| 1. |
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| 2. |
- Gauthier, Marie-Soleil, et al.
(author)
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The Metabolically Healthy But Obese Phenotype Is Associated With Lower Plasma Levels of Persistent Organic Pollutants as Compared to the Metabolically Abnormal Obese Phenotype
- 2014
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In: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 99:6, s. E1061-E1066
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Journal article (peer-reviewed)abstract
- Context: Although obesity is strongly linked to insulin resistance and type 2 diabetes, a subset of obese individuals termed metabolically healthy but obese(MHO) appears relatively protected from the development of cardiometabolic complications. The origins of this metabolically healthy phenotype remain unclear. Recently, persistent organic pollutants (POPs) have emerged as potential endocrine disruptors.Objective: The aim of this study was to test the hypothesis that the MHO phenotype presents lower circulating levels of POPs as compared to the metabolically abnormal obese (MAO) phenotype.Design, Setting, and Patients: We conducted a cross-sectional study of 76 nondiabetic obese (body mass index >= 30 kg/m(2)) postmenopausal women.Main Outcome Measures: Plasma concentrations of 21 POPs as well as cardiometabolic risk factors were analyzed.Results: For similar age, body mass index, and fat mass index, MHO women (n = 40) showed higher insulin sensitivity levels and a more favorable cardiometabolic profile than MAO women (n = 36), as evidenced by a 2-fold increase in glucose disposal rates measured by the hyperinsulinemic-euglycemic clamp (P = .001). Among 18 detectable pollutants measured, MAO women had higher plasma concentrations of 12 POPs (fold increase, 1.4-2.9; P < .001-.036). Logistic regression analyses showed that the prevalence of the MAO phenotype was significantly associated with higher levels of total dioxin and non-dioxin-like polychlorinated biphenyls (odds ratio, 4.7; 95% confidence interval, 1.8-12.5; P = .002), as well as trans-nonachlor (odds ratio, 6.1; 95% CI, 2.2-16.4; P < .001).Conclusion: Our study demonstrates that the metabolically healthy and abnormal phenotypes have distinct plasma POP profiles.
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| 3. |
- Geng, Dawei, 1986-, et al.
(author)
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Analysis of brominated flame retardants and their derivatives by atmospheric pressure chemical ionization using gas chromatography coupled to tandem quadrupole mass spectrometry
- 2017
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In: Talanta. - Amsterdam, Netherlands : Elsevier. - 0039-9140 .- 1873-3573. ; 162, s. 618-624
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Journal article (peer-reviewed)abstract
- A validated method using an atmospheric pressure chemical ionization source for coupling gas chromatography (GC-APCI) to tandem quadrupole mass spectrometry (MS/MS) for the determination of brominated flame retardants (BFRs) is presented. Polybrominated diphenyl ethers (PBDEs), their methoxylated derivatives (MeO-PBDEs) and other emerging BFRs were included in this study. The method showed good linearity and repeatability. The relative standard deviation (RSD) of the relative response factors (RRFs) of all compounds was less than 16%. Repeatability for BFRs was tested on one or two concentration levels of calibration standardswith RSDs for RRFs below 16%. The lowest calibration standards (0.075 –0.1 pg/μL for emerging BFRs, BDE 209 and MeO-PBDEs mixtures, 0.625 –6.25 pg/μL for Br1-9 PBDEs mixtures) were used as instrument detection limits (IDL). The method was applied on biotic samples, including fish, osprey, and seal. In general, BDE209 and decabromodiphenyl ethane (DBDPE) were detected in 50% of the seal samples. A 100% detection rate was achieved for 6-MeO-BDE47 in all the samples (72 –580 pg/g ww in osprey samples, 24 000 –96 000 pg/g ww in seal samples and 78–99 pg/g ww in fish samples). AllBr3-6PBDEs (BDE28, 47, 99, 100, 153, 154) were detected in all the samples (ranging from 12 to 20 000 pg/g ww), while BDE183 was detected in 60% of the osprey eggs, 20% of the seal samples and below MDL in all fish samples. The results presented indicate the capability of the GC-APCI-MS/MS system for the detection and quantification of BFRs.
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| 4. |
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| 5. |
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| 6. |
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| 7. |
- Geng, Dawei, 1986-, et al.
(author)
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Effect of perfluorooctanesulfonic acid (PFOS) on the liver lipid metabolism of the developing chicken embryo
- 2019
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In: Ecotoxicology and Environmental Safety. - : Elsevier. - 0147-6513 .- 1090-2414. ; 170, s. 691-698
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Journal article (peer-reviewed)abstract
- Perfluorooctanesulfonate (PFOS) is a well-known contaminant in the environment and it has shown to disrupt multiple biological pathways, particularly those related with lipid metabolism. In this study, we have studied the impact of in ovo exposure to PFOS on lipid metabolism in livers in developing chicken embryos using lipidomics for detailed characterization of the liver lipidome. We used an avian model (Gallus gallus domesticus) for in ovo treatment at two levels of PFOS. The lipid profile of the liver of the embryo was investigated by ultra-high performance liquid chromatography combined with quadrupole-time-of-flight mass spectrometry and by gas chromatography mass spectrometry. Over 170 lipids were identified, covering phospholipids, ceramides, di- and triacylglycerols, cholesterol esters and fatty acid composition of the lipids. The PFOS exposure caused dose dependent changes in the lipid levels, which included upregulation of specific phospholipids associated with the phosphatidylethanolamine N-methyltransferase (PEMT) pathway, triacylglycerols with low carbon number and double bond count as well as of lipotoxic ceramides and diacylglycerols. Our data suggest that at lower levels of exposure, mitochondrial fatty acid β-oxidation is suppressed while the peroxisomal fatty acid β -oxidation is increased. At higher doses, however, both β -oxidation pathways are upregulated.
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| 8. |
- Geng, Dawei, 1986-, et al.
(author)
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Gas chromatography/atmospheric pressure chemical ionization/mass spectrometry for the analysis of organochlorine pesticides and polychlorinated biphenyls in human serum
- 2016
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In: Journal of Chromatography A. - Amsterdam, Netherlands : Elsevier. - 0021-9673 .- 1873-3778. ; 1453, s. 88-98
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Journal article (peer-reviewed)abstract
- A method using a novel atmospheric pressure chemical ionization source for coupling gas chromatography (GC/APCI) to triple quadrupole mass spectrometry (MS/MS) for the determination of organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) regulated by the Stockholm Convention is presented. One microliter injection of a six-point calibration curve of native PCBs and OCPs, ranging from 0.04 to 300 pg/μL, was performed. The relative standard deviation (RSD) of the relative response factors (RRFs) was less than 15% with a coefficient of determination (r2) >0.995. Meanwhile, two calibration solutions (CS), CS 2 (0.4 pg/μL) and CS 3 (4 pg/μL) were analyzed to study the repeatability calculated for both area and RRFs. The RSD for RRF ranged from 3.1 to 16% and 3.6 to 5.5% for CS 2 and CS 3, respectively. The limits of detection (LOD) determined by peak-to-peak signal-to-noise ratio (S/N) of 3 were compared between the GC/APCI/MS/MS and a GC coupled to high resolution mass spectrometry (GC/HRMS) system. GC/APCI/MS/MS resulted in lower LOD for most of the compounds, except for PCB#74, cis-chlordane and trans-chlordane. GC/APCI/MS/MS and GC/HRMS were also compared by performing analysis on 75 human serum samples together with eight QA/QC serum samples. The comparison between GC/APCI/MS/MS system and GC/HRMS system for 16 of the targeted compounds was carried out. No statistically significant difference was discovered. Due to increased sensitivity and user friendly operation under atmospheric pressure, GC/APCI/MS/MS is a powerful alternative technique that can easily meet the specification of GC/HRMS.
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| 9. |
- Geng, Dawei, 1986-
(author)
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Gas chromatography-atmospheric pressure chemical ionization-tandem mass spectrometry methods for the determination of environmental contaminants
- 2016
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Doctoral thesis (other academic/artistic)abstract
- The recent developments and improvements of instrumental methods for the analyses of the environmental contaminants, especially the persistent organic pollutants (POPs), have made it possible to detect and quantify these at very low concentrations in environmental and biotic matrices.The main objective of this thesis is to demonstrate the capability of the atmospheric pressure chemical ionization technique (APCI), using gas chromatography coupled to tandem mass spectrometry for the determination of a wide range of environmental contaminants, including the POPs regulated by Stockholm Convention, such as polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), but also the derivates of PBDEs and novel brominated flame retardants (NBFRs).The APCI was operated in charge transfer condition, preferably producing molecular ions. Multiple reaction monitoring (MRM) experiments were optimized by adjusting cone voltage, collision energy and dwell time. Optimization of source parameters, such as gas flows and temperatures was also performed. Low concentration standards were analyzed, achieving a visible chromatographic peak for 2 fg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) demonstrating the excellent sensitivity of the system. Adequate linearity and repeatability were observed for all the studied compounds. The performance of APCI methods was validated against the conventional methods using gas chromatography coupled to high resolution mass spectrometry for chlorinated compounds in a wide range of matrices including environmental, air, human and food matrices.The GC-APCI-MS/MS method was successfully applied to a set of 75 human serum samples to study the circulating levels of POPs in epidemiologic studies. Moreover the method was utilized to establish temporal trends of POPs in osprey eggs samples collected during the past five decades.
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| 10. |
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| 11. |
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| 12. |
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| 13. |
- Klionsky, Daniel J., et al.
(author)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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In: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Research review (peer-reviewed)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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| 14. |
- Li, Honghua, et al.
(author)
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Levels and distribution of hexabromocyclododecane (HBCD) in environmental samples near manufacturing facilities in Laizhou Bay area, East China
- 2012
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In: Journal of Environmental Monitoring. - : Royal Society of Chemistry (RSC). - 1464-0325 .- 1464-0333. ; 14:10, s. 2591-2597
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Journal article (peer-reviewed)abstract
- A total of 55 samples including soil, sediment, plants (cypress, reed and seepweed) and aquatic species were collected at locations around hexabromocyclododecane (HBCD) manufacturing facilities in Laizhou Bay area, East China. HBCD was determined at concentrations ranging between 0.88 and 6901 ng g(-1) dry weight (dw), 2.93-1029 ng g(-1) dw, 8.88-160241 ng g(-1) dw, and 7.09-815 ng g(-1) lipid weight (lw), respectively. Significant negative correlations (r(2) = 0.54, p = 0.006) were observed between HBCD concentrations in soils and the distance from the manufacturing facility, and the concentrations became constant when the distance was >4 km. The calculation results on the bioaccumulation factors (BAFs) suggested that HBCD may be accumulated in plants. Tissue-specific bioaccumulation of HBCD diastereoisomers was found in aquatic species. For example, in crabs the highest concentrations of HBCD (815 ng g(-1) lw for female and 446 ng g(-1) lw for male) were observed in the gill. Besides the gill, α-HBCD was more preferentially accumulated in the spermary and ovary, while β- and γ-HBCD were more accumulated in the muscle. A similar distribution was also observed in roe and muscle of goby fish.
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| 15. |
- Li, YingMing, et al.
(author)
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Levels and distribution of polychlorinated biphenyls in the atmosphere close to Chinese Great Wall Station, Antarctica : Results from XAD-resin passive air sampling
- 2012
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In: Chinese Science Bulletin. - Beijing : Science Press. - 1001-6538 .- 1861-9541. ; 57:13, s. 1499-1503
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Journal article (peer-reviewed)abstract
- Antarctica is an important research region for assessing persistence and long-range atmospheric transport (LRAT) of persistent organic pollutants (POPs). In this study, XAD-resin passive air sampling was conducted near the Chinese Great Wall Station, Antarctica, during a one-year sampling period in 2009-2010. The air concentrations of polychlorinated biphenyls (PCBs) were at a very low level, with total PCBs in the range of 26.74-45.08 pg m(-3). PCB profiles were dominated by tetra-PCBs, tri-PCBs and di-PCBs, indicating LRAT was responsible for the pollutants in the Antarctic atmosphere. The sampling site near the Chinese Great Wall Station did not show higher PCB levels than the other sites, suggesting that PCB sources associated with the Great Wall Station were negligible. PCB-11 is a non-Aroclor congener, which has specific sources compared to other Aroclor PCB congeners. PCB-11 was observed in all air samples, with an average concentration of 1.22 pg m(-3). To our knowledge, this study is the first investigation of PCB levels and distribution in the atmosphere around the Chinese Great Wall Station, Antarctica.
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| 16. |
- Li, Yingming, et al.
(author)
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Study of PCBs and PBDEs in King George Island, Antarctica, using PUF passive air sampling
- 2012
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In: Atmospheric Environment. - : Elsevier. - 1352-2310 .- 1873-2844. ; 51, s. 140-145
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Journal article (peer-reviewed)abstract
- Polyurethane foam (PUF)-disk based passive air samplers were deployed in King George Island, Antarctica, during the austral summer of 2009-2010, to investigate levels, distributions and potential sources of polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) in Antarctic air. The atmospheric levels of Sigma indicator PCBs and Sigma(14) PBDEs ranged from 1.66 to 6.50 pg m(-3) and from 0.67 to 2.98 pg m(-3), respectively. PCBs homologue profiles were dominated by di-PCBs, tri-PCBs and tetra-PCBs, whereas BDE-17 and BDE-28 were the predominant congeners of PBDEs, which could be explained by long-range atmospheric transport processes. However, the sampling sites close to the Antarctic research stations showed higher atmospheric concentrations of PCBs and PBDEs than the other sites, reflecting potential local sources from the Antarctic research stations. The non-Aroclor congener PCB-11 was found in all the air samples, with air concentrations of 3.60-31.4 pg m(-3) (average 15.2 pg m(-3)). Comparison between the results derived from PUF-disk passive air sampling and high-volume air sampling validates the feasibility of using the passive air samplers in Antarctic air. To our knowledge, this study is the first employment of PUF-disk based passive air samplers in Antarctic atmosphere.
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| 17. |
- Lützhøft, Ditte Olsen, et al.
(author)
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Marked gut microbiota dysbiosis and increased imidazole propionate are associated with a NASH Göttingen Minipig model
- 2022
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In: BMC Microbiology. - : BioMed Central (BMC). - 1471-2180. ; 22:1
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Journal article (peer-reviewed)abstract
- BACKGROUND: Gut microbiota dysbiosis is associated with the development of non-alcoholic steatohepatitis (NASH) through modulation of gut barrier, inflammation, lipid metabolism, bile acid signaling and short-chain fatty acid production. The aim of this study was to describe the impact of a choline-deficient amino acid defined high fat diet (CDAHFD) on the gut microbiota in a male Göttingen Minipig model and on selected pathways implicated in the development of NASH.RESULTS: Eight weeks of CDAHFD resulted in a significantly altered colon microbiota mainly driven by the bacterial families Lachnospiraceae and Enterobacteriaceae, being decreased and increased in relative abundance, respectively. Metabolomics analysis revealed that CDAHFD decreased colon content of short-chain fatty acid and increased colonic pH. In addition, serum levels of the microbially produced metabolite imidazole propionate were significantly elevated as a consequence of CDAHFD feeding. Hepatic gene expression analysis showed upregulation of mechanistic target of rapamycin (mTOR) and Ras Homolog, MTORC1 binding in addition to downregulation of insulin receptor substrate 1, insulin receptor substrate 2 and the glucagon receptor in CDAHFD fed minipigs. Further, the consequences of CDAHFD feeding were associated with increased levels of circulating cholesterol, bile acids, and glucagon but not total amino acids.CONCLUSIONS: Our results indicate imidazole propionate as a new potentially relevant factor in relation to NASH and discuss the possible implication of gut microbiota dysbiosis in the development of NASH. In addition, the study emphasizes the need for considering the gut microbiota and its products when developing translational animal models for NASH.
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| 18. |
- McGlinchey, Aidan J, 1984-, et al.
(author)
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Metabolic signatures across the full spectrum of non-alcoholic fatty liver disease
- 2022
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In: JHEP Reports. - : Elsevier. - 2589-5559. ; 4:5
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Journal article (peer-reviewed)abstract
- Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is a progressive liver disease with potentially severe complications including cirrhosis and hepatocellular carcinoma. Previously, we have identified circulating lipid signatures associating with liver fat content and non-alcoholic steatohepatitis (NASH). Here, we develop a metabolomic map across the NAFLD spectrum, defining interconnected metabolic signatures of steatosis (non-alcoholic fatty liver, NASH, and fibrosis).Methods: We performed mass spectrometry analysis of molecular lipids and polar metabolites in serum samples from the European NAFLD Registry patients (n = 627), representing the full spectrum of NAFLD. Using various univariate, multivariate, and machine learning statistical approaches, we interrogated metabolites across 3 clinical perspectives: steatosis, NASH, and fibrosis.Results: Following generation of the NAFLD metabolic network, we identify 15 metabolites unique to steatosis, 18 to NASH, and 15 to fibrosis, with 27 common to all. We identified that progression from F2 to F3 fibrosis coincides with a key pathophysiological transition point in disease natural history, with n = 73 metabolites altered.Conclusions: Analysis of circulating metabolites provides important insights into the metabolic changes during NAFLD progression, revealing metabolic signatures across the NAFLD spectrum and features that are specific to NAFL, NASH, and fibrosis. The F2-F3 transition marks a critical metabolic transition point in NAFLD pathogenesis, with the data pointing to the pathophysiological importance of metabolic stress and specifically oxidative stress.Clinical Trials registration: The study is registered at Clinicaltrials.gov (NCT04442334).Lay summary: Non-alcoholic fatty liver disease is characterised by the build-up of fat in the liver, which progresses to liver dysfunction, scarring, and irreversible liver failure, and is markedly increasing in its prevalence worldwide. Here, we measured lipids and other small molecules (metabolites) in the blood with the aim of providing a comprehensive molecular overview of fat build-up, liver fibrosis, and diagnosed severity. We identify a key metabolic 'watershed' in the progression of liver damage, separating severe disease from mild, and show that specific lipid and metabolite profiles can help distinguish and/or define these cases.
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| 19. |
- McGlinchey, Aidan J, 1984-, et al.
(author)
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Metabolomics approaches to identify biomarkers of nonalcoholic fatty liver disease
- 2020
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In: Journal of Hepatology. - : Elsevier. - 0168-8278 .- 1600-0641. ; 73:Suppl. 1, s. S438-S438
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Journal article (other academic/artistic)abstract
- Background and Aims: Nonalcoholic fatty liver disease (NAFLD) is a progressive liver disease that is strongly associated with type 2 diabetes. Accurate, non-invasive diagnostic tests to deliniate the different stages: degree of steatosis, grade of nonalcoholic steatohepatitis (NASH) and stage fibrosis represent an unmet medical need. In our previous studies, we successfully identified specific serum molecular lipid signatures which associate with the amount of liver fat as well as with NASH. Here we report underlying associations between clinical data, lipidomic profiles, metabolic profiles and clinical outcomes, including downstream identification of potential biomarkers for various stages of the disease.Method: We leverage several statistical and machine-learning approaches to analyse clinical, lipidomic and metabolomic profiles of individuals from the European Horizon 2020 project: Elucidating Pathways of Steatohepatitis (EPoS). We interrogate data on patients representing the full spectrum of NAFLD/NASH derived from the EPoS European NAFLD Registry (n = 627). We condense the EPoS lipidomic data into lipid clusters and subsequently apply non-rejection-rate-pruned partial correlation network techniques to facilitate network analysis between the datasets of lipidomic, metabolomic and clinical data. For biomarker identification, random forest ensemble classification and neural network machine learning approaches were used to both search for valid disease biomarkers and to assess the relative improvement over clinical-data-only classification versus addition of our lipidomic and metabolomic datasets.Results: We found that steatosis grade was strongly associated with (1) an increase of triglycerides with low carbon number and double bond count as well as (2) a decrease of specific phospholipids, including lysophosphatidylcholines. In addition to the network topology as a result itself, we also present lipid clusters (LCs) of interest to the derived network of proposed interactions in our NAFLD data from the EPoS cohort, along with our proposed biomarkers for various disease outcomes, as put forward by our current machine learning analyses.Conclusion: Our findings suggest that dysregulation of lipid metabolism in progressive stages of NAFLD is reflected in circulation and may thus hold diagnostic value as well as offer new insights about the NAFLD pathogenesis. Using this cohort as a proof-of-concept, we demonstrate current progress in tuning the accuracy of neural network and random forest approaches with a view to predicting various subtypes of NAFLD patient using a minimal set of lipidomic and metabolic markers. A detailed network-based picture emerges between lipids, polar metabolites and clinical variables. Lipidomic/metabolomic markers may provide an alternative method of NAFLD patient classification and risk stratification to guide therapy.
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| 20. |
- McGlinchey, Aidan J, 1984-, et al.
(author)
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Prenatal exposure to perfluoroalkyl substances modulates neonatal serum phospholipids, increasing risk of type 1 diabetes
- 2020
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In: Environment International. - : Elsevier. - 0160-4120 .- 1873-6750. ; 143
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Journal article (peer-reviewed)abstract
- In the last decade, increasing incidence of type 1 diabetes (T1D) stabilized in Finland, a phenomenon that coincides with tighter regulation of perfluoroalkyl substances (PFAS). Here, we quantified PFAS to examine their effects, during pregnancy, on lipid and immune-related markers of T1D risk in children. In a mother-infant cohort (264 dyads), high PFAS exposure during pregnancy associated with decreased cord serum phospholipids and progression to T1D-associated islet autoantibodies in the offspring. This PFAS-lipid association appears exacerbated by increased human leukocyte antigen-conferred risk of T1D in infants. Exposure to a single PFAS compound or a mixture of organic pollutants in non-obese diabetic mice resulted in a lipid profile characterized by a similar decrease in phospholipids, a marked increase of lithocholic acid, and accelerated insulitis. Our findings suggest that PFAS exposure during pregnancy contributes to risk and pathogenesis of T1D in offspring.
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| 21. |
- McGlinchey, Aidan J, 1984-, et al.
(author)
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The Metabolomics of Non-Alcoholic Fatty Liver Disease : Of Networks and Biomarkers
- 2021
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In: Journal of Hepatology. - : Elsevier. - 0168-8278 .- 1600-0641. ; 75:Suppl. 2, s. S579-S580
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Journal article (other academic/artistic)abstract
- Background and aims: Non-alcoholic fatty liver disease (NAFLD), the leading cause of chronic liver disease, affects 25%+ of people worldwide. Detailed understanding of the metabolomics of NAFLD, and non-invasive diagnostic techniques for the stages of NAFLD are unavailable. We identify specific serum molecular lipid signatures to these ends.First, we leverage lipidomic and polar metabolomic data (n = 643) subjects, to produce a clear, meaningful interaction map, linking lipids, metabolites, clinical factors and disease outcomes. We find non-spurious associations therein, as features of interest, and for downstream analysis.Third, NAFLD fibrosis biomarker identification was performed using machine learning, with our candidate lipids/metabolites to be forwarded to a successor project; the LITMUS project, towards clinically-applicable, non-invasive, sensitive and specific classification of NAFLD patients.Method: Serum lipids and polar metabolites were measured by mass spectrometry in the EPoS cohort of patients (n = 176 lipids and n = 36 polar metabolites), combined with clinical data from (n = 643 subjects), followed by model-based clustering, giving 10 lipid clusters (LCs).Correlations were calculated pairwise between (1) all LCs, (2) “input” clinical data (height, weight, BMI, blood platelet count) and (3) outcomes (fibrosis, steatosis, NAS score, etc.). Non-rejection rates (NRRs) were calculated for relationships, remove spurious associations (NRR > 0.4). We project the remaining associations as a network; a novel metabolomic overview NAFLD.ANOVA and Tukey’s Honest Significant Differences (Tukey HSDs) revealed detailed metabolic signatures across NAFLD, fibrosis and steatosis stages.Random forest machine learning was used to classify NAFLD patients: LOW (0-1 fibrosis grade) or HIGH (2–4 fibrosis grade), using individual lipids and metabolites, identifying putative biomarkers.Results: In linewith our previous findings, many lipids associate with steatosis and fibrosis in NAFLD. Our novel overview network revealsas sociations between specific LCs and clinical variables, such as TGs (LC3), and a subgroup of TGs of lowest and highest carbon numbers (LC9) along with PC (O)s (LC7) positively associating with NAFLD score and fibrosis. Conversely, LPCs (LC4), particularly sphingomyelins (SMs, LC6), negatively associated with these variables. Many other metabolites changing across NAFLD stages beg further discussion.Conclusion: In addition to generation of a novel metabolomic network of NAFLD, we demonstrate feasibility of lipidomic and metabolomic data to classify NAFLD patients’fibrosis grades (median AUC: 0.765), competitive with gold-standard clinical variables (age, BMI, sex, diabetes, liver AST/ALT, platelet count) (median AUC: 0.778). These biomarkers are being taken forward (LITMUS project) to develop clinical testing.
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| 22. |
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| 23. |
- Mullin, Lauren, 1984-, et al.
(author)
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Rapid separation of hexabromocyclododecane diastereomers using a novel method combining convergence chromatography and tandem mass spectrometry
- 2015
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In: Analytical Methods. - : Royal Society of Chemistry. - 1759-9660 .- 1759-9679. ; 7:7, s. 2950-2958
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Journal article (peer-reviewed)abstract
- Analysis of the brominated flame retardant hexabromocyclododecane (HBCDD) is characterized by the separation of its three predominant diastereomers. This analysis is typically performed using reversed phase liquid chromatography (RPLC) coupled with mass spectrometric (MS) detection with analysis times in the order of 10 minutes or greater. Here we describe a rapid method using supercritical CO2 and methanol to baseline separate the three most abundant HBCDD diastereomers within a three minute run time using a High Strength Silica (HSS) C18 1.8 mu m particle size column. A unique elution order of the alpha-, beta- and gamma-HBCDD diastereomers using supercritical CO2 was observed, and can be used as an orthogonal separation for further confidence in diastereomer identification when used in conjuction with RPLC. A tandem quadrupole mass spectrometer with negative mode electrospray ionization was used for detection, operating in multiple reaction monitoring (MRM) mode. Ionization was enhanced by the addition of a make-up flow, which was introduced to the post-column effluent. Method limit of detection (LOD) and limit of quantification (LOQ) for alpha-, beta- and gamma-HBCDD were based on peak-to-peak signal to noise ratios of greater than 3 or 10, respectively. The LOD for all HBCDD diastereomers as solvent standards was 100 fg on-column, and LOQs 500 fg on-column for alpha- and gamma-HBCDD and 250 fg on-column for beta-HBCDD. In order to test the efficiency of this method, small subsets of complex human serum and whale blubber extracts were analyzed using this method, resulting in positive detections in samples of alpha-HBCDD.
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| 24. |
- Sen, Partho, 1983-, et al.
(author)
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Genome-scale metabolic modeling of human hepatocytes reveals dysregulation of glycosphingolipid pathways in progressive non-alcoholic fatty liver disease
- 2021
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In: Journal of Hepatology. - : Elsevier. - 0168-8278 .- 1600-0641. ; 75:Suppl. 2, s. S256-S256
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Journal article (other academic/artistic)abstract
- Background and aims: Non-alcoholic fatty liver disease (NAFLD) is a spectrum of chronic liver diseases intertwined with the metabolic disorders. The prevalence of NAFLD is rapidly increasing worldwide, while the pathologyand the underlying mechanism driving NAFLD is not fully understood. In NAFLD, a series of metabolic changes takes place in the liver. However, the alteration of the metabolic pathways in the human liver along the progression of NAFLD,i.e., transition from non-alcoholic steatosis (NAFL) to steatohepatitis (NASH) through cirrhosis remains to be discovered. Here, we sought to examine the metabolic pathways of the human liver across the full histological spectrum of NAFLD.Method: We analyzed the whole liver tissue transcriptomic (RNA-Seq)1 and serum metabolomics data obtained from a large cohort of histologically characterized patients derived from the European NAFLD Registry (n = 206), and developed genome-scale metabolic models (GEMs) of human hepatocytes at different stages of NAFLD. The integrative approach employed in this study has enabled us to understand the regulation of the metabolic pathways of human liver in NAFL, and with progressive NASH-associated fibrosis (F0-F4).Results: Our study identified several metabolic signatures in the liver and blood of these patients, specifically highlighting the alteration of vitamins (A, E) and glycosphingolipids, and their link with complex glycosaminoglycans in advanced fibrosis. Furthermore, by applying genome-scale metabolic modeling, we were able to identify the metabolic differences among carriers of widely validated genetic variants associated with NAFLD/NASH disease severity in three genes (PNPLA3,TM6SF2andHSD17B13).Conclusion: The study provides insights into the underlying pathways of the progressive-fibrosing steatohepatitis. Of note, there is a marked dysregulation of the glycosphingolipid metabolism in the liver of the patients with advanced fibrosis.
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- Sen, Partho, 1983-, et al.
(author)
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Quantitative modeling of human liver reveals dysregulation of glycosphingolipid pathways in nonalcoholic fatty liver disease
- 2022
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In: iScience. - : Cell Press. - 2589-0042. ; 25:9
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Journal article (peer-reviewed)abstract
- Nonalcoholic fatty liver disease (NAFLD) is an increasingly prevalent disease that is associated with multiple metabolic disturbances, yet the metabolic pathways underlying its progression are poorly understood. Here, we studied metabolic pathways of the human liver across the full histological spectrum of NAFLD. We analyzed whole liver tissue transcriptomics and serum metabolomics data obtained from a large, prospectively enrolled cohort of 206 histologically characterized patients derived from the European NAFLD Registry and developed genome-scale metabolic models (GEMs) of human hepatocytes at different stages of NAFLD. We identified several metabolic signatures in the liver and blood of these patients, specifically highlighting the alteration of vitamins (A, E) and glycosphingolipids, and their link with complex glycosaminoglycans in advanced fibrosis. Furthermore, we derived GEMs and identified metabolic signatures of three common NAFLD-associated gene variants (PNPLA3, TM6SF2, and HSD17B13). The study demonstrates dysregulated liver metabolic pathways which may contribute to the progression of NAFLD.
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