| 1. |
- Zhang, C., et al.
(author)
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The acute effect of metabolic cofactor supplementation: a potential therapeutic strategy against non-alcoholic fatty liver disease
- 2020
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In: Molecular Systems Biology. - : EMBO. - 1744-4292. ; 16:4
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Journal article (peer-reviewed)abstract
- The prevalence of non-alcoholic fatty liver disease (NAFLD) continues to increase dramatically, and there is no approved medication for its treatment. Recently, we predicted the underlying molecular mechanisms involved in the progression of NAFLD using network analysis and identified metabolic cofactors that might be beneficial as supplements to decrease human liver fat. Here, we first assessed the tolerability of the combined metabolic cofactors including l-serine, N-acetyl-l-cysteine (NAC), nicotinamide riboside (NR), and l-carnitine by performing a 7-day rat toxicology study. Second, we performed a human calibration study by supplementing combined metabolic cofactors and a control study to study the kinetics of these metabolites in the plasma of healthy subjects with and without supplementation. We measured clinical parameters and observed no immediate side effects. Next, we generated plasma metabolomics and inflammatory protein markers data to reveal the acute changes associated with the supplementation of the metabolic cofactors. We also integrated metabolomics data using personalized genome-scale metabolic modeling and observed that such supplementation significantly affects the global human lipid, amino acid, and antioxidant metabolism. Finally, we predicted blood concentrations of these compounds during daily long-term supplementation by generating an ordinary differential equation model and liver concentrations of serine by generating a pharmacokinetic model and finally adjusted the doses of individual metabolic cofactors for future human clinical trials.
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| 2. |
- Darmanis, Spyros, et al.
(author)
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Identification of Candidate Serum Proteins for Classifying Well-Differentiated Small Intestinal Neuroendocrine Tumors
- 2013
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:11, s. e81712-
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Journal article (peer-reviewed)abstract
- BackgroundPatients with well-differentiated small intestine neuroendocrine tumors (WD-SI-NET) are most often diagnosed at a metastatic stage of disease, which reduces possibilities for a curative treatment. Thus new approaches for earlier detection and improved monitoring of the disease are required.Materials and methodsSuspension bead arrays targeting 124 unique proteins with antibodies from the Human Protein Atlas were used to profile biotinylated serum samples. Discoveries from a cohort of 77 individuals were followed up in a cohort of 132 individuals both including healthy controls as well as patients with untreated primary WD-SI-NETs, lymph node metastases and liver metastases.Results A set of 20 antibodies suggested promising proteins for further verification based on technically verified statistical significance. Proceeding, we assessed the classification performance in an independent cohort of patient serum, achieving, classification accuracy of up to 85% with different subsets of antibodies in respective pairwise group comparisons. The protein profiles of nine targets, namely IGFBP2, IGF1, SHKBP1, ETS1, IL1α, STX2, MAML3, EGR3 and XIAP were verified as significant contributors to tumor classification.ConclusionsWe propose new potential protein biomarker candidates for classifying WD-SI-NET at different stage of disease. Further evaluation of these proteins in larger sample sets and with alternative approaches is needed in order to further improve our understanding of their functional relation to WD-SI-NET and their eventual use in diagnostics.
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| 3. |
- Mardinoglu, Adil, 1982, et al.
(author)
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Elevated Plasma Levels of 3-Hydroxyisobutyric Acid Are Associated With Incident Type 2 Diabetes
- 2018
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In: Ebiomedicine. - : Elsevier BV. - 2352-3964. ; 27, s. 151-155
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Journal article (peer-reviewed)abstract
- Branched-chain amino acids (BCAAs) metabolite, 3-Hydroxyisobutyric acid (3-HIB) has been identified as a secreted mediator of endothelial cell fatty acid transport and insulin resistance (IR) using animal models. To identify if 3-HIB is a marker of human IR and future risk of developing Type 2 diabetes (T2D), we measured plasma levels of 3-HIB and associated metabolites in around 10,000 extensively phenotyped individuals. The levels of 3-HIB were increased in obesity but not robustly associated with degree of IR after adjusting for BMI. Nevertheless, also after adjusting for obesity and plasma BCAA, 3-HIB levels were associated with future risk of incident T2D. We also examined the effect of 3-HIB on fatty acid uptake in human cells and found that both HUVEC and human cardiac endothelial cells respond to 3-HIB whereas human adipose tissue-derived endothelial cells do not respond to 3-HIB. In conclusion, we found that increased plasma level of 3-HIB is a marker of future risk of T2D and 3-HIB may be important for the regulation of metabolic flexibility in heart and muscles.
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| 4. |
- Mardinoglu, Adil, 1982, et al.
(author)
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An Integrated Understanding of the Rapid Metabolic Benefits of a Carbohydrate-Restricted Diet on Hepatic Steatosis in Humans
- 2018
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In: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 27:3
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Journal article (peer-reviewed)abstract
- A carbohydrate-restricted diet is a widely recommended intervention for non-alcoholic fatty liver disease (NAFLD), but a systematic perspective on the multiple benefits of this diet is lacking. Here, we performed a short-term intervention with an isocaloric low-carbohydrate diet with increased protein content in obese subjects with NAFLD and characterized the resulting alterations in metabolism and the gut microbiota using a multi-omics approach. We observed rapid and dramatic reductions of liver fat and other cardiometabolic risk factors paralleled by (1) marked decreases in hepatic de novo lipogenesis; (2) large increases in serum beta-hydroxybutyrate concentrations, reflecting increased mitochondrial beta-oxidation; and (3) rapid increases in folate-producing Streptococcus and serum folate concentrations. Liver transcriptomic analysis on biopsy samples from a second cohort revealed downregulation of the fatty acid synthesis pathway and upregulation of folate-mediated one-carbon metabolism and fatty acid oxidation pathways. Our results highlight the potential of exploring diet-microbiota interactions for treating NAFLD.
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| 5. |
- Jotanovic, Jelena, et al.
(author)
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Transcriptome Analysis Reveals Distinct Patterns Between the Invasive and Noninvasive Pituitary Neuroendocrine Tumors
- 2024
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In: Journal of the Endocrine Society. - : Oxford University Press. - 2472-1972. ; 8:5
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Journal article (peer-reviewed)abstract
- Although most pituitary neuroendocrine tumors (PitNETs)/pituitary adenomas remain intrasellar, a significant proportion of tumors show parasellar invasive growth and 6% to 8% infiltrate the bone structures, thus affecting the prognosis. There is an unmet need to identify novel markers that can predict the parasellar growth of PitNETs. Furthermore, mechanisms that regulate bone invasiveness of PitNETs and factors related to tumor vascularization are largely unknown.We used genome-wide mRNA analysis in a cohort of 77 patients with PitNETs of different types to explore the differences in gene expression patterns between invasive and noninvasive tumors with respect to the parasellar growth and regarding the rare phenomenon of bone invasiveness. Additionally, we studied the genes correlated to the contrast enhancement quotient, a novel radiological parameter of tumor vascularization.Most of the genes differentially expressed related to the parasellar growth were genes involved in tumor invasiveness. Differentially expressed genes associated with bone invasiveness are involved in NF-κB pathway and antitumoral immune response. Lack of clear clustering regarding the parasellar and bone invasiveness may be explained by the influence of the cell lineage-related genes in this heterogeneous cohort of PitNETs.Our transcriptomics analysis revealed differences in the molecular fingerprints between invasive, including bone invasive, and noninvasive PitNETs, although without clear clustering. The contrast enhancement quotient emerged as a radiological parameter of tumor vascularization, correlating with several angiogenesis-related genes. Several of the top genes related to the PitNET invasiveness and vascularization have potential prognostic and therapeutic application requiring further research.
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| 6. |
- Lovric, Alen, et al.
(author)
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Characterization of different fat depots in NAFLD using inflammation-associated proteome, lipidome and metabolome
- 2018
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8
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Journal article (peer-reviewed)abstract
- Non-alcoholic fatty liver disease (NAFLD) is recognized as a liver manifestation of metabolic syndrome, accompanied with excessive fat accumulation in the liver and other vital organs. Ectopic fat accumulation was previously associated with negative effects at the systemic and local level in the human body. Thus, we aimed to identify and assess the predictive capability of novel potential metabolic biomarkers for ectopic fat depots in non-diabetic men with NAFLD, using the inflammation-associated proteome, lipidome and metabolome. Myocardial and hepatic triglycerides were measured with magnetic spectroscopy while function of left ventricle, pericardial and epicardial fat, subcutaneous and visceral adipose tissue were measured with magnetic resonance imaging. Measured ectopic fat depots were profiled and predicted using a Random Forest algorithm, and by estimating the Area Under the Receiver Operating Characteristic curves. We have identified distinct metabolic signatures of fat depots in the liver (TAG50:1, glutamate, diSM18:0 and CE20:3), pericardium (N-palmitoyl-sphinganine, HGF, diSM18:0, glutamate, and TNFSF14), epicardium (sphingomyelin, CE20:3, PC38:3 and TNFSF14), and myocardium (CE20:3, LAPTGF-beta 1, glutamate and glucose). Our analyses highlighted non-invasive biomarkers that accurately predict ectopic fat depots, and reflect their distinct metabolic signatures in subjects with NAFLD.
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| 7. |
- Sahebekhtiari, Navid, et al.
(author)
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Plasma Proteomics Analysis Reveals Dysregulation of Complement Proteins and Inflammation in Acquired Obesity—A Study on Rare BMI-Discordant Monozygotic Twin Pairs
- 2019
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In: Proteomics - Clinical Applications. - : Wiley. - 1862-8354 .- 1862-8346. ; 13:4
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Journal article (peer-reviewed)abstract
- Purpose: The purpose of this study is to elucidate the effect of excess body weight and liver fat on the plasma proteome without interference from genetic variation. Experimental Design: The effect of excess body weight is assessed in young, healthy monozygotic twins from pairs discordant for body mass index (intrapair difference (Δ) in BMI > 3 kg m −2 , n = 26) with untargeted LC-MS proteomics quantification. The effect of liver fat is interrogated via subgroup analysis of the BMI-discordant twin cohort: liver fat discordant pairs (Δliver fat > 2%, n = 12) and liver fat concordant pairs (Δliver fat < 2%, n = 14), measured by magnetic resonance spectroscopy. Results: Seventy-five proteins are differentially expressed, with significant enrichment for complement and inflammatory response pathways in the heavier co-twins. The complement dysregulation is found in obesity in both the liver fat subgroups. The complement and inflammatory proteins are significantly associated with adiposity measures, insulin resistance and impaired lipids. Conclusions and Clinical Relevance: The early pathophysiological mechanisms in obesity are incompletely understood. It is shown that aberrant complement regulation in plasma is present in very early stages of clinically healthy obese persons, independently of liver fat and in the absence of genetic variation that typically confounds human studies.
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| 8. |
- Piening, B. D., et al.
(author)
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Integrative Personal Omics Profiles during Periods of Weight Gain and Loss
- 2018
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In: Cell Systems. - : Elsevier BV. - 2405-4712 .- 2405-4720. ; 6:2
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Journal article (peer-reviewed)abstract
- Advances in omics technologies now allow an unprecedented level of phenotyping for human diseases, including obesity, in which individual responses to excess weight are heterogeneous and unpredictable. To aid the development of better understanding of these phenotypes, we performed a controlled longitudinal weight perturbation study combining multiple omics strategies (genomics, transcriptomics, multiple proteomics assays, metabolomics, and microbiomics) during periods of weight gain and loss in humans. Results demonstrated that: (1) weight gain is associated with the activation of strong inflammatory and hypertrophic cardiomyopathy signatures in blood; (2) although weight loss reverses some changes, a number of signatures persist, indicative of long-term physiologic changes; (3) we observed omics signatures associated with insulin resistance that may serve as novel diagnostics; (4) specific biomolecules were highly individualized and stable in response to perturbations, potentially representing stable personalized markers. Most data are available open access and serve as a valuable resource for the community.
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| 9. |
- Robinson, Jonathan, 1986, et al.
(author)
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An atlas of human metabolism
- 2020
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In: Science Signaling. - : American Association for the Advancement of Science (AAAS). - 1945-0877 .- 1937-9145. ; 13:624
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Journal article (peer-reviewed)abstract
- Genome-scale metabolic models (GEMs) are valuable tools to study metabolism and provide a scaffold for the integrative analysis of omics data. Researchers have developed increasingly comprehensive human GEMs, but the disconnect among different model sources and versions impedes further progress. We therefore integrated and extensively curated the most recent human metabolic models to construct a consensus GEM, Human1. We demonstrated the versatility of Human1 through the generation and analysis of cell- and tissue-specific models using transcriptomic, proteomic, and kinetic data. We also present an accompanying web portal, Metabolic Atlas (https://www.metabolicatlas.org/), which facilitates further exploration and visualization of Human1 content. Human1 was created using a version-controlled, open-source model development framework to enable community-driven curation and refinement. This framework allows Human1 to be an evolving shared resource for future studies of human health and disease.
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| 10. |
- Ritsinger, V., et al.
(author)
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Elevated levels of insulin-like growth factor-binding protein 1 predict outcome after acute myocardial infarction : A long-term follow-up of the glucose tolerance in patients with acute myocardial infarction (GAMI) cohort
- 2018
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In: Diabetes & Vascular Disease Research. - : SAGE Publications Ltd. - 1479-1641 .- 1752-8984. ; 15:5, s. 387-395
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Journal article (peer-reviewed)abstract
- Objective: To investigate the long-term prognostic value of insulin-like growth factor-binding protein 1 in patients with acute myocardial infarction. Methods: Patients (n = 180) with admission glucose < 11 mmol/L without previously known diabetes admitted for an acute myocardial infarction in 1998–2000 were followed for mortality and cardiovascular events (first of cardiovascular mortality/acute myocardial infarction/stroke/severe heart failure) until the end of 2011 (median 11.6 years). Fasting levels of insulin-like growth factor-binding protein 1 at day 2 were related to outcome in Cox proportional hazard regression analyses. Results: Median age was 64 years, 69% were male and median insulin-like growth factor-binding protein 1 was 20 µg/L. Total mortality was 34% (n = 61) and 44% (n = 80) experienced a cardiovascular event during a median follow-up time of 11.6 years. After age adjustment, insulin-like growth factor-binding protein 1 was associated with all-cause (1.40; 1.02–1.93, p = 0.039) and cancer mortality (2.09; 1.15–3.79, p = 0.015) but not with cardiovascular death (p = 0.29) or cardiovascular events (p = 0.57). After adjustments also for previous myocardial infarction, previous heart failure and body mass index, insulin-like growth factor-binding protein 1 was still associated with all-cause mortality (1.38; 1.01–1.89, p = 0.046). Conclusion: In patients with acute myocardial infarction without previously known diabetes, high insulin-like growth factor-binding protein 1 was associated with long-term all-cause and cancer mortality but not with cardiovascular events.
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