Ozone-derived Oxysterols Affect Liver X Receptor (LXR) Signaling

Speen, Adam M.; Kim, Hye-Young H.; Bauer, Rebecca N.; Meyer, Mark J.; Gowdy, Kymberly M.; Fessler, Michael B.; Duncan, Kelly; Liu, Wei; Porter, Ned A.; Jaspers, Ilona

doi:10.1074/jbc.m116.732362

Cited by 25 publications

(31 citation statements)

References 78 publications

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“…Foamy alveolar macrophages accumulate in the lungs of smokers [44,45]. Interestingly, it was reported that ozone exposure decreases the expression of ABCA1 in human bronchial epithelial cells [46].And this is closely correlated to lipid reverse transport. The model of lung in ammation results from ozone exposure bears many similarities to the cigarette smoke exposure model [17].…”

Section: Discussionmentioning

confidence: 97%

liver X receptors inhibit pulmonary inflammation and airway remodeling induced by ozone exposure in mice

Yu¹,

Zheng²,

Wang³

et al. 2020

Preprint

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Ozone (O3) exposure can lead to airway inflammation, hyperreactivity and airway remodeling. Liver X receptors (LXRs) play an important role in attenuating inflammation. The therapeutic effects of LXRs on ozone-induced pulmonary inflammation and airway remodeling were examined. C57/BL6 mice were exposed to ozone for 1 or 6 weeks. LXR agonist T0901317 was administered to mice at one hour before ozone exposure. As expected, ozone-exposed mice developed lung inflammation with augmented neutrophil, macrophage, TNF-α, IL-6, IL-8 and G-CSF in the bronchoalveolar lavage fluid and serum. The increase in MMP-9 and α-SMA expression, and collagen deposition around airway reflected the airway remodeling in ozone-exposed mice. Compared with ozone-exposed mice, LXR agonist T0901317 inhibited the ozone-induced inflammation after 1 and 6 weeks in the ozone exposure model. In addition, the treatment with the LXR agonist prevented alveolar enlargement and reduced airway remodeling in 6-week ozone-induced mice. Therefore, LXRs may repress pulmonary inflammation and attenuate the progression of airway remodeling.

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Section: Discussionmentioning

confidence: 97%

liver X receptors inhibit pulmonary inflammation and airway remodeling induced by ozone exposure in mice

Yu¹,

Zheng²,

Wang³

et al. 2020

Preprint

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“…6 ). The first one has been used as an efficient tool for detecting adducts of lipid-derived electrophiles, including secosterol aldehydes, in proteins in vitro and in complex samples [40] , [65] , [66] . This assay allowed us to detect secosterol aldehyde-modified SOD1 species directly in SDS-PAGE gels.…”

Section: Discussionmentioning

confidence: 99%

Cholesterol secosterol aldehyde adduction and aggregation of Cu,Zn-superoxide dismutase: Potential implications in ALS

et al. 2018

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by degeneration of upper and lower motor neurons. While the fundamental causes of the disease are still unclear, the accumulation of Cu,Zn-superoxide dismutase (SOD1) immunoreactive aggregates is associated with familial ALS cases. Cholesterol 5,6-secosterol aldehydes (Seco A and Seco B) are reported to contribute to neurodegenerative disease pathology by inducing protein modification and aggregation. Here we have investigated the presence of secosterol aldehydes in ALS SOD1-G93A rats and their capacity to induce SOD1 aggregation. Secosterol aldehydes were analyzed in blood plasma, spinal cord and motor cortex of ALS rats at the pre-symptomatic and symptomatic stages. Seco B was significantly increased in plasma of symptomatic ALS rats compared to pre-symptomatic animals, suggesting an association with disease progression. In vitro experiments showed that both Seco A and Seco B induce the formation of high molecular weight (HMW) SOD1 aggregates with amorphous morphology. SOD1 adduction to ω-alkynyl-secosterols analyzed by click assay showed that modified proteins are only detected in the HMW region, indicating that secosterol adduction generates species highly prone to aggregate. Of note, SOD1-secosterol adducts containing up to five secosterol molecules were confirmed by MALDI-TOF analysis. Interestingly, mass spectrometry sequencing of SOD1 aggregates revealed preferential secosterol adduction to Lys residues located at the electrostatic loop (Lys 122, 128 and 136) and nearby the dimer interface (Lys 3 and 9). Altogether, our results show that secosterol aldehydes are increased in plasma of symptomatic ALS rats and represent a class of aldehydes that can potentially modify SOD1 enhancing its propensity to aggregate.

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“…Speen and co-worker prepared alkynyl-tagged secosterols to discriminate secosterol-protein adduct by click chemistry and found that secosterol-A adducted to liver X receptor (LXR). ( 55 ) This adducts formation inactivates LXR activities, which could be associated with secosterol-induced proinflammatory activities.…”

Section: Chemical and Biological Propertiesmentioning

confidence: 99%

Biochemical properties of cholesterol aldehyde secosterol and its derivatives

Miyoshi

2018

J. Clin. Biochem. Nutr.

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Elevated levels of cholesterol aldehyde, 3β-hydroxy-5-oxo-5,6-secocholestan-6-al (secosterol-A, also called 5,6-secosterol), and its aldolization product (secosterol-B) have been detected in human atherosclerotic plaques and tissues samples of brains affected by neurodegeneration, such as Alzheimer’s disease and Lewy body dementia suggesting that increased formation of these compounds may be associated with inflammation-related diseases. Secosterol-A and secosterol-B, and also further oxidized products seco-A-COOH and seco-B-COOH induce several pro-inflammatory activities in vitro. Accumulating evidences demonstrate that the covalent bindings of these secosterols to target proteins seem to be critical to trigger their pro-inflammatory activities. One of the molecular mechanisms of protein adduct formations is that aldehydic function of secosterol-A and secosterol-B is reactive and form Schiff bases with ε- or N-terminal amino groups of proteins. In other cases, it is recently suggested that Michael acceptor moiety formed by the dehydration of not only secosterol-A and secosterol-B but also seco-A-COOH may react with nucleophilic site on target proteins. In this review, I summarize and provide an overview of formation mechanism of secosterols in in vitro and in vivo, patho- or physiological concentrations in biological and clinical samples, and molecular mechanisms of pro-inflammatory activities of secosterols.

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Ozone-derived Oxysterols Affect Liver X Receptor (LXR) Signaling

Abstract: Edited by Dennis Voelker

Cited by 25 publications

References 78 publications

liver X receptors inhibit pulmonary inflammation and airway remodeling induced by ozone exposure in mice

liver X receptors inhibit pulmonary inflammation and airway remodeling induced by ozone exposure in mice

Cholesterol secosterol aldehyde adduction and aggregation of Cu,Zn-superoxide dismutase: Potential implications in ALS

Biochemical properties of cholesterol aldehyde secosterol and its derivatives

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