The Oxysterol Synthesising Enzyme CH25H Contributes to the Development of Intestinal Fibrosis

Raselli, Tina; Wyss, Adrian; Alvarado, Milliette; Weder, Bruce; Mamie, Céline; Spalinger, Marianne R.; Haaften, Wouter T. van; Dijkstra, Gerard; Sailer, Andreas W.; Silva, Pedro Henrique Imenez; Wagner, Carsten A.; Toševski, Vinko; Leibl, Sebastian; Scharl, Michael; Rogler, Gerhard; Hausmann, Martin; Misselwitz, Benjamin

doi:10.1093/ecco-jcc/jjz039

Cited by 27 publications

(22 citation statements)

References 81 publications

(108 reference statements)

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“…Literature data suggest that oxysterols are associated with various cardiovascular, metabolic, neurodegenerative and cancerous pathologies. A strong correlation has been observed between cholesterol 25-hydroxylase, i.e., CH25H, mRNA expression and that of fibrosis markers in human intestinal samples from Crohn's disease patients [24]. In addition, the oxysterols 25-hydroxycholesterol and 7-ketocholesterol induce damage to the barrier tissues such as the vascular endothelium and intestinal epithelium, which may lead to disturbances of local immune homeostasis [21].…”

Section: Discussionmentioning

confidence: 99%

The Protective Effect of Dabigatran and Rivaroxaban on DNA Oxidative Changes in a Model of Vascular Endothelial Damage with Oxidized Cholesterol

Woźniak

Broncel

Bukowska

et al. 2020

IJMS

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Background: Atherosclerotic plaques are unstable, and their release may result in thrombosis; therefore, currently, antiplatelet therapy with anticoagulants is recommended for the treatment of acute coronary syndrome. The aim of this study was to assess the effect of oxidized cholesterol on human umbilical vascular endothelial cells (HUVECs). The study also examines the protective and repairing effect of dabigatran and rivaroxaban in a model of vascular endothelial damage with 25-hydroxycholesterol (25-OHC). Methods: HUVECs were treated with compounds induce DNA single-strand breaks (SSBs) using the comet assay. Oxidative DNA damage was detected using endonuclease III (Nth) or human 8 oxoguanine DNA glycosylase (hOOG1). Reactive oxygen species (ROS) formation was determined using flow cytometry. Results: 25-hydroxycholesterol caused DNA SSBs, induced oxidative damage and increased ROS in the HUVECs; ROS level was lowered by dabigatran and rivaroxaban. Only dabigatran was able to completely repair the DNA SSBs induced by oxysterol. Dabigatran was able to reduce the level of oxidative damage of pyrimidines induced by oxysterol to the level of control cells. Conclusions: Observed changes strongly suggest that the tested anticoagulants induced indirect repair of DNA by inhibiting ROS production. Furthermore, dabigatran appears to have a higher antioxidant activity than rivaroxaban.

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Section: Discussionmentioning

confidence: 99%

The Protective Effect of Dabigatran and Rivaroxaban on DNA Oxidative Changes in a Model of Vascular Endothelial Damage with Oxidized Cholesterol

Woźniak

Broncel

Bukowska

et al. 2020

IJMS

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“…[63] The expression of Ch25h was recently shown to be induced in primary lung fibroblasts by the activated eosinophils and was suggested to contribute to the development of IPF. [64] Thus, the panel of 17 genes included in PFS17 reflect the complex biology perturbed during the process of lung fibrosis and reflect the involvement of multiple cell types and as a result, can be effective for screening pro-fibrotic stressors in ex vivo lung organ surrogate systems.…”

Section: Discussionmentioning

confidence: 99%

21st Century Tools for Nanotoxicology: Transcriptomic Biomarker Panel and Precision‐Cut Lung Slice Organ Mimic System for the Assessment of Nanomaterial‐Induced Lung Fibrosis

Rahman

Williams

Gelda

et al. 2020

Small

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There is an urgent need for reliable toxicity assays to support the human health risk assessment of an ever increasing number of engineered nanomaterials (ENMs). Animal testing is not a suitable option for ENMs. Sensitive in vitro models and mechanism‐based targeted in vitro assays that enable accurate prediction of in vivo responses are not yet available. In this proof‐of‐principle study, publicly available mouse lung transcriptomics data from studies investigating xenobiotic‐induced lung diseases are used and a 17‐gene biomarker panel (PFS17) applicable to the assessment of lung fibrosis is developed. The PFS17 is validated using a limited number of in vivo mouse lung transcriptomics datasets from studies investigating ENM‐induced responses. In addition, an ex vivo precision‐cut lung slice (PCLS) model is optimized for screening of potentially inflammogenic and pro‐fibrotic ENMs. Using bleomycin and a multiwalled carbon nanotube, the practical application of the PCLS method as a sensitive alternative to whole animal tests to screen ENMs that may potentially induce inhalation toxicity is shown. Conditional to further optimization and validation, it is established that a combination of PFS17 and the ex vivo PCLS method will serve as a robust and sensitive approach to assess lung inflammation and fibrosis induced by ENMs.

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“…The other explanation is that the different microbiota conditions in the animal facilities account for this discrepancy. Another study demonstrated reduced intestinal fibrosis in Ch25h −/− mice using the DSS-induced chronic colitis model 25 , however, a role for CH25H in IBD has not yet been investigated.…”

Section: Discussionmentioning

confidence: 99%

“…A recent clinical study showed elevated CH25H expression in IBD patients 24 ; CH25H was involved in intestinal fibrosis 25 ; however, the role of CH25H in IBD has not yet been investigated. To our knowledge, this is the first study showing the ability of 25-HC to alleviate intestinal inflammation in colitic mice.…”

Section: Introductionmentioning

confidence: 99%

Cholesterol 25-hydroxylase protects against experimental colitis in mice by modulating epithelial gut barrier function

Sheng

Zhou

et al. 2020

Sci Rep

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Cholesterol 25-hydroxylase (CH25H) encodes the enzyme that converts cholesterol to 25-hydroxycholesterol (25-HC). 25-HC has been demonstrated to be involved in the pathogenesis of inflammatory bowel disease. However, the role of CH25H in experimental colitis remains unknown. Dextran sulfate sodium (DSS)-induced colitis was monitored in wild type and Ch25h −/− mice in 8-weekold male for 7 days by assessment of body weight, histology, inflammatory cellular infiltration, and colon length. The function of CH25H was investigated using loss-of-function and gain-of-function such as Ch25h-deficient mice, supplementation with exogenous 25-HC and treatment of 25-HC into Caco2 and HCT116 colonic epithelial cells. Ch25h −/− mice with DSS-induced colitis exhibited aggravated injury, including higher clinical colitis scores, severe injury of the epithelial barrier, lower tight junction protein levels and higher levels of IL-6. Supplementation with exogenous 25-HC ameliorated disease symptoms and reduced the extent of damage in DSS-induced colitis, which was characterized by lower colon damage, higher tight junction protein expression, significantly decreased local and systemic production of pro-inflammatory cytokines IL-6. In Caco2 and HCT116 cells, 25-HC induced tight junction genes expression in colon cancer epithelial cells. These effects of CH25H were obtained by promoting ATF3 expression. Taken together, our findings reveal a protective role for 25-HC in DSS-induced colitis and the ability of CH25H to maintain epithelial gut barrier function through ATF3 expression. Supplementation with exogenous 25-HC ameliorates disease symptoms, which provides a new therapeutic strategy for ulcerative colitis. Abbreviations 25-HC 25-Hydroxycholesterol IBD Inflammatory bowel disease DSS Dextran sulfate sodium CD Corhn's disease UC Ulcerative colitis WT Wild type CH25H Cholesterol 25-hydroxylase EAE Experimental autoimmune encephalomyelitis HβCD 2-Hydroxypropyl-β-cyclodextrin BMDMs Bone marrow-derived macrophages Inflammatory bowel disease (IBD), which encompasses Corhn's disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disorder with increasing incidence and prevalence in many countries 1. Many genetic and

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The Oxysterol Synthesising Enzyme CH25H Contributes to the Development of Intestinal Fibrosis

Cited by 27 publications

References 81 publications

The Protective Effect of Dabigatran and Rivaroxaban on DNA Oxidative Changes in a Model of Vascular Endothelial Damage with Oxidized Cholesterol

The Protective Effect of Dabigatran and Rivaroxaban on DNA Oxidative Changes in a Model of Vascular Endothelial Damage with Oxidized Cholesterol

21st Century Tools for Nanotoxicology: Transcriptomic Biomarker Panel and Precision‐Cut Lung Slice Organ Mimic System for the Assessment of Nanomaterial‐Induced Lung Fibrosis

Cholesterol 25-hydroxylase protects against experimental colitis in mice by modulating epithelial gut barrier function

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