.

Language: Английский

Citations

22
25-Hydroxycholesterol in health and diseases DOI Creative Commons
Cindy Nguyen, Julien Saint‐Pol,

Shiraz Dib

et al.

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

Published: Dec. 16, 2023

Language: Английский

Citations

19
Chemical Inhibition of Sterol Biosynthesis DOI Creative Commons
Eric S. Peeples, Károly Mirnics, Željka Korade

et al.

Biomolecules, Journal Year: 2024, Volume and Issue: 14(4), P. 410 - 410

Published: March 28, 2024

Cholesterol is an essential molecule of life, and its synthesis can be inhibited by both genetic nongenetic mechanisms. Hundreds chemicals that we are exposed to in our daily lives alter sterol biosynthesis. These also encompass various classes FDA-approved medications, including (but not limited to) commonly used antipsychotic, antidepressant, antifungal, cardiovascular medications. medications interfere with enzymes the post-lanosterol biosynthetic pathway, giving rise complex biochemical changes throughout body. The consequences these short- long-term homeostatic disruptions mostly unknown. We performed a comprehensive review literature built catalogue chemical agents capable inhibiting This process identified significant gaps existing knowledge, which fall into two main areas: mechanisms biosynthesis altered arise from inhibitions different steps pathway. outcome reinforced inhibition often-overlooked mechanism result adverse there need develop new safety guidelines for use (novel already approved) side effects, especially during pregnancy.

Language: Английский

Citations

7
Effects of Oxysterols on Immune Cells and Related Diseases DOI Creative Commons
Fábio Alessandro de Freitas, Débora Levy, Cadiele Oliana Reichert

et al.

Cells, Journal Year: 2022, Volume and Issue: 11(8), P. 1251 - 1251

Published: April 7, 2022

Oxysterols are the products of cholesterol oxidation. They have a wide range effects on several cells, organs, and systems in body. also an influence physiology immune system, from cell maturation migration to innate humoral responses. In this regard, oxysterols been involved diseases that component, autoimmune neurodegenerative inflammatory diseases, atherosclerosis, cancer. Here, we review data participation oxysterols, mainly 25-hydroxycholesterol 7α,25-dihydroxycholesterol, system related diseases. The these main oxysterol receptors, LXR EBI2, cells (B T macrophages, dendritic oligodendrocytes, astrocytes), immune-related such as intestinal cancer, respiratory discussed.

Language: Английский

Citations

26
Targeting squalene epoxidase in the treatment of metabolic-related diseases: current research and future directions DOI Creative Commons
Mingzhu Chen, Yuting Yang,

Shiting Chen

et al.

PeerJ, Journal Year: 2024, Volume and Issue: 12, P. e18522 - e18522

Published: Nov. 22, 2024

Metabolic-related diseases are chronic caused by multiple factors, such as genetics and the environment. These difficult to cure seriously affect human health. Squalene epoxidase (SQLE), second rate-limiting enzyme in cholesterol synthesis, plays an important role synthesis alters gut microbiota tumor immunity. Research has shown that SQLE is expressed many tissues organs involved occurrence development of various metabolic-related diseases, cancer, nonalcoholic fatty liver disease, diabetes mellitus, obesity. inhibitors, terbinafine, NB598, natural compounds, their derivatives, can effectively ameliorate fungal infections, cancer. In this review, we provide overview recent research progress on diseases. Further regulation expression highly for developing drugs treatment with good pharmacological activity.

Language: Английский

Citations

3
Effect of Treatment on Steroidome in Women with Multiple Sclerosis DOI Open Access
Martin Hill,

Radmila Kancheva,

Marta Velíková

et al.

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(5), P. 1835 - 1835

Published: Feb. 20, 2025

Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disease of the central nervous system. The manifestation MS related to steroid changes during menstrual cycle and pregnancy. As data focusing on effect anti-MS drug treatment steroidome are scarce, we evaluated steroidomic (79 steroids) in 61 female patients reproductive age 39 (29, 47) years (median with quartiles) after drugs GC-MS/MS platform immunoassays (cortisol estradiol). were assessed using levels molar ratios (SMRs) that may reflect activities steroidogenic enzymes (SMRs). A repeated measures ANOVA, followed by multiple comparisons OPLS models, used for statistical analyses. decreased follicular phase. Anti-CD20 monoclonal antibodies (mAb), such as ofatumumab ocrelizumab; inhibitors sphingosine-1-phosphate receptor (S1PRI); IFNβ-1a circulating 17-hydroxy-pregnanes shifted CYP17A1 functioning from hydroxylase- toward lyase step. Decreased conjugated/unconjugated found drugs, especially glatiramer acetate anti-CD20 mAb. In luteal phase, IFN-β1a increased steroidogenesis; both ocrelizumab AKR1D1, S1PRI SRD5A functioning. mAb reduced catalyzing synthesis immunomodulatory 7α/β 16α-hydroxy-androgens, which affect severity MS. above findings be important concerning alterations bioactive steroids, cortisol; active androgens estrogens; neuroactive, neuroprotective, steroids terms optimization treatment.

Language: Английский

Citations

0
Oxy210, a Semi-Synthetic Oxysterol, Exerts Anti-Inflammatory Effects in Macrophages via Inhibition of Toll-like Receptor (TLR) 4 and TLR2 Signaling and Modulation of Macrophage Polarization DOI Open Access

Feng Wang,

Frank Stappenbeck,

Liu-Ya Tang

et al.

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(10), P. 5478 - 5478

Published: May 13, 2022

Inflammatory responses by the innate and adaptive immune systems protect against infections are essential to health survival. Many diseases including atherosclerosis, osteoarthritis, rheumatoid arthritis, psoriasis, obesity involve persistent chronic inflammation. Currently available anti-inflammatory agents, non-steroidal drugs, steroids, biologics, often unsafe for use due adverse effects. The development of effective non-toxic agents remains an important research arena. We previously reported that oral administration Oxy210, a semi-synthetic oxysterol, ameliorates non-alcoholic steatohepatitis (NASH) induced high-fat diet in APOE*3-Leiden.CETP humanized mouse model NASH inhibits expression hepatic circulating levels inflammatory cytokines. Here, we show Oxy210 also diet-induced white adipose tissue inflammation mice, evidenced inhibition IL-6, MCP-1, CD68 macrophage marker. related analogs exhibit effects macrophages treated with lipopolysaccharide vitro, mediated through toll-like receptor 4 (TLR4), TLR2, AP-1 signaling, independent cyclooxygenase enzymes or steroid receptors. correlated polarization. propose its structural may be attractive candidates future therapeutic targeting diseases.

Language: Английский

Citations

13
A basic model for the association of ligands with membrane cholesterol: application to cytolysin binding DOI Creative Commons

Yvonne Lange,

S. M. Ali Tabei, Theodore L. Steck

et al.

Journal of Lipid Research, Journal Year: 2023, Volume and Issue: 64(4), P. 100344 - 100344

Published: Feb. 13, 2023

Almost all the cholesterol in cellular membranes is associated with phospholipids simple stoichiometric complexes. This limits binding of sterol ligands such as filipin and perfringolysin O (PFO) to a small fraction total. We offer mathematical model that characterizes this complexity. It posits accessible has two forms: active cholesterol, which not complexed phospholipids; extractable can capture competitively from phospholipid Simulations based on match published data for association PFO oligomers liposomes, plasma membranes, isolated endoplasmic reticulum. The shows how probe greatly underestimates abundance when its affinity so weak it competes poorly membrane phospholipids. Two examples are understaining by failure domain D4 label their cytoplasmic leaflets. Conversely, exaggerated staining endolysosomes suggests being uncomplexed, readily available. also applicable intrinsic proteins. For example, supports hypothesis sharp threshold regulation homeostatic reticulum proteins derives cooperativity weakly held Thus, explicates complexity inherent like cholesterol.

Language: Английский

Citations

8
Phytosterols in human serum as measured using a liquid chromatography tandem mass spectrometry DOI Creative Commons

Yu Chun Teng,

Marie Claire Gielen,

Nina M De Gruijter

et al.

The Journal of Steroid Biochemistry and Molecular Biology, Journal Year: 2024, Volume and Issue: 241, P. 106519 - 106519

Published: April 12, 2024

Phytosterols are lipophilic compounds found in plants with structural similarity to mammalian cholesterol. They cannot be endogenously produced by mammals and therefore always originate from diet. There has been increased interest dietary phytosterols over the last few decades due their association a variety of beneficial health effects including low-density lipoprotein cholesterol lowering, anti-inflammatory anti-cancerous effects. proposed as potential moderators for diseases associated central nervous system where homeostasis is imperative (multiple sclerosis, dementia, etc.) ability reach brain. Here we utilised an enzyme-assisted derivatisation sterol analysis (EADSA) combination liquid chromatography tandem mass spectrometry (LC-MSn) characterise phytosterol content human serum. As little 100 fg plant was injected on reversed phase LC column. The method allows semi-quantitative measurements derivatives simultaneously measurement metabolites. identification serum based comparison retention times MS2, MS3 spectra library authentic standards. Free campesterol concentration range 0.30 - 4.10 µg/mL, β-sitosterol 0.16 3.37 µg/mL fucosterol at lowest 0.05 0.38 ten individuals. This analytical methodology could applied other biological fluids tissues.

Language: Английский

Citations

2