| 1. |
- Alves, Marina Amaral, et al.
(författare)
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Systems biology approaches to study lipidomes in health and disease
- 2021
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Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier. - 1388-1981 .- 1879-2618. ; 1866:2
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Forskningsöversikt (refereegranskat)abstract
- Lipids have many important biological roles, such as energy storage sources, structural components of plasma membranes and as intermediates in metabolic and signaling pathways. Lipid metabolism is under tight homeostatic control, exhibiting spatial and dynamic complexity at multiple levels. Consequently, lipid-related disturbances play important roles in the pathogenesis of most of the common diseases. Lipidomics, defined as the study of lipidomes in biological systems, has emerged as a rapidly-growing field. Due to the chemical and functional diversity of lipids, the application of a systems biology approach is essential if one is to address lipid functionality at different physiological levels. In parallel with analytical advances to measure lipids in biological matrices, the field of computational lipidomics has been rapidly advancing, enabling modeling of lipidomes in their pathway, spatial and dynamic contexts. This review focuses on recent progress in systems biology approaches to study lipids in health and disease, with specific emphasis on methodological advances and biomedical applications.
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| 2. |
- Dickens, Alex M., et al.
(författare)
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Dysregulated Lipid Metabolism Precedes Onset of Psychosis
- 2021
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Ingår i: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 89:3, s. 288-297
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: A key clinical challenge in the management of individuals at clinical high risk for psychosis (CHR) is that it is difficult to predict their future clinical outcomes. Here, we investigated if the levels of circulating molecular lipids are related to adverse clinical outcomes in this group.METHODS: Serum lipidomic analysis was performed in 263 CHR individuals and 51 healthy control subjects, who were then clinically monitored for up to 5 years. Machine learning was used to identify lipid profiles that discriminated between CHR and control subjects, and between subgroups of CHR subjects with distinct clinical outcomes.RESULTS: At baseline, compared with control subjects, CHR subjects (independent of outcome) had higher levels of triacylglycerols with a low acyl carbon number and a double bond count, as well as higher levels of lipids in general. CHR subjects who subsequently developed psychosis (n = 50) were distinguished from those that did not (n = 213) on the basis of lipid profile at baseline using a model with an area under the receiver operating curve of 0.81 (95% confidence interval = 0.69-0.93). CHR subjects who became psychotic had lower levels of ether phospholipids than CHR individuals who did not (p < .01).CONCLUSIONS: Collectively, these data suggest that lipidomic abnormalities predate the onset of psychosis and that blood lipidomic measures may be useful in predicting which CHR individuals are most likely to develop psychosis.
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| 3. |
- Lamichhane, Santosh, et al.
(författare)
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Association Between Circulating Lipids and Future Weight Gain in Individuals With an At-Risk Mental State and in First-Episode Psychosis
- 2021
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Ingår i: Schizophrenia Bulletin. - : Oxford University Press. - 0586-7614 .- 1745-1701. ; 47:1, s. 160-169
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Tidskriftsartikel (refereegranskat)abstract
- Patients with schizophrenia have a lower than average life span, largely due to the increased prevalence of cardiometabolic comorbidities. There is an unmet public health need to identify individuals with psychotic disorders who have a high risk of rapid weight gain and who are at risk of developing metabolic complications. Here, we applied mass spectrometry-based lipidomics in a prospective study comprising 48 healthy controls (CTR), 44 first-episode psychosis (FEP) patients, and 22 individuals at clinical high risk (CHR) for psychosis, from 2 study centers (Turku, Finland and London, UK). Baseline serum samples were analyzed using lipidomics, and body mass index (BMI) was assessed at baseline and after 12 months. We found that baseline triacylglycerols (TGs) with low double-bond counts and carbon numbers were positively associated with the change in BMI at follow-up. In addition, a molecular signature comprised of 2 TGs (TG[48:0] and TG[45:0]) was predictive of weight gain in individuals with a psychotic disorder, with an area under the receiver operating characteristic curve (AUROC) of 0.74 (95% CI: 0.60-0.85). When independently tested in the CHR group, this molecular signature predicted said weight change with AUROC = 0.73 (95% CI: 0.61-0.83). We conclude that molecular lipids may serve as a predictor of weight gain in psychotic disorders in at-risk individuals and may thus provide a useful marker for identifying individuals who are most prone to developing cardiometabolic comorbidities.
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| 4. |
- Lamichhane, Santosh, et al.
(författare)
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Linking Gut Microbiome and Lipid Metabolism : Moving beyond Associations
- 2021
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Ingår i: Metabolites. - : MDPI. - 2218-1989 .- 2218-1989. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Various studies aiming to elucidate the role of the gut microbiome-metabolome co-axis in health and disease have primarily focused on water-soluble polar metabolites, whilst non-polar microbial lipids have received less attention. The concept of microbiota-dependent lipid biotransformation is over a century old. However, only recently, several studies have shown how microbial lipids alter intestinal and circulating lipid concentrations in the host, thus impacting human lipid homeostasis. There is emerging evidence that gut microbial communities play a particularly significant role in the regulation of host cholesterol and sphingolipid homeostasis. Here, we review and discuss recent research focusing on microbe-host-lipid co-metabolism. We also discuss the interplay of human gut microbiota and molecular lipids entering host systemic circulation, and its role in health and disease.
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| 5. |
- Oresic, Matej, 1967-, et al.
(författare)
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Exposure to environmental contaminants is associated with sex-specific disturbances of hepatic lipid metabolism in non-alcoholic fatty liver disease
- 2021
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Ingår i: Journal of Hepatology. - : Elsevier. - 0168-8278 .- 1600-0641. ; 75:Suppl. 2, s. S605-S606
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background and aims: Liver has a vital role in metabolism, distribution, and excretion of exogenous chemicals. The endocrine disrupting chemicals (EDCs) may act as a‘second hit’in the progression of NAFLD, advancing the earlier stages of liver pathology such as steatosis to more severe stages. A specific class of ECDs that have been linked with NAFLD are perfluorinated alkyl substances (PFAS), a class of commonly used industrial chemicals that humans are widelyexposed to. Due to the their structural similarity with fatty acids, PFAS may disrupt hepatic lipid metabolism. Furthermore, functionally, PFAS share some features with bile acids, including similar enterohepatic circulation. Nevertheless, human data linking PFAS exposure and lipid metabolism in the liver are currently lacking. The principal aim of our study was to define the impact of PFAS exposure on hepatic metabolism, with specific focus on bile acid and lipid metabolism.Method: In a well-characterized human NAFLD cohort of 105 individuals, we investigated the impact of PFAS exposure on liver metabolism in the individuals with NAFLD. Average BMI was 45.65 ± 5.99 kg/m2, with liver fat content varying between 0% and 80%. We comprehensively characterized both hepatic (liver biopsy) and serum metabolome using four analytical platforms, and measured PFAS in serum. We investigated the association between the NAFLD (liver fat %, NASH grade, fibrosis stage, insulin resistance), PFAS exposure, and metabolome.Results: PFAS exposurewas associated with NAFLD (Figure) as well as with changes in hepatic lipid and bile acid metabolism. Importantly, we observed sex-specific association between chemical exposure and NAFLD, linked with sex-specific changes in both hepatic and circulating metabolome. We noticed differences not only in the exposure profiles between the males and females, but, notably, also the impact of the exposure, as characterized both with the impact on metabolome but also on clinical parameters was clearly different between the males and females.Conclusion: Our results implicate that females may be more sensitive to the harmful impacts of PFAS. The results also suggest that the changes reported in the lipid metabolism due to PFAS exposure may be secondary to the interplay of PFAS and bile acids
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| 6. |
- Petersen, Anders Ø., et al.
(författare)
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Conjugated C-6 hydroxylated bile acids in serum relate to human metabolic health and gut Clostridia species
- 2021
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Knowledge about in vivo effects of human circulating C-6 hydroxylated bile acids (BAs), also called muricholic acids, is sparse. It is unsettled if the gut microbiome might contribute to their biosynthesis. Here, we measured a range of serum BAs and related them to markers of human metabolic health and the gut microbiome. We examined 283 non-obese and obese Danish adults from the MetaHit study. Fasting concentrations of serum BAs were quantified using ultra-performance liquid chromatography-tandem mass-spectrometry. The gut microbiome was characterized with shotgun metagenomic sequencing and genome-scale metabolic modeling. We find that tauro- and glycohyocholic acid correlated inversely with body mass index (P = 4.1e-03, P = 1.9e-05, respectively), waist circumference (P = 0.017, P = 1.1e-04, respectively), body fat percentage (P = 2.5e-03, P = 2.3e-06, respectively), insulin resistance (P = 0.051, P = 4.6e-4, respectively), fasting concentrations of triglycerides (P = 0.06, P = 9.2e-4, respectively) and leptin (P = 0.067, P = 9.2e-4). Tauro- and glycohyocholic acids, and tauro-a-muricholic acid were directly linked with a distinct gut microbial community primarily composed of Clostridia species (P = 0.037, P = 0.013, P = 0.027, respectively). We conclude that serum conjugated C-6-hydroxylated BAs associate with measures of human metabolic health and gut communities of Clostridia species. The findings merit preclinical interventions and human feasibility studies to explore the therapeutic potential of these BAs in obesity and type 2 diabetes.
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| 7. |
- Sen, Partho, et al.
(författare)
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1-Deoxyceramides : key players in lipotoxicity and progression to type 2 diabetes?
- 2021
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Ingår i: Acta Physiologica. - : John Wiley & Sons. - 1748-1708 .- 1748-1716. ; 232:1
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Tidskriftsartikel (refereegranskat)abstract
- Ceramides are bioactive sphingolipids, comprised of sphingosine and a fatty acyl chain. They have been recognized as key mediators of lipotoxicity; a phenomenon where excess fat in adipose tissue leads to de novo synthesis of ceramides and their precursor dihydroceramides (DHCer). This occurs in adipose tissue as well as in the periphery. Accumulation of these ceramides is associated with insulin resistance, de novo lipogenesis, and inflammation1 , thus increasing the risk of cardiometabolic diseases such as type 2 diabetes (T2D) and atherosclerosis. Recently, in this journal, Hannish and colleagues reported that another, non-canonical class of ceramides, the 1-deoxyceramides (DoxCer), is highly enriched in visceral adipose tissue (VAT) as well as in serum of obese patients with T2D2 . This study also clarified previously-reported discrepancies in the literature concerning the association of DHCer with the risk of T2D, as the signals from DHCer can be easily confused with the signals from DoxCer in mass spectrometric (MS) analysis of lipids.
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| 8. |
- Sen, Partho, 1983-, et al.
(författare)
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Deep learning meets metabolomics : a methodological perspective
- 2021
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Ingår i: Briefings in Bioinformatics. - : Oxford University Press. - 1467-5463 .- 1477-4054. ; 22:2, s. 1531-1542
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Forskningsöversikt (refereegranskat)abstract
- Deep learning (DL), an emerging area of investigation in the fields of machine learning and artificial intelligence, has markedly advanced over the past years. DL techniques are being applied to assist medical professionals and researchers in improving clinical diagnosis, disease prediction and drug discovery. It is expected that DL will help to provide actionable knowledge from a variety of 'big data', including metabolomics data. In this review, we discuss the applicability of DL to metabolomics, while presenting and discussing several examples from recent research. We emphasize the use of DL in tackling bottlenecks in metabolomics data acquisition, processing, metabolite identification, as well as in metabolic phenotyping and biomarker discovery. Finally, we discuss how DL is used in genome-scale metabolic modelling and in interpretation of metabolomics data. The DL-based approaches discussed here may assist computational biologists with the integration, prediction and drawing of statistical inference about biological outcomes, based on metabolomics data.
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| 9. |
- Sen, Partho, 1983-, et al.
(författare)
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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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Ingår i: Journal of Hepatology. - : Elsevier. - 0168-8278 .- 1600-0641. ; 75:Suppl. 2, s. S256-S256
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)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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| 10. |
- Sen, Partho, et al.
(författare)
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Quantitative analysis of human CD4+T-cell differentiation reveals subset-specific regulation of glycosphingolipid pathways
- 2021
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Ingår i: European Journal of Immunology. - : John Wiley & Sons. - 0014-2980 .- 1521-4141. ; 51:Suppl. 1, s. 237-237
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- T‐cells are sentinels of adaptive immune responses. T‐cell activation, proliferation and differentiation involves metabolic reprogramming involving the interplay of genes, proteins and metabolites. Here, we aim to understand the metabolic pathways involved in the activation and functional differentiation of human CD4+ T‐cell subsets (Th1, Th2, Th17 and iTregs). We combined genome‐scale metabolic modeling, gene expression data, targeted and non‐targeted lipidomics experiments, together with in vitro gene knockdown experiments and showed that human CD4+ T cells undergo specific metabolic changes during activation and functional differentiation. In addition, we identified and confirmed the importance of ceramide and glycosphingolipid biosynthesis pathways in Th17 differentiation and effector functions. Through in vitro gene knockdown experiments, we substantiated the requirement of serine palmitoyl transferase, a de novo sphingolipid pathway in the expression of proinflammatory cytokine (IL17A and IL17F) by Th17 cells. Our findings may provide a comprehensive resource for identifying CD4+ T‐cell‐specific targets for their selective manipulation under disease conditions, particularly, diseases characterized by an imbalance of Th17/nTreg cells.
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