Targeted Metabolomics Analysis on Obstructive Sleep Apnea Patients after Multilevel Sleep Surgery

Alterki, Abdulmohsen; Joseph, Shibu; Thanaraj, Thangavel Alphonse; Al-Khairi, Irina; Cherian, Preethi; Channanath, Arshad; Devarajan, Sriraman; Ebrahim, Mahmoud; Ibrahim, Alaaeldin; Tiss, Ali; Al-Mulla, Fahd; Rahman, Anas M. Abdel; Abubaker, Jehad; Abu‐Farha, Mohamed

doi:10.3390/metabo10090358

“…Patients with OSA usually have abnormal metabolism of glucose and lipids. Though obesity is one of the main risk factors of OSA, many investigations have shown that OSA can have an independent effect on dyslipidemia as well as obesity ( Karkinski et al, 2017 ; Silva et al, 2018 ; Alterki et al, 2020 ). In non-obese patients, OSA could aggravate abnormal lipid metabolism ( Karkinski et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

“…However, it has also been reported that after eliminating interference factors, only severe OSA had an independent association with dyslipidemia ( Martínez-Cerón et al, 2021 ). Treatment with OSA, either multilevel sleep surgery or continuous positive airway pressure (CPAP) therapy, has a positive impact on the metabolic status ( Alterki et al, 2020 ; Simon et al, 2020 ). So, the question is, which key factors through what signaling pathways contribute to abnormal lipid metabolism in patients with OSA.…”

Section: Introductionmentioning

confidence: 99%

Identification and Validation of Prognostic Factors of Lipid Metabolism in Obstructive Sleep Apnea

Lu

¹

,

Wang

²

,

Dai

³

2021

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Background: Obstructive sleep apnea (OSA) is considered to be an independent factor affecting lipid metabolism. This study explored the relationship between immune genes and lipid metabolism in OSA.Methods: Immune-related Differentially Expressed Genes (DEGs) were identified by analyzing microarray data sets from the Gene Expression Omnibus (GEO) database. Subsequently, we conducted protein-protein interaction (PPI) network analysis and calculated their Gene Ontology (GO) semantic similarity. The GO, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, Disease Ontology (DO), gene set enrichment analysis (GSEA), and gene set variation analysis (GSVA) were employed for functional enrichment analyses and to determine the most significant functional terms. Combined with the results of boruta and random forest, we selected predictors to build a prognostic model, along with seeking out the potential TFs and target drugs for the predictive genes.Results: Immune-related DEGs included 64 genes upregulated and 98 genes downregulated. The enrichment analysis might closely associate with cell adhesion and T cell-mediated immunity pathways and there were many DEGs involved in lipid and atherosclerosis signaling pathways. The highest-ranking hub gene in PPI network have been reported lowly expressed in OSA. In line with the enrichment analysis, DO analysis reveal that respiratory diseases may be associated with OSA besides immune system disorders. Consistent with the result of the KEGG pathway, the analysis of GSVA revealed that the pro-inflammation pathways are associated with OSA. Monocytes and CD8 T cells were the predominant immune cells in adipose tissue. We built a prognostic model with the top six genes, and the prognostic genes were involved in the polarization of macrophage and differentiation of T lymphocyte subsets. In vivo experimental verification revealed that EPGN, LGR5, NCK1 and VIP were significantly down-regulated while PGRMC2 was significantly up-regulated in mouse model of OSA.Conclusions: Our study demonstrated strong associations between immune genes and the development of dyslipidemia in OSA. This work promoted the molecular mechanisms and potential targets for the regulation of lipid metabolism in OSA.

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“…It can provide insight into the metabolic processes and pathogenesis of human diseases from a systematic perspective. A few studies used this approach to study the association between OSA and the change of metabolites (Ferrarini et al, 2013;Xu et al, 2016;Alterki et al, 2020;Humer et al, 2020;Reutrakul et al, 2021). Ferrarini et al (2013) collected plasma samples of 33 OSA patients and analyzed them with LC-QTOF-MS.…”

Section: Discussionmentioning

confidence: 99%

Untargeted Metabolomic Profiling of Liver in a Chronic Intermittent Hypoxia Mouse Model

Chen

¹

,

Huang

²

,

Huang

³

et al. 2021

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Obstructive sleep apnea (OSA) has been demonstrated to be associated with liver injury. Nevertheless, the mechanisms linking the two disorders remain largely unexplored to date. Based on UHPLC/Q-TOF MS platform, the present study aimed to study the hepatic metabolomic profiling in a chronic intermittent hypoxia (CIH) mouse model to identify altered metabolites and related metabolic pathways. C57BL/6 Mice (n = 12 each group) were exposed to intermittent hypoxia or control conditions (room air) for 12 weeks. At the end of the exposure, liver enzymes and histological changes were assessed. Untargeted metabolomics approach by UHPLC/Q-TOF MS and orthogonal partial least squares-discriminant analysis (OPLS-DA) were applied to screen altered metabolites in mice liver. Bioinformatics analyses were applied to identify the related metabolic pathways. CIH treatment caused a remarkable liver injury in mice. A total of 27 differential metabolites in negative ion mode and 44 in positive ion mode were identified between the two groups. These metabolites were correlated to multiple biological and metabolic processes, including various amino acid metabolism, membrane transport, lipid metabolism, carbohydrate metabolism, nucleotide metabolism, ferroptosis, etc. three differential metabolites including glutathione, glutathione disulfide, arachidonic acid (peroxide free) were identified in the ferroptosis pathway. CIH was associated with a significant metabolic profiling change in mice liver. The metabolites in amino acid metabolism, membrane transport, lipid metabolism, carbohydrate metabolism, nucleotide metabolism, and ferroptosis played an important role in CIH-induced liver injury. These findings contribute to a better understanding of the mechanisms linking OSA and liver injury and help identify potential therapeutic targets.

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“…The study population was diagnosed using Type I PSG test as detailed [ 29 ]. This test involves an overnight sleep in a sleep lab, during which biophysiological data was captured to formulate a comprehensive picture of participants' sleep architecture.…”

Section: Methodsmentioning

confidence: 99%

The Rise of IGFBP4 in People with Obstructive Sleep Apnea and Multilevel Sleep Surgery Recovers Its Basal Levels

Alterki

¹

,

Alshawaf

²

,

Al-Khairi

³

et al. 2021

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IGFBP4 is the smallest member of the insulin-like growth factor binding protein family (IGFBP). It is a hepatic protein that plays a role in modulating the activity and bioavailability of IGF-I. The expression of IGFBP4 was found to increase under conditions of hypoxia. Obstructive sleep apnea (OSA) is a common disorder, characterized by cyclic episodes of intermittent hypoxia and fragmented sleep. Our aim was to quantify levels of circulating IGFBP1, IGFBP2, IGFBP3, IGFBP4, and IGFBP7 in fasting plasma samples of 69 Kuwaiti participants and explore its correlation with indices of OSA. The quantification was performed using multiplexing assay. The study involved 28 controls and 41 patients with OSA. Levels of circulating IGFBP4 were significantly higher in people with OSA ( 289.74 ± 23.30 ng/ml) compared to the control group ( 217.60 ± 21.74 ng/ml, p = 0.028 ). The increase in IGFBP4 correlated significantly and positively with AHI ( r = .574 , p = .01 ) and AI ( r = .794 , p = .001 ) in people with moderate and severe OSA. There was a significant decline in circulating IGFBP4 after 3 months of surgery ( 225.89 ± 18.16 ng/ml, p = 0.012 ). This was accompanied by a prominent improvement in OSA (AHI 8.97 ± 2.37 events/h, p = 0.001 ). In this study, our data showed a significant increase in circulating IGFBP4 in people with OSA. We also report a significant positive correlation between IGFBP4 and indices of OSA at baseline, which suggests IGFBP4 as a potential diagnostic biomarker for OSA. There was a significant improvement in OSA after 3 months of surgical intervention, which concurred with a significant decline in IGFBP4 levels. Altogether, the detected change suggests a potential link between IGFBP4 and OSA or an OSA-related factor, whereby OSA might play a role in triggering the induction of IGFBP4 expression.

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Targeted Metabolomics Analysis on Obstructive Sleep Apnea Patients after Multilevel Sleep Surgery

Cited by 13 publications

References 63 publications

Identification and Validation of Prognostic Factors of Lipid Metabolism in Obstructive Sleep Apnea

Identification and Validation of Prognostic Factors of Lipid Metabolism in Obstructive Sleep Apnea

Untargeted Metabolomic Profiling of Liver in a Chronic Intermittent Hypoxia Mouse Model

The Rise of IGFBP4 in People with Obstructive Sleep Apnea and Multilevel Sleep Surgery Recovers Its Basal Levels

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