7-Keto-cholesterol and 25-hydroxy-1 cholesterol rapidly enhance ROS production in human neutrophils

Álba, Gonzalo; Reyes-Quiróz, María Edith; Sáenz, Javier; Geniz, Isabel; Jiménez, Juan; Martı́n-Nieto, José; Pintado, Elizabeth; Sobrino, Francisco; Santa-María, Consuelo

doi:10.1007/s00394-015-1142-4

Cited by 17 publications

(8 citation statements)

References 40 publications

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“…However, excessive ROS accumulation can damage cellular proteins, lipids and DNA, leading to cell dysfunction, senescence and even cell death 49–51 . Gonzalo Alba et al reported that excessive cholesterol enhanced ROS production in human neutrophils 52 . In the hyperlipidemia/hyperlipedimia mice/rats models, it was found that long-term high-fat diets led to the activation/elevation of NADPH Oxidase Catalytic Subunit-Like 3 (NOX3), uncoupling protein 2 (UCP2) and uncoupling protein 3 (UCP3), causing mitochondrial damage and apoptosis in inner ear 53,54 .…”

Section: Discussionmentioning

confidence: 99%

Deletion of OSBPL2 in auditory cells increases cholesterol biosynthesis and drives reactive oxygen species production by inhibiting AMPK activity

et al. 2019

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Oxysterol-binding protein like 2 ( OSBPL2 ) was identified as a novel causal gene for autosomal dominant nonsyndromic hearing loss. However, the pathogenesis of OSBPL2 deficits in ADNSHL was still unclear. The function of OSBPL2 as a lipid-sensing regulator in multiple cellular processes suggested that OSBPL2 might play an important role in the regulation of cholesterol-homeostasis, which was essential for inner ear. In this study the potential roles of OSBPL2 in cholesterol biosynthesis and ROS production were investigated in Osbpl2 -KO OC1 cells and osbpl2b -KO zebrafish. RNA-seq-based analysis suggested that OSBPL2 was implicated in cholesterol biosynthesis and AMPK signaling pathway. Furthermore, Osbpl2/osbpl2b -KO resulted in a reduction of AMPK activity and up-regulation of Srebp2/srebp2, Hmgcr/hmgcr and Hmgcs1/hmgcs1 , key genes in the sterol biosynthetic pathway and associated with AMPK signaling. In addition, OSBPL2 was also found to interact with ATIC, key activator of AMPK. The levels of total cholesterol and ROS in OC1 cells or zebrafish inner ear were both increased in Osbpl2/osbpl2b -KO mutants and the mitochondrial damage was detected in Osbpl2 -KO OC1 cells. This study uncovered the regulatory roles of OSBPL2 in cellular cholesterol biosynthesis and ROS production. These founds might contribute to the deep understanding of the pathogenesis of OSBPL2 mutation in ADNSHL.

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Section: Discussionmentioning

confidence: 99%

Deletion of OSBPL2 in auditory cells increases cholesterol biosynthesis and drives reactive oxygen species production by inhibiting AMPK activity

et al. 2019

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“…Autoxidised cholesterols, including 7-KC and 7β-OHC have been shown to affect the bioavailability of other reactive oxygen and nitrogen species, by chemical interaction with nitric oxide. In addition, oxysterols easily diffuse into membranes where they affect receptor and enzyme function [34] ; furthermore, 7-KC promotes translocation of cytosolic NADPH oxidase components to the membrane in neutrophils and enhances rapid reactive oxygen species production [35] are well-known activators of NADPH oxidase.…”

Section: Discussionmentioning

confidence: 99%

Simvastatin reduces circulating oxysterol levels in men with hypercholesterolaemia

et al. 2018

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Oxysterols (OHC) are biologically active cholesterol metabolites circulating in plasma that may be formed enzymatically (e.g. 24S-OHC, 25-OHC and 27-OHC) or by autoxidative mechanisms (e.g. 7-ketocholesterol, 7β-OHC and 25-OHC). Oxysterols are more soluble than cholesterol and are reported to exert inflammatory, cytoprotective and apoptotic effects according to concentration and species. Esterified oxysterols have been analysed in people with dementia and cardiovascular diseases although there is no consistent relationship between oxysterol esters and disease. However, oxysterol esters are held in lipoprotein core and may not relate to the concentration and activity of plasma free oxysterols. Methodological limitations have challenged the analysis of free oxysterols to date.We have developed a fast, sensitive and specific quantitative LC-MS/MS, multiple reaction monitoring (MRM) method to target five oxysterols in human plasma with analyte recoveries between 72% and 82% and sensitivities between 5 and 135 pg/ml. A novel method was used to investigate the hypothesis that simvastatin may reduce the concentrations of specific plasma free oxysterols in hypercholesterolaemia.Twenty healthy male volunteers were recruited (aged 41–63 years); ten were asymptomatic with high plasma cholesterol > 6.5 mM and ten were healthy with normal plasma cholesterol (< 6.5 mM). Simvastatin (40 mg/day) was prescribed to those with hypercholesterolaemia. Plasma samples were taken from both groups at baseline and after three months. Simvastatin reduced plasma cholesterol by ~35% (p < 0.05) at the end of three months.Oxysterols generated by autoxidation (but not enzymatically) were elevated up to 45 fold in hypercholesterolaemic midlife men. Plasma oxysterols were restored to those of healthy controls after simvastatin intervention suggesting that autoxidation is either prevented by simvastatin directly or that autoxidation is less prevalent when plasma cholesterol concentrations are within the normal range.

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“…7-oxysterols induce the induction and nuclear translocation of p53 in M1-t-p53 cells, enhancing LMP, mitochondrial translocation of Bax, mitochondrial membrane permeabilization, and the cytosolic release of cytochrome c, and cell death [31]. 7KCh has been shown to increase ROS levels in human neurocytes [32] rapidly. In addition, miRNA-1 was found to regulate the LXRα-ROS-mitochondrial pathway to regulate cardiomyocyte apoptosis [33].…”

Section: Discussionmentioning

confidence: 99%

Activation of LXRs Reduces Oxysterol Lipotoxicity in RPE Cells by Promoting Mitochondrial Function

Xie

et al. 2022

Nutrients

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Effective treatments for age-related macular degeneration (AMD), the most prevalent neurodegenerative form of blindness in older adults, are lacking. Genome-wide association studies have identified lipid metabolism and inflammation as AMD-associated pathogenic changes. Liver X receptors (LXRs) play a critical role in intracellular homeostases, such as lipid metabolism, glucose homeostasis, inflammation, and mitochondrial function. However, its specific role in AMD and its underlying molecular mechanisms remain unknown. In this study, we investigated the effects of lipotoxicity in human retinal pigmental epithelial (ARPE-19) cells and evaluated how LXRs reduce 7-ketocholesterol (7KCh) lipotoxicity in RPE cells using models, both in vivo and in vitro. A decrease in oxidative lipid accumulation was observed in mouse retinas following the activation of the LXRs; this result was also confirmed in cell experiments. At the same time, LXRs activation reduced RPE cell apoptosis induced by oxysterols. We found that oxysterols decreased the mitochondrial membrane potential in ARPE-19 cells, while LXR agonists counteracted these effects. In cultured ARPE-19 cells, activating LXRs reduced p62, mTOR, and LC3I/II levels, and the knockdown of LXRs elevated the expression of these proteins, indicating that activating LXRs could boost mitophagy. The findings of this study suggest LXR-active pharmaceuticals as a potential therapeutic target for dry AMD.

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7-Keto-cholesterol and 25-hydroxy-1 cholesterol rapidly enhance ROS production in human neutrophils

Cited by 17 publications

References 40 publications

Deletion of OSBPL2 in auditory cells increases cholesterol biosynthesis and drives reactive oxygen species production by inhibiting AMPK activity

Deletion of OSBPL2 in auditory cells increases cholesterol biosynthesis and drives reactive oxygen species production by inhibiting AMPK activity

Simvastatin reduces circulating oxysterol levels in men with hypercholesterolaemia

Activation of LXRs Reduces Oxysterol Lipotoxicity in RPE Cells by Promoting Mitochondrial Function

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