The oxysterome and its receptors as pharmacological targets in inflammatory diseases

Guillemot-Legris, Owein; Muccioli, Giulio G.

doi:10.1111/bph.15479

Cited by 16 publications

(4 citation statements)

References 153 publications

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“…However, also oxysterols of enzymatic source could become noxious when present in excess, due to metabolic disorders or, more frequently, to chronic inflammatory processes. Indeed, disproportionate levels of 27OHC have been found associated with quite a number of human pathological conditions, almost always characterized by a chronic inflammatory status [ 1 , 16 ]. Notably, the key cells of chronic inflammation are the macrophages, that are rich in cholesterol 27-hydroxylase (CYP27A1), the enzyme generating 27OHC [ 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

Oxysterols: From redox bench to industry

et al. 2022

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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.

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Section: Introductionmentioning

confidence: 99%

Oxysterols: From redox bench to industry

et al. 2022

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“…LXRs are master regulators of lipid metabolism, cholesterol homeostasis, and inflammation [4,5], and as such, are involved in numerous physiological and pathological processes such as atherosclerosis, cancer, diabetes mellitus, and the loss of specific neurons in the substantia nigra, spinal cord, retina, and cochlea. LXRs are receptors with potent anti-inflammatory effects and have emerged as important targets for inflammatory diseases [6,7]. In addition to synthetic LXRs agonists, such as T0901317 and GW3965, sterol-based LXR agonists attenuate dextran sulfate colitis-induced weight loss with a reduced expression of inflammatory 2 of 12 markers in the large intestine of mice [8].…”

Section: Introductionmentioning

confidence: 99%

Loss of ERβ in Aging LXRαβ Knockout Mice Leads to Colitis

Song,

Wu,

Dai

et al. 2023

IJMS

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Liver X receptors (LXRα and LXRβ) are oxysterol-activated nuclear receptors that play key roles in cholesterol homeostasis, the central nervous system, and the immune system. We have previously reported that LXRαβ-deficient mice are more susceptible to dextran sodium sulfate (DSS)-induced colitis than their WT littermates, and that an LXR agonist protects against colitis in mice mainly via the regulation of the immune system in the gut. We now report that both LXRα and LXRβ are expressed in the colonic epithelium and that in aging LXRαβ−/− mice there is a reduction in the intensity of goblet cells, mucin (MUC2), TFF3, and estrogen receptor β (ERβ) levels. The cytoplasmic compartment of the surface epithelial cells was markedly reduced and there was a massive invasion of macrophages in the lamina propria. The expression and localization of β-catenin, α-catenin, and E-cadherin were not changed, but the shrinkage of the cytoplasm led to an appearance of an increase in staining. In the colonic epithelium there was a reduction in the expression of plectin, a hemidesmosome protein whose loss in mice leads to spontaneous colitis, ELOVL1, a fatty acid elongase protein coding gene whose overexpression is found in colorectal cancer, and non-neuronal choline acetyltransferase (ChAT) involved in the regulation of epithelial cell adhesion. We conclude that in aging LXRαβ−/− mice, the phenotype in the colon is due to loss of ERβ expression.

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“…Oxysterols constitute a growing family of oxygenated cholesterol metabolites that impact on a plethora of fatal diseases including atherosclerosis, cancer, neurodegenerative diseases and aging (1)(2)(3)(4). Depending on their chemical structures, these metabolites exert distinct biological properties through various molecular mechanisms that could involve either nuclear receptors (e.g., Liver-X-Receptor, LXR; retinoid-related orphan receptor, ROR; estrogen receptor alpha, ERα; glucocorticoid receptor alpha, GRα) (5)(6)(7)(8), G-protein coupled receptors (e.g., smoothened, SMO; CXC-motif-chemokine receptor 2, CXCR2; Epstein-Barr virus-induced gene 2, EBI2) (9)(10)(11)(12)(13), enzymes (e.g., sterol O-acyltransferase/Acyl-coA cholesterol acyltransferase, SOAT/ACAT; cholesterol-5,6-epoxide hydrolase, ChEH; and 3-hydroxy-3-methylglutaryl-coenzyme A reductase, HMG-CoAR; 11β-hydroxysteroid dehydrogenase type 2, (HSD2) (14)(15)(16) or transporters (e.g., ions transporters, insulin-induced gene, INSIG; sterol or oxysterol binding proteins (ORP) proteins; Nieman-Pick C1 and C1 like 1, (NPC1 and NPC1L1) (17,18).…”

Section: Introductionmentioning

confidence: 99%

27-hydroxylation of oncosterone by CYP27A1 switchs its activity from pro-tumor to anti-tumor

Ayadi,

Friedrichs,

Soulès

et al. 2023

Preprint

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Oncosterone (6-oxo-cholestane-3beta,5alpha-diol; OCDO) is an oncometabolite and a tumor promoter on estrogen receptor alpha positive breast cancer (ER(+) BC) and triple negative breast cancers (TN BC). OCDO is an oxysterol formed in three steps from cholesterol: 1) oxygen addition at the double bond to give alpha- or beta- isomers of 5,6-epoxycholestanols (5,6-EC), 2) hydrolyses of the epoxide ring of 5,6-ECs to give cholestane-3beta, 5alpha, 6beta-triol (CT), and 3) oxidation of the C6 hydroxyl of CT to give OCDO. On the other hand, cholesterol can be hydroxylated by CYP27A1 at the ultimate methyl carbon of its side chain to give 27-hydroxycholesterol (27HC), which is a tumor promoter for ER(+) BC. It is currently unknown whether OCDO and its precursors can be hydroxylated at position C27 by CYP27A1, as is the impact of such modification on the proliferation of ER(+) and TN BC cells. We investigated, herein, whether 27-hydroxylated-5,6-ECs, -CT and -OCDO exist as metabolites and can be produced by cells expressing CYP27A1. We report, for the first time, that these compounds exist as metabolites in human. We give pharmacological and genetic evidences that CYP27A1 is responsible for their production. Importantly, we found that 27-hydroxy-OCDO (27H-OCDO) inhibits BC cells proliferation and blocks OCDO and 27-HC induced proliferation in BC cells, showing that this metabolic conversion commutes the proliferative properties of OCDO into antiproliferative ones. These data suggest an unprecedented role of CYP27A1 in the control of breast carcinogenesis by inhibiting the tumor promoter activities of oncosterone and 27-HC.

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The oxysterome and its receptors as pharmacological targets in inflammatory diseases

Cited by 16 publications

References 153 publications

Oxysterols: From redox bench to industry

Oxysterols: From redox bench to industry

Loss of ERβ in Aging LXRαβ Knockout Mice Leads to Colitis

27-hydroxylation of oncosterone by CYP27A1 switchs its activity from pro-tumor to anti-tumor

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