Oxysterols in the pathogenesis of major chronic diseases

Poli, Giuseppe; Biasi, Fiorella; Leonarduzzi, Gabriella

doi:10.1016/j.redox.2012.12.001

Cited by 255 publications

(224 citation statements)

References 46 publications

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“…Oxysterols are oxygenated derivatives of cholesterol or byproducts of cholesterol synthesis (6)(7)(8)(9). Some oxysterols serve as key intermediates for bile acid and steroid synthesis and function as signaling molecules or receptor ligands modulating cell proliferation and apoptosis, lipid and cholesterol synthesis, transportation and metabolism, and immune responses.…”

Section: L-17-producing Cd4mentioning

confidence: 99%

Oxysterols are agonist ligands of RORγt and drive Th17 cell differentiation

Soroosh

Xue

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

223

200

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The RAR-related orphan receptor gamma t (RORγt) is a nuclear receptor required for generating IL-17-producing CD4 + Th17 T cells, which are essential in host defense and may play key pathogenic roles in autoimmune diseases. Oxysterols elicit profound effects on immune and inflammatory responses as well as on cholesterol and lipid metabolism. Here, we describe the identification of several naturally occurring oxysterols as RORγt agonists. The most potent and selective activator for RORγt is 7β, 27-dihydroxycholesterol (7β, 27-OHC). We show that these oxysterols reverse the inhibitory effect of an RORγt antagonist, ursolic acid, in RORγ-or RORγt-dependent cell-based reporter assays. These ligands bind directly to recombinant RORγ ligand binding domain (LBD), promote recruitment of a coactivator peptide, and reduce binding of a corepressor peptide to RORγ LBD. In primary cells, 7β, 27-OHC and 7α, 27-OHC enhance the differentiation of murine and human IL-17-producing Th17 cells in an RORγt-dependent manner. Importantly, we showed that Th17, but not Th1 cells, preferentially produce these two oxysterols. In vivo, administration of 7β, 27-OHC in mice enhanced IL-17 production. Mice deficient in CYP27A1, a key enzyme in generating these oxysterols, showed significant reduction of IL-17-producing cells, including CD4+ and γδ + T cells, similar to the deficiency observed in RORγt knockout mice. Our results reveal a previously unknown mechanism for selected oxysterols as immune modulators and a direct role for CYP27A1 in generating these RORγt agonist ligands, which we propose as RORγt endogenous ligands, driving both innate and adaptive IL-17-dependent immune responses.

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Section: L-17-producing Cd4mentioning

confidence: 99%

Oxysterols are agonist ligands of RORγt and drive Th17 cell differentiation

Soroosh

Xue

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

223

200

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“…However, an overabundance of oxysterols can cause several diseases, such as cardiovascular disease, retina degeneration, inflammatory bowel disease, atherosclerosis, and neurodegenerative disorders [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

Separation and Determination of Some of the Main Cholesterol-Related Compounds in Blood by Gas Chromatography-Mass Spectrometry (Selected Ion Monitoring Mode)

et al. 2018

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Oxysterols are metabolites produced in the first step of cholesterol metabolism, which is related to neurodegenerative disorder. They can be detected by testing blood, plasma, serum, or cerebrospinal fluid. In this study, some cholesterol precursors and oxysterols were determined by gas chromatography coupled to mass spectrometry. The selected cholesterol-related compounds were desmosterol, lathosterol, lanosterol, 7α-hydroxycholesterol, 7β-hydroxycholesterol, 24(S)-hydroxycholesterol, 25-hydroxycholesterol, 7-ketocholesterol, and 27-hydroxycholesterol. A powerful method was developed and validated considering various analytical parameters, such as linearity index, detection and quantification limits, selectivity and matrix effect, precision (repeatability), and trueness (recovery factor) for each cholesterol-related compound. 7α-hydroxycholesterol, 7β-hydroxycholesterol, and desmosterol exhibited the lowest detection and quantification limits, with 0.01 and 0.03 µg/mL, respectively, in the three cases. 7-ketocholesterol and lathosterol showed matrix effect percentages between 95.5% and 104.8%, respectively (demonstrating a negligible matrix effect), and very satisfactory repeatability values (i.e., overall performance of the method). Next, the method was applied to the analysis of a very interesting selection of mouse plasma samples (9 plasma extracts of non-transgenic and transgenic mice that had been fed different diets). Although the number of samples was limited, the current study led to some biologically relevant conclusions regarding brain cholesterol metabolism.

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“…Cholesterol oxidation products in circulating low density lipoproteins (LDL), collectively termed oxysterols, are considered to play a critical role in the initiation and development of a number of chronic diseases, including atherosclerosis, neurodegenerative pathologies, and diabetes [1]. High levels of oxysterols (20 to 30 µM) have long been known to occur in hyper-cholesterolemic subjects [2,3,4,5], and increased concentrations in plasma and cerebrospinal fluid are correlated to enhanced risk of cardiovascular and Alzheimer's diseases, respectively [6,7,8,9].…”

Section: Introductionmentioning

confidence: 99%

Oxysterol Mixture in Hypercholesterolemia-Relevant Proportion Causes Oxidative Stress-Dependent Eryptosis

Tesoriere

Attanzio

Allegra

et al. 2014

Cell Physiol Biochem

108

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Background/Aims: Oxysterol activity on the erythrocyte (RBC) programmed cell death (eryptosis) had not been studied yet. Effects of an oxysterol mixture in hyper-cholesterolemic-relevant proportion, and of individual compounds, were investigated on RBCs from healthy humans. Methods: Membrane phosphatidylserine (PS) externalization, calcium entry, ROS production, amino-phospholipid translocase (APLT) activity were evaluated by cytofluorimetric assays, cell volume from forward scatter. Prostaglandin PGE2 was measured by ELISA; GSH-adducts and lipoperoxides by spectrophotometry. Involvement of protein kinase C and caspase was investigated by inhibitors staurosporin, calphostin C, and Z-DEVD-FMK, respectively. Results: Oxysterols caused PS externalization and cell shrinkage, associated with PGE2release, opening of PGE2-dependent calcium channels, ROS production, GSH depletion, membrane lipid oxidation. Addition of antioxidants prevented Ca²⁺ influx and eryptosis. Calcium removal prevented cell shrinkage, with small effect (-20%) on the PS exposure, whereas ROS generation was unaltered. Either in the presence or absence of calcium i) oxysterols inhibited APLT, ii) staurosporin, calphostin C, Z-DEVD-FMK blunted and iii) antioxidants fully prevented the oxysterol-induced PS externalization. Only 7-ketocholesterol and cholestan-3β,5α,6β-triol were individually active. Eryptosis was observed in RBCs isolated after ex vivo spiking of human whole blood with the oxysterol mixture. Conclusions: Oxysterols induce an oxidative stress-dependent eryptosis, involving calcium-independent mechanisms. Eryptotic activity of oxysterols may be relevant in vivo.

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Oxysterols in the pathogenesis of major chronic diseases

Cited by 255 publications

References 46 publications

Oxysterols are agonist ligands of RORγt and drive Th17 cell differentiation

Oxysterols are agonist ligands of RORγt and drive Th17 cell differentiation

Separation and Determination of Some of the Main Cholesterol-Related Compounds in Blood by Gas Chromatography-Mass Spectrometry (Selected Ion Monitoring Mode)

Oxysterol Mixture in Hypercholesterolemia-Relevant Proportion Causes Oxidative Stress-Dependent Eryptosis

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