Lipidomic analysis of fibroblasts from Zellweger spectrum disorder patients identifies disease-specific phospholipid ratios

Herzog, Katharina; Pras‐Raves, Mia L.; Vervaart, Martin A. T.; Luyf, Angela C. M.; Kampen, Antoine H. C. van; Wanders, Ronald J. A.; Waterham, Hans R.; Vaz, Frédéric M.

doi:10.1194/jlr.m067470

Cited by 69 publications

(91 citation statements)

References 31 publications

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“…The analysis of cholesterol and cholesterol esters was performed using an HPLC‐MS system consisting of an Ultimate 3000 binary HPLC pump, a vacuum degasser, a column temperature controller, an auto sampler and a Q‐exactive plus mass spectrometer (Thermo Scientific, Waltham, MA, USA). For the cholesterol esters, 5 µL of the lipid extract was injected onto a “normal phase column” LiChrospher 2 × 250‐mm silica‐60 column, 5 µm particle diameter (Merck, Darmstadt, Germany) as previously described . For the quantification of cholesterol, 5 µL of the same lipid extracted was injected onto a “reverse phase column” Acquity UPLC HSS T3, 1.8 µm particle diameter (Waters, Milford Massachusetts, USA) and measured as previously described (https://doi.org/10.1016/j.chroma.2014.08.088).…”

Section: Methodsmentioning

confidence: 99%

Industrial Trans Fatty Acids Stimulate SREBP2‐Mediated Cholesterogenesis and Promote Non‐Alcoholic Fatty Liver Disease

Oteng

Loregger

Weeghel

et al. 2019

Molecular Nutrition Food Res

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Scope The mechanisms underlying the deleterious effects of trans fatty acids on plasma cholesterol and non‐alcoholic fatty liver disease (NAFLD) are unclear. Here, the aim is to investigate the molecular mechanisms of action of industrial trans fatty acids. Methods and results Hepa1‐6 hepatoma cells were incubated with elaidate, oleate, or palmitate. C57Bl/6 mice were fed diets rich in trans‐unsaturated, cis‐unsaturated, or saturated fatty acids. Transcriptomics analysis of Hepa1‐6 cells shows that elaidate but not oleate or palmitate induces expression of genes involved in cholesterol biosynthesis. Induction of cholesterogenesis by elaidate is mediated by increased sterol regulatory element‐binding protein 2 (SREBP2) activity and is dependent on SREBP cleavage–activating protein (SCAP), yet independent of liver‐X receptor and ubiquitin regulatory X domain‐containing protein 8. Elaidate decreases intracellular free cholesterol levels and represses the anticholesterogenic effect of exogenous cholesterol. In mice, the trans‐unsaturated diet increases the ratio of liver to gonadal fat mass, steatosis, hepatic cholesterol levels, alanine aminotransferase activity, and fibrosis markers, suggesting enhanced NAFLD, compared to the cis‐unsaturated and saturated diets. Conclusion Elaidate induces cholesterogenesis in vitro by activating the SCAP–SREBP2 axis, likely by lowering intracellular free cholesterol and attenuating cholesterol‐dependent repression of SCAP. This pathway potentially underlies the increase in liver cholesterol and NAFLD by industrial trans fatty acids.

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Section: Methodsmentioning

confidence: 99%

Industrial Trans Fatty Acids Stimulate SREBP2‐Mediated Cholesterogenesis and Promote Non‐Alcoholic Fatty Liver Disease

Oteng

Loregger

Weeghel

et al. 2019

Molecular Nutrition Food Res

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“…Our data suggests that these diseases might have multiple identifiable biomarkers. Using a multimarker approach or specific biomarkers ratios, which is common in cardiovascular risk assessment [46], instead of only single compounds, we could better differentiate between different diseases and potentially also between patients with different severity of the defects which has been proven recently for Zellweger syndrome patients differentiation [19]. The latter was not pursued here, since we only studied complete enzyme deficiencies.…”

Section: Discussionmentioning

confidence: 99%

“…Several inborn errors of metabolism (IEM) have their metabolic phenotypes characterized [17]. However, for many diseases no known biomarker profile exists [18] or their sensitivity is low causing some patients to be wrongly diagnosed in the screening process [19]. Additionally, clinical presentations of IEM are often non-specific and are described as a spectrum rather than a clear one gene -one phenotype -one disease relation.…”

Section: Introductionmentioning

confidence: 99%

Cofactors revisited – predicting the impact of flavoprotein-related diseases on a genome scale

Wegrzyn

Stolle

Rienksma

et al. 2018

Preprint

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Flavin adenine dinucleotide (FAD) and its precursor flavin mononucleotide (FMN) are redox cofactors that are required for the activity of more than hundred human enzymes. Mutations in the genes encoding these proteins cause severe phenotypes, including a lack of energy supply and accumulation of toxic intermediates. Ideally, patients should be diagnosed before they show symptoms so that treatment and/or preventive care can start immediately. This can be achieved by standardized newborn screening tests. However, many of the flavin-related diseases lack appropriate biomarker profiles. Genome-scale metabolic models can aid in biomarker research by predicting altered profiles of potential biomarkers. Unfortunately, current models, including the most recent human metabolic reconstructions Recon and HMR, typically treat enzyme-bound flavins incorrectly as free metabolites. This in turn leads to artificial degrees of freedom in pathways that are strictly coupled. Here, we present a reconstruction of human metabolism with a curated and extended flavoproteome. To illustrate the functional consequences, we show that simulations with the curated model -unlike simulations with earlier Recon versions -correctly predict the metabolic impact of multiple-acyl-CoA-dehydrogenase deficiency as well as of systemic flavin-depletion. Moreover, simulations with the new model allowed us to identify a larger number of biomarkers in flavoproteome-related diseases, without loss of accuracy. We conclude that adequate inclusion of cofactors in constraintbased modelling contributes to higher precision in computational predictions.

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“…In our own laboratory we developed a lipidomics platform that is able to detect a large variety of different lipids including phospholipids, neutral lipids, ceramides, sphingolipids, gangliosides, and sulfatides of which more than 1200 have been identified and thousands of others remain to be identified . This lipidomic platform has been used successfully for the discovery of new defects including SERAC1 deficiency but also for the identification of new and improved biomarkers . Similarly, Lefeber and coworker have set up a glycomics platform which has already demonstrated its great power in the identification of new IEMs .…”

Section: Multi‐omics and Inborn Errors Of Metabolismmentioning

confidence: 99%

“…23 This lipidomic platform has been used successfully for the discovery of new defects including SERAC1 deficiency 24 but also for the identification of new and improved biomarkers. [25][26][27] Similarly, Lefeber and coworker 28 have set up a glycomics platform which has already demonstrated its great power in the identification of new IEMs. 29,30 Most of these methods use mass spectrometry as detection system but it should be mentioned that NMR has also been used successfully in the field of IEMS 31,32 (see Reference 33 for recent review).…”

Section: Multi-omics and Inborn Errors Of Metabolismmentioning

confidence: 99%

Translational Metabolism: A multidisciplinary approach towards precision diagnosis of inborn errors of metabolism in the omics era

Wanders

Vaz

Ferdinandusse

et al. 2019

J of Inher Metab Disea

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The laboratory diagnosis of inborn errors of metabolism has been revolutionized in recent years, thanks to the amazing developments in the field of DNA sequencing including whole exome and whole genome sequencing (WES and WGS). Interpretation of the results coming from WES and/or WGS analysis is definitely not trivial especially since the biological relevance of many of the variants identified by WES and/or WGS, have not been tested experimentally and prediction programs like POLYPHEN‐2 and SIFT are far from perfect. Correct interpretation of WES and/or WGS results can only be achieved by performing functional studies at multiple levels (different metabolomics platforms, enzymology, in vitro and in vivo flux analysis), often requires studies in model organisms like zebra fish, Caenorhabditis elegans, Saccharomyces cerevisiae, mutant mice and others, and also requires the input of many different disciplines to make this Translational Metabolism approach effective.

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Lipidomic analysis of fibroblasts from Zellweger spectrum disorder patients identifies disease-specific phospholipid ratios

Cited by 69 publications

References 31 publications

Industrial Trans Fatty Acids Stimulate SREBP2‐Mediated Cholesterogenesis and Promote Non‐Alcoholic Fatty Liver Disease

Industrial Trans Fatty Acids Stimulate SREBP2‐Mediated Cholesterogenesis and Promote Non‐Alcoholic Fatty Liver Disease

Cofactors revisited – predicting the impact of flavoprotein-related diseases on a genome scale

Translational Metabolism: A multidisciplinary approach towards precision diagnosis of inborn errors of metabolism in the omics era

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