Cholesterolomics: An update

Griffiths, William J.; Abdel-Khalik, Jonas; Yutuc, Eylan; Morgan, Alwena H.; Gilmore, Ian S.; Hearn, Tom; Wang, Yuqin

doi:10.1016/j.ab.2017.01.009

Cited by 42 publications

(20 citation statements)

References 80 publications

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“…Oxysterols can be found in several chemical forms and are enzymatically produced in the first steps of cholesterol (Chol) metabolism [6,7]. For example, Alzheimer's disease (AD) pathology is initiated (or accelerated) by a deregulation of the metabolism of Chol, sphingolipids, and fatty acids; in fact, hypercholesterolemia is an important risk factor for AD [8,9].…”

Section: Introductionmentioning

confidence: 99%

Separation and Determination of Some of the Main Cholesterol-Related Compounds in Blood by Gas Chromatography-Mass Spectrometry (Selected Ion Monitoring Mode)

et al. 2018

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Oxysterols are metabolites produced in the first step of cholesterol metabolism, which is related to neurodegenerative disorder. They can be detected by testing blood, plasma, serum, or cerebrospinal fluid. In this study, some cholesterol precursors and oxysterols were determined by gas chromatography coupled to mass spectrometry. The selected cholesterol-related compounds were desmosterol, lathosterol, lanosterol, 7α-hydroxycholesterol, 7β-hydroxycholesterol, 24(S)-hydroxycholesterol, 25-hydroxycholesterol, 7-ketocholesterol, and 27-hydroxycholesterol. A powerful method was developed and validated considering various analytical parameters, such as linearity index, detection and quantification limits, selectivity and matrix effect, precision (repeatability), and trueness (recovery factor) for each cholesterol-related compound. 7α-hydroxycholesterol, 7β-hydroxycholesterol, and desmosterol exhibited the lowest detection and quantification limits, with 0.01 and 0.03 µg/mL, respectively, in the three cases. 7-ketocholesterol and lathosterol showed matrix effect percentages between 95.5% and 104.8%, respectively (demonstrating a negligible matrix effect), and very satisfactory repeatability values (i.e., overall performance of the method). Next, the method was applied to the analysis of a very interesting selection of mouse plasma samples (9 plasma extracts of non-transgenic and transgenic mice that had been fed different diets). Although the number of samples was limited, the current study led to some biologically relevant conclusions regarding brain cholesterol metabolism.

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Section: Introductionmentioning

confidence: 99%

Separation and Determination of Some of the Main Cholesterol-Related Compounds in Blood by Gas Chromatography-Mass Spectrometry (Selected Ion Monitoring Mode)

et al. 2018

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“…We identified SREBF2, PPARA, RXRG and other transcription factors, some of which have been studied and implicated in Alzheimer's disease. SREBF2 expression enhances cholesterol levels 41 and presumably oxysterol and cholestenoic acid levels which are ligands of LXR 42 . LXRs and the genes regulated by LXRs such as ABCA1, ABCG1 and APOE, modulate intracellular cholesterol content and cholesterol efflux and have been associated with AD pathogenesis 43 .…”

Section: Transcriptional Regulation Of Bile Acid and Cholesterol Genesmentioning

confidence: 99%

Identifying differences in bile acid pathways for cholesterol clearance in Alzheimer’s disease using metabolic networks of human brain regions

Baloni

Funk

Yan

et al. 2019

Preprint

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Alzheimer's disease (AD) is the leading cause of dementia, with metabolic dysfunction seen years before the emergence of clinical symptoms. Increasing evidence suggests a role for primary and secondary bile acids, the end-product of cholesterol metabolism, influencing pathophysiology in AD. In this study, we analyzed transcriptomes from 2114 post-mortem brain samples from three independent cohorts and identified that the genes involved in alternative bile acid synthesis pathway was expressed in brain compared to the classical pathway. These results were supported by targeted metabolomic analysis of primary and secondary bile acids measured from post-mortem brain samples of 111 individuals. We reconstructed brain region-specific metabolic networks using data from three independent cohorts to assess the role of bile acid metabolism in AD pathophysiology. Our metabolic network analysis suggested that taurine transport, bile acid synthesis and cholesterol metabolism differed in AD and cognitively normal individuals. Using the brain transcriptional regulatory network, we identified putative transcription factors regulating these metabolic genes and influencing altered metabolism in AD. Intriguingly, we find bile acids from the brain metabolomics whose synthesis cannot be explained by enzymes we find in the brain, suggesting they may originate from an external source such as the gut microbiome. These findings motivate further research into bile acid metabolism and transport in AD to elucidate their possible connection to cognitive decline.

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“…Cholesterol is present at the site of mitochondrial ROS production and susceptible to auto-oxidation into oxysterols. Heightened oxysterol levels are being used as biomarkers for neurodegenerative diseases and lysosomal storage disorder progression (Griffiths et al, 2017;Testa et al, 2016). Cholesterol can be enzymatically broken down into 24hydroxycholesterol (24-OHC) and 27-hydroxycholesterol or auto-oxidized by ROS to products like 7-KC, 4α-hydroxycholesterol (4α-OHC), 4β-hydroxycholesterol (4β-OHC), Table also shows the chemical structures of the TSPO ligands along with their pharmacological effects and clinical or preclinical use.…”

Section: Oxysterols -Schrodinger's Cat Of Mitochondrial Cholesterolmentioning

confidence: 99%

Exploring mitochondrial cholesterol signalling for therapeutic intervention in neurological conditions

Desai

Campanella

2019

British J Pharmacology

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The pharmacological targeting of cholesterol levels continues to generate interest due to the undoubted success of therapeutic agents, such as statins, in extending life expectancy by modifying the prognosis of diseases associated with the impairment of lipid metabolism. Advances in our understanding of mitochondrial dysfunction in chronic age‐related diseases of the brain have disclosed an emerging role for mitochondrial cholesterol in their pathophysiology, thus delineating an opportunity to provide mechanistic insights and explore strategies of intervention. This review draws attention to novel signalling mechanisms in conditions linked with impaired metabolism associated with impaired handling of cholesterol and its oxidized forms (oxysterols) by mitochondria. By emphasizing the role of mitochondrial cholesterol in neurological diseases, we here call for novel approaches and new means of assessment. Linked Articles This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc

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Cholesterolomics: An update

Cited by 42 publications

References 80 publications

Separation and Determination of Some of the Main Cholesterol-Related Compounds in Blood by Gas Chromatography-Mass Spectrometry (Selected Ion Monitoring Mode)

Separation and Determination of Some of the Main Cholesterol-Related Compounds in Blood by Gas Chromatography-Mass Spectrometry (Selected Ion Monitoring Mode)

Identifying differences in bile acid pathways for cholesterol clearance in Alzheimer’s disease using metabolic networks of human brain regions

Exploring mitochondrial cholesterol signalling for therapeutic intervention in neurological conditions

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