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  • 1. Adiels, Martin
    et al.
    Mardinoglu, Adil
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab. Chalmers University of Technology, Sweden.
    Taskinen, Marja-Riitta
    Boren, Jan
    Kinetic Studies to Elucidate Impaired Metabolism of Triglyceride-rich Lipoproteins in Humans2015Inngår i: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 6, artikkel-id 342Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    To develop novel strategies for prevention and treatment of dyslipidemia, it is essential to understand the pathophysiology of dyslipoproteinemia in humans. Lipoprotein metabolism is a complex system in which abnormal concentrations of various lipoprotein particles can result from alterations in their rates of production, conversion, and/or catabolism. Traditional methods that measure plasma lipoprotein concentrations only provide static estimates of lipoprotein metabolism and hence limited mechanistic information. By contrast, the use of tracers labeled with stable isotopes and mathematical modeling, provides us with a powerful tool for probing lipid and lipoprotein kinetics in vivo and furthering our understanding of the pathogenesis of dyslipoproteinemia.

  • 2.
    Altay, Özlem
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Nielsen, Jens
    Chalmers Univ Technol, Dept Biol & Biol Engn, Gothenburg, Sweden..
    Uhlén, Mathias
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Boren, Jan
    Univ Gothenburg, Sahlgrenska Univ Hosp, Dept Mol & Clin Med, Gothenburg, Sweden..
    Mardinoglu, Adil
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Systems biology perspective for studying the gut microbiota in human physiology and liver diseases2019Inngår i: EBioMedicine, E-ISSN 2352-3964, Vol. 49, s. 364-373Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    The advancement in high-throughput sequencing technologies and systems biology approaches have revolutionized our understanding of biological systems and opened a new path to investigate unacknowledged biological phenomena. In parallel, the field of human microbiome research has greatly evolved and the relative contribution of the gut microbiome to health and disease have been systematically explored. This review provides an overview of the network-based and translational systems biology-based studies focusing on the function and composition of gut microbiota. We also discussed the association between the gut microbiome and the overall human physiology, as well as hepatic diseases and other metabolic disorders.

  • 3.
    Benfeitas, Rui
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Bidkhori, Gholamreza
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Mukhopadhyay, Bani
    NIAAA, Lab Physiol Studies, NIH, Bethesda, MD USA..
    Klevstig, Martina
    Univ Gothenburg, Sahlgrenska Univ Hosp, Dept Mol & Clin Med, Gothenburg, Sweden..
    Arif, Muhammad
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Systembiologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Zhang, Cheng
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Systembiologi.
    Lee, Sunjae
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Cinar, Resat
    NIAAA, Lab Physiol Studies, NIH, Bethesda, MD USA..
    Nielsen, Jens
    Chalmers Univ Technol, Dept Biol & Biol Engn, Gothenburg, Sweden..
    Uhlén, Mathias
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Systembiologi.
    Boren, Jan
    Univ Gothenburg, Sahlgrenska Univ Hosp, Dept Mol & Clin Med, Gothenburg, Sweden..
    Kunos, George
    NIAAA, Lab Physiol Studies, NIH, Bethesda, MD USA..
    Mardinoglu, Adil
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH Royal Inst Technol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Characterization of heterogeneous redox responses in hepatocellular carcinoma patients using network analysis2019Inngår i: EBioMedicine, E-ISSN 2352-3964, Vol. 40, s. 471-487Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Redox metabolism is often considered a potential target for cancer treatment, but a systematic examination of redox responses in hepatocellular carcinoma (HCC) is missing. Methods: Here, we employed systems biology and biological network analyses to reveal key roles of genes associated with redox metabolism in HCC by integrating multi-omics data. Findings: We found that several redox genes, including 25 novel potential prognostic genes, are significantly co-expressed with liver-specific genes and genes associated with immunity and inflammation. Based on an integrative analysis, we found that HCC tumors display antagonistic behaviors in redox responses. The two HCC groups are associated with altered fatty acid, amino acid, drug and hormone metabolism, differentiation, proliferation, and NADPH-independent vs - dependent antioxidant defenses. Redox behavior varies with known tumor subtypes and progression, affecting patient survival. These antagonistic responses are also displayed at the protein and metabolite level and were validated in several independent cohorts. We finally showed the differential redox behavior using mice transcriptomics in HCC and noncancerous tissues and associated with hypoxic features of the two redox gene groups. Interpretation: Our integrative approaches highlighted mechanistic differences among tumors and allowed the identification of a survival signature and several potential therapeutic targets for the treatment of HCC. (C) 2018 Published by Elsevier B.V.

  • 4.
    Benfeitas, Rui
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab. Royal Institute of Technology, KTH.
    Bidkhori, Gholamreza
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Mukhopadhyay, Bani
    Klevstig, Martina
    Arif, Muhammad
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Systembiologi.
    Zhang, Cheng
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Lee, Sunjae
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Cinar, Resat
    Nielsen, Jens
    Uhlén, Mathias
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Boren, Jan
    Kunos, George
    Mardinoglu, Adil
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Characterization of heterogeneous redox responses in hepatocellular carcinoma patients using network analysis2019Inngår i: EBioMedicine, E-ISSN 2352-3964Artikkel i tidsskrift (Fagfellevurdert)
    Fulltekst (pdf)
    fulltext
  • 5.
    Bidkhori, Gholamreza
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Benfeitas, Rui
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Elmas, Ezgi
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Kararoudi, Meisam Naeimi
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Arif, Muhammad
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Uhlén, Mathias
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Nielsen, Jens
    Chalmers Univ Technol, Dept Biol & Biol Engn, Gothenburg, Sweden..
    Mardinoglu, Adil
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Metabolic Network-Based Identification and Prioritization o f Anticancer Targets Based on Expression Data in Hepatocellular Carcinoma2018Inngår i: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 9, artikkel-id 916Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Hepatocellular carcinoma (HCC) is a deadly form of liver cancer with high mortality worldwide. Unfortunately, the large heterogeneity of this disease makes it difficult to develop effective treatment strategies. Cellular network analyses have been employed to study heterogeneity in cancer, and to identify potential therapeutic targets. However, the existing approaches do not consider metabolic growth requirements, i.e., biological network functionality, to rank candidate targets while preventing toxicity to non-cancerous tissues. Here, we developed an algorithm to overcome these issues based on integration of gene expression data, genome-scale metabolic models, network controllability, and dispensability, as well as toxicity analysis. This method thus predicts and ranks potential anticancer non-toxic controlling metabolite and gene targets. Our algorithm encompasses both objective-driven and-independent tasks, and uses network topology to finally rank the predicted therapeutic targets. We employed this algorithm to the analysis of transcriptomic data for 50 HCC patients with both cancerous and non-cancerous samples. We identified several potential targets that would prevent cell growth, including 74 anticancer metabolites, and 3 gene targets (PRKACA, PGS1, and CRLS1). The predicted anticancer metabolites showed good agreement with existing FDA-approved cancer drugs, and the 3 genes were experimentally validated by performing experiments in HepG2 and Hep3B liver cancer cell lines. Our observations indicate that our novel approach successfully identifies therapeutic targets for effective treatment of cancer. This approach may also be applied to any cancer type that has tumor and non-tumor gene or protein expression data.

  • 6.
    Bidkhori, Gholamreza
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Benfeitas, Rui
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Klevstig, Martina
    Zhang, Cheng
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Nielsen, Jens
    Uhlén, Mathias
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Boren, Jan
    Mardinoglu, Adil
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Metabolic network-based stratification of hepatocellular carcinoma reveals three distinct tumor subtypes2018Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Hepatocellular carcinoma (HCC) is one of the most frequent forms of liver cancer, and effective treatment methods are limited due to tumor heterogeneity. There is a great need for comprehensive approaches to stratify HCC patients, gain biological insights into subtypes, and ultimately identify effective therapeutic targets. We stratified HCC patients and characterized each subtype using transcriptomics data, genome-scale metabolic networks and network topology/controllability analysis. This comprehensive systems-level analysis identified three distinct subtypes with substantial differences in metabolic and signaling pathways reflecting at genomic, transcriptomic, and proteomic levels. These subtypes showed large differences in clinical survival associated with altered kynurenine metabolism, WNT/beta-catenin-associated lipid metabolism, and PI3K/AKT/mTOR signaling. Integrative analyses indicated that the three subtypes rely on alternative enzymes (e.g., ACSS1/ACSS2/ACSS3, PKM/PKLR, ALDOB/ALDOA, MTHFD1L/MTHFD2/MTHFD1) to catalyze the same reactions. Based on systems-level analysis, we identified 8 to 28 subtype-specific genes with pivotal roles in controlling the metabolic network and predicted that these genes may be targeted for development of treatment strategies for HCC subtypes by performing in silico analysis. To validate our predictions, we performed experiments using HepG2 cells under normoxic and hypoxic conditions and observed opposite expression patterns between genes expressed in high/moderate/low-survival tumor groups in response to hypoxia, reflecting activated hypoxic behavior in patients with poor survival. In conclusion, our analyses showed that the heterogeneous HCC tumors can be stratified using a metabolic network-driven approach, which may also be applied to other cancer types, and this stratification may have clinical implications to drive the development of precision medicine.

    Fulltekst (pdf)
    fulltext
  • 7. Bjornson, Elias
    et al.
    Boren, Jan
    Mardinoglu, Adil
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. Chalmers University, Sweden.
    Personalized Cardiovascular Disease Prediction and Treatment-A Review of Existing Strategies and Novel Systems Medicine Tools2016Inngår i: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 7, artikkel-id 2Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Cardiovascular disease (CVD) continues to constitute the leading cause of death globally. CVD risk stratification is an essential tool to sort through heterogeneous populations and identify individuals at risk of developing CVD. However, applications of current risk scores have recently been shown to result in considerable misclassification of high-risk subjects. In addition, despite long standing beneficial effects in secondary prevention, current CVD medications have in a primary prevention setting shown modest benefit in terms of increasing life expectancy. A systems biology approach to CVD risk stratification may be employed for improving risk-estimating algorithms through addition of high-throughput derived omics biomarkers. In addition, modeling of personalized benefit-of-treatment may help in guiding choice of intervention. In the area of medicine, realizing that CVD involves perturbations of large complex biological networks, future directions in drug development may involve moving away from a reductionist approach toward a system level approach. Here, we review current CVD risk scores and explore how novel algorithms could help to improve the identification of risk and maximize personalized treatment benefit. We also discuss possible future directions in the development of effective treatment strategies for CVD through the use of genome-scale metabolic models (GEMs) as well as other biological network-based approaches.

  • 8. Bosley, Jim
    et al.
    Borén, Christofer
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Lee, Sunjae
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Grotli, Morten
    Nielsen, Jens
    KTH, Centra, Science for Life Laboratory, SciLifeLab. Chalmers University of Technology, Sweden.
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Boren, Jan
    Mardinoglu, Adil
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab. Chalmers University of Technology, Sweden.
    Improving the economics of NASH/NAFLD treatment through the use of systems biology2017Inngår i: Drug Discovery Today, ISSN 1359-6446, E-ISSN 1878-5832, Vol. 22, nr 10, s. 1532-1538Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease (NAFLD). We surveyed NASH therapies currently in development, and found a significant variety of targets and approaches. Evaluation and clinical testing of these targets is an expensive and time-consuming process. Systems biology approaches could enable the quantitative evaluation of the likely efficacy and safety of different targets. This motivated our review of recent systems biology studies that focus on the identification of targets and development of effective treatments for NASH. We discuss the potential broader use of genome-scale metabolic models and integrated networks in the validation of drug targets, which could facilitate more productive and efficient drug development decisions for the treatment of NASH.

  • 9. Cadenas, Cristina
    et al.
    Vosbeck, Sonja
    Edlund, Karolina
    Grgas, Katharina
    Madjar, Katrin
    Hellwig, Birte
    Adawy, Alshaimaa
    Glotzbach, Annika
    Stewart, Joanna D.
    Lesjak, Michaela S.
    Franckenstein, Dennis
    Claus, Maren
    Hayen, Heiko
    Schriewer, Alexander
    Gianmoena, Kathrin
    Thaler, Sonja
    Schmidt, Marcus
    Micke, Patrick
    Ponten, Fredrik
    Mardinoglu, Adil
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Zhang, Cheng
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Käfferlein, Keiko U.
    Watzl, Carsten
    Frank, Sasa
    Rahnenfuhrer, Jörg
    Marchan, Rosemarie
    Hengstler, Jan G.
    LIPG-promoted lipid storage mediates adaptation to oxidative stress in breast cancer2019Inngår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 145, nr 4, s. 901-915Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Endothelial lipase (LIPG) is a cell surface associated lipase that displays phospholipase A1 activity towards phosphatidylcholine present in high-density lipoproteins (HDL). LIPG was recently reported to be expressed in breast cancer and to support proliferation, tumourigenicity and metastasis. Here we show that severe oxidative stress leading to AMPK activation triggers LIPG upregulation, resulting in intracellular lipid droplet accumulation in breast cancer cells, which supports survival. Neutralizing oxidative stress abrogated LIPG upregulation and the concomitant lipid storage. In human breast cancer, high LIPG expression was observed in a limited subset of tumours and was significantly associated with shorter metastasis-free survival in node-negative, untreated patients. Moreover, expression of PLIN2 and TXNRD1 in these tumours indicated a link to lipid storage and oxidative stress. Altogether, our findings reveal a previously unrecognized role for LIPG in enabling oxidative stress-induced lipid droplet accumulation in tumour cells that protects against oxidative stress, and thus supports tumour progression.

    Fulltekst (pdf)
    fulltext
  • 10.
    Cadirci, Kenan
    et al.
    Hlth Sci Univ, Erzurum Reg Training & Res Hosp, Dept Internal Med, Erzurum, Turkey..
    Ozdemir Tozlu, Ozlem
    Erzurum Tech Univ, Fac Sci, Dept Mol Biol & Genet, Erzurum, Turkey..
    Turkez, Hasan
    Ataturk Univ, Fac Med, Dept Med Biol, Erzurum, Turkey.;Univ G dAnnunzio, Dept Pharm, Chieti, Italy..
    Mardinoglu, Adil
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Systembiologi. KTH, Centra, Science for Life Laboratory, SciLifeLab. Kings Coll London, Fac Dent Oral & Craniofacial Sci, Ctr Host Microbiome Interact, London SE19 1RT, England..
    The in vitro cytotoxic, genotoxic, and oxidative damage potentials of the oral artificial sweetener aspartame on cultured human blood cells2020Inngår i: Turkish Journal of Medical Sciences, ISSN 1300-0144, E-ISSN 1303-6165, Vol. 50, nr 2, s. 448-454Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background/aim: Aspartame (APM, L-aspartyl-L-phenylalanine methylester) is a low-calorie, nonsaccharide artificial sweetener widely used in foods and beverages. When metabolized by the body, APM is broken down into aspartic acid, phenylalanine amino acids, and a third substance, methanol. Since the amino acid phenylalanine serves as a neurotransmitter building block affecting the brain, and methanol is converted into toxic formaldehyde, APM has deleterious effects on the body and brain. Thus, its safety and, toxicity have been the subjects of concern ever since it was first discovered. Although many studies have been performed on it, due to the presence of conflicting data in the literature, there are still numerous question marks concerning APM. Therefore, the safety of aspartame was tested using in vitro methods. Materials and methods: We aimed to evaluate the in vitro cytotoxic effects by using 3-(4,5-dimetylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase release tests, genotoxic damage potential by using chromosome aberration (CA) assay, and antioxidant/oxidant activity by using total antioxidant capacity (TAC) and total oxidative stress (TOS) analysis in primary human whole blood cell cultures. Results: The results of the MTT test showed that APM led to significant decreases in cell viability in a clear concentration-dependent manner. Moreover, an increase in CA frequency was found in the cells treated with APM. However, APM treatments did not cause any significant changes in TAC and TOS levels in whole blood cultures. Conclusion: Overall, the obtained results showed that APM had genotoxicity potential and a concentration-dependent cytotoxic activity in human blood cells.

  • 11. Cao, Junyue
    et al.
    Packer, Jonathan
    Waterston, Robert
    Trapnell, Cole
    Shendure, Jay
    Rajaram, Satwik
    Wu, Lani F.
    Altschuler, Steven J.
    Liang, Jackson
    O'Brien, Lucy Erin
    Eizenberg-Magar, Inbal
    Rimer, Jacob
    Friedman, Nir
    Metzl-Raz, Eyal
    Kafri, Moshe
    Yaakov, Gilad
    Soifer, Ilya
    Gurvich, Yonat
    Barkai, Naama
    Mardinoglu, Adil
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för bioteknologi (BIO).
    Ponten, Fredrik
    Uhlén, Mathias
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för bioteknologi (BIO).
    Rahi, Sahand Jamal
    Cross, Frederick R.
    Baumgart, Meike
    Noack, Stephan
    Principles of Systems Biology, No. 212017Inngår i: CELL SYSTEMS, ISSN 2405-4712, Vol. 5, nr 3, s. 158-160Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    This month: relating single cells to populations (Cao/Packer, Wu/Altschuler, O'Brien, Friedman), an excess of ribosomes (Barkai), human pathology atlas (Uhlen), signatures of feedback (Rahi), and major genome redesign (Baumgart).

  • 12. Casey, John R.
    et al.
    Mardinoglu, Adil
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.
    Nielsen, Jens
    KTH, Centra, Science for Life Laboratory, SciLifeLab. Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden; Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Lyngby, Denmark.
    Karl, David M.
    Adaptive Evolution of Phosphorus Metabolism in Prochlorococcus2016Inngår i: MSYSTEMS, ISSN 2379-5077, Vol. 1, nr 6, artikkel-id UNSP e00065Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Inorganic phosphorus is scarce in the eastern Mediterranean Sea, where the high-light-adapted ecotype HLI of the marine picocyanobacterium Prochlorococcus marinus thrives. Physiological and regulatory control of phosphorus acquisition and partitioning has been observed in HLI both in culture and in the field; however, the optimization of phosphorus metabolism and associated gains for its phosphorus-limited-growth (PLG) phenotype have not been studied. Here, we reconstructed a genome-scale metabolic network of the HLI axenic strain MED4 (iJC568), consisting of 568 metabolic genes in relation to 794 reactions involving 680 metabolites distributed in 6 subcellular locations. iJC568 was used to quantify metabolic fluxes under PLG conditions, and we observed a close correspondence between experimental and computed fluxes. We found that MED4 has minimized its dependence on intracellular phosphate, not only through drastic depletion of phosphorus-containing biomass components but also through network-wide reductions in phosphate-reaction participation and the loss of a key enzyme, succinate dehydrogenase. These alterations occur despite the stringency of having relatively few pathway redundancies and an extremely high proportion of essential metabolic genes (47%; defined as the percentage of lethal in silico gene knockouts). These strategies are examples of nutrient-controlled adaptive evolution and confer a dramatic growth rate advantage to MED4 in phosphorus-limited regions. IMPORTANCE Microbes are known to employ three basic strategies to compete for limiting elemental resources: (i) cell quotas may be adjusted by alterations to cell physiology or by substitution of a more plentiful resource, (ii) stressed cells may synthesize high-affinity transporters, and (iii) cells may access more costly sources from internal stores, by degradation, or by petitioning other microbes. In the case of phosphorus, a limiting resource in vast oceanic regions, the cosmopolitan cyanobacterium Prochlorococcus marinus thrives by adopting all three strategies and a fourth, previously unknown strategy. By generating a detailed model of its metabolism, we found that strain MED4 has evolved a way to reduce its dependence on phosphate by minimizing the number of enzymes involved in phosphate transformations, despite the stringency of nearly half of its metabolic genes being essential for survival. Relieving phosphorus limitation, both physiologically and throughout intermediate metabolism, substantially improves phosphorus-specific growth rates.

  • 13. Choi, M. J.
    et al.
    Jung, S. -B
    Lee, S. E.
    Kang, S. G.
    Lee, J. H.
    Ryu, M. J.
    Chung, H. K.
    Chang, J. Y.
    Kim, Y. K.
    Hong, H. J.
    Kim, H.
    Kim, H. J.
    Lee, C. -H
    Mardinoglu, Adil
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Systembiologi. Kings Coll London, Fac Dent Oral & Craniofacial Sci, Ctr Host Microbiome Interact, London, England.
    Yi, H. -S
    Shong, M.
    An adipocyte-specific defect in oxidative phosphorylation increases systemic energy expenditure and protects against diet-induced obesity in mouse models2020Inngår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aims/hypothesis: Mitochondrial oxidative phosphorylation (OxPhos) is essential for energy production and survival. However, the tissue-specific and systemic metabolic effects of OxPhos function in adipocytes remain incompletely understood. Methods: We used adipocyte-specific Crif1 (also known as Gadd45gip1) knockout (AdKO) mice with decreased adipocyte OxPhos function. AdKO mice fed a normal chow or high-fat diet were evaluated for glucose homeostasis, weight gain and energy expenditure (EE). RNA sequencing of adipose tissues was used to identify the key mitokines affected in AdKO mice, which included fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15). For in vitro analysis, doxycycline was used to pharmacologically decrease OxPhos in 3T3L1 adipocytes. To identify the effects of GDF15 and FGF21 on the metabolic phenotype of AdKO mice, we generated AdKO mice with global Gdf15 knockout (AdGKO) or global Fgf21 knockout (AdFKO). Results: Under high-fat diet conditions, AdKO mice were resistant to weight gain and exhibited higher EE and improved glucose tolerance. In vitro pharmacological and in vivo genetic inhibition of OxPhos in adipocytes significantly upregulated mitochondrial unfolded protein response-related genes and secretion of mitokines such as GDF15 and FGF21. We evaluated the metabolic phenotypes of AdGKO and AdFKO mice, revealing that GDF15 and FGF21 differentially regulated energy homeostasis in AdKO mice. Both mitokines had beneficial effects on obesity and insulin resistance in the context of decreased adipocyte OxPhos, but only GDF15 regulated EE in AdKO mice. Conclusions/interpretation: The present study demonstrated that the adipose tissue adaptive mitochondrial stress response affected systemic energy homeostasis via cell-autonomous and non-cell-autonomous pathways. We identified novel roles for adipose OxPhos and adipo-mitokines in the regulation of systemic glucose homeostasis and EE, which facilitated adaptation of an organism to local mitochondrial stress.

  • 14.
    Danielsson, Frida
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Fasterius, Erik
    KTH, Skolan för bioteknologi (BIO), Proteomik (stängd 20130101).
    Sullivan, Devin
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Hases, Linnea
    KTH, Centra, Science for Life Laboratory, SciLifeLab. Karolinska Institute, Huddinge, Sweden.
    Sanli, Kemal
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Zhang, Cheng
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Mardinoglu, Adil
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Al-Khalili Szigyarto, Cristina
    KTH, Skolan för bioteknologi (BIO), Proteomik (stängd 20130101).
    Huss, M.
    Uhlén, Mathias
    KTH, Skolan för bioteknologi (BIO), Proteomik (stängd 20130101). KTH, Centra, Science for Life Laboratory, SciLifeLab. Technical University of Denmark, Hørsholm, Denmark.
    Williams, Cecilia
    KTH, Centra, Science for Life Laboratory, SciLifeLab. Karolinska Institute, Huddinge, Sweden.
    Lundberg, Emma
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Transcriptome profiling of the interconnection of pathways involved in malignant transformation and response to hypoxia2018Inngår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 9, nr 28, s. 19730-19744Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In tumor tissues, hypoxia is a commonly observed feature resulting from rapidly proliferating cancer cells outgrowing their surrounding vasculature network. Transformed cancer cells are known to exhibit phenotypic alterations, enabling continuous proliferation despite a limited oxygen supply. The four-step isogenic BJ cell model enables studies of defined steps of tumorigenesis: the normal, immortalized, transformed, and metastasizing stages. By transcriptome profiling under atmospheric and moderate hypoxic (3% O2) conditions, we observed that despite being highly similar, the four cell lines of the BJ model responded strikingly different to hypoxia. Besides corroborating many of the known responses to hypoxia, we demonstrate that the transcriptome adaptation to moderate hypoxia resembles the process of malignant transformation. The transformed cells displayed a distinct capability of metabolic switching, reflected in reversed gene expression patterns for several genes involved in oxidative phosphorylation and glycolytic pathways. By profiling the stage-specific responses to hypoxia, we identified ASS1 as a potential prognostic marker in hypoxic tumors. This study demonstrates the usefulness of the BJ cell model for highlighting the interconnection of pathways involved in malignant transformation and hypoxic response.

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  • 15. Elsemman, Ibrahim E.
    et al.
    Mardinoglu, Adil
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab. Chalmers University of Technology, Sweden.
    Shoaie, Saeed
    Soliman, Taysir H.
    Nielsen, Jens
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab. Chalmers University of Technology, Sweden.
    Systems biology analysis of hepatitis C virus infection reveals the role of copy number increases in regions of chromosome 1q in hepatocellular carcinoma metabolism2016Inngår i: Molecular Biosystems, ISSN 1742-206X, E-ISSN 1742-2051, Vol. 12, nr 5, s. 1496-1506Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Hepatitis C virus (HCV) infection is a worldwide healthcare problem; however, traditional treatment methods have failed to cure all patients, and HCV has developed resistance to new drugs. Systems biology-based analyses could play an important role in the holistic analysis of the impact of HCV on hepatocellular metabolism. Here, we integrated HCV assembly reactions with a genome-scale hepatocyte metabolic model to identify metabolic targets for HCV assembly and metabolic alterations that occur between different HCV progression states (cirrhosis, dysplastic nodule, and early and advanced hepatocellular carcinoma (HCC)) and healthy liver tissue. We found that diacylglycerolipids were essential for HCV assembly. In addition, the metabolism of keratan sulfate and chondroitin sulfate was significantly changed in the cirrhosis stage, whereas the metabolism of acyl-carnitine was significantly changed in the dysplastic nodule and early HCC stages. Our results explained the role of the upregulated expression of BCAT1, PLOD3 and six other methyltransferase genes involved in carnitine biosynthesis and S-adenosylmethionine metabolism in the early and advanced HCC stages. Moreover, GNPAT and BCAP31 expression was upregulated in the early and advanced HCC stages and could lead to increased acyl-CoA consumption. By integrating our results with copy number variation analyses, we observed that GNPAT, PPOX and five of the methyltransferase genes (ASH1L, METTL13, SMYD2, TARBP1 and SMYD3), which are all located on chromosome 1q, had increased copy numbers in the cancer samples relative to the normal samples. Finally, we confirmed our predictions with the results of metabolomics studies and proposed that inhibiting the identified targets has the potential to provide an effective treatment strategy for HCV-associated liver disorders.

  • 16. Ghaffari, Pouyan
    et al.
    Mardinoglu, Adil
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab. Chalmers University of Technology, Sweden.
    Nielsen, Jens
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab. Chalmers University of Technology, Sweden; Technical University of Denmark, Denmark.
    Cancer Metabolism: A Modeling Perspective2015Inngår i: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 6, artikkel-id 382Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Tumor cells alter their metabolism to maintain unregulated cellular proliferation and survival, but this transformation leaves them reliant on constant supply of nutrients and energy. In addition to the widely studied dysregulated glucose metabolism to fuel tumor cell growth, accumulating evidences suggest that utilization of amino acids and lipids contributes significantly to cancer cell metabolism. Also recent progresses in our understanding of carcinogenesis have revealed that cancer is a complex disease and cannot be understood through simple investigation of genetic mutations of cancerous cells. Cancer cells present in complex tumor tissues communicate with the surrounding microenvironment and develop traits which promote their growth, survival, and metastasis. Decoding the full scope and targeting dysregulated metabolic pathways that support neoplastic transformations and their preservation requires both the advancement of experimental technologies for more comprehensive measurement of omics as well as the advancement of robust computational methods for accurate analysis of the generated data. Here, we review cancer-associated reprogramming of metabolism and highlight the capability of genome-scale metabolic modeling approaches in perceiving a system-level perspective of cancer metabolism and in detecting novel selective drug targets.

  • 17. Harms, Matthew J.
    et al.
    Li, Qian
    Lee, Sunjae
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Zhang, Cheng
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Kull, Bengt
    Hallen, Stefan
    Thorell, Anders
    Alexandersson, Ida
    Hagberg, Carolina E.
    Peng, Xiao-Rong
    Mardinoglu, Adil
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Spalding, Kirsty L.
    Boucher, Jeremie
    Mature Human White Adipocytes Cultured under Membranes Maintain Identity, Function, and Can Transdifferentiate into Brown-like Adipocytes2019Inngår i: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247Artikkel i tidsskrift (Fagfellevurdert)
    Fulltekst (pdf)
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  • 18.
    Haversen, Liliana
    et al.
    Univ Gothenburg, Dept Mol & Clin Med, Wallenberg Lab, Gothenburg, Sweden.;Sahlgrens Univ Hosp, Gothenburg, Sweden..
    Sundelin, Jeanna Perman
    AstraZeneca, Strateg Planning & Operat, Cardiovasc & Metab Dis, IMED Biotech Unit, Gothenburg, Sweden..
    Mardinoglu, Adil
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH). Kings Coll London, Ctr Host Microbiome Interact, Dent Inst, London SE1 9RT, England..
    Rutberg, Mikael
    Univ Gothenburg, Dept Mol & Clin Med, Wallenberg Lab, Gothenburg, Sweden.;Sahlgrens Univ Hosp, Gothenburg, Sweden..
    Stahlman, Marcus
    Univ Gothenburg, Dept Mol & Clin Med, Wallenberg Lab, Gothenburg, Sweden.;Sahlgrens Univ Hosp, Gothenburg, Sweden..
    Wilhelmsson, Ulrika
    Univ Gothenburg, Dept Clin Neurosci, Ctr Brain Repair, Gothenburg, Sweden..
    Hulten, Lillemor Mattsson
    Univ Gothenburg, Dept Mol & Clin Med, Wallenberg Lab, Gothenburg, Sweden.;Sahlgrens Univ Hosp, Gothenburg, Sweden..
    Pekny, Milos
    Univ Gothenburg, Dept Clin Neurosci, Ctr Brain Repair, Gothenburg, Sweden..
    Fogelstrand, Per
    Univ Gothenburg, Dept Mol & Clin Med, Wallenberg Lab, Gothenburg, Sweden.;Sahlgrens Univ Hosp, Gothenburg, Sweden..
    Fog Bentzon, Jacob
    Aarhus Univ, Dept Clin Med, Aarhus, Denmark.;Ctr Nacl Invest Cardiovasc Carlos III CNIC, Madrid, Spain..
    Levin, Malin
    Univ Gothenburg, Dept Mol & Clin Med, Wallenberg Lab, Gothenburg, Sweden.;Sahlgrens Univ Hosp, Gothenburg, Sweden..
    Boren, Jan
    Univ Gothenburg, Dept Mol & Clin Med, Wallenberg Lab, Gothenburg, Sweden.;Sahlgrens Univ Hosp, Gothenburg, Sweden..
    Vimentin deficiency in macrophages induces increased oxidative stress and vascular inflammation but attenuates atherosclerosis in mice2018Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, artikkel-id 16973Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The aim was to clarify the role of vimentin, an intermediate filament protein abundantly expressed in activated macrophages and foam cells, in macrophages during atherogenesis. Global gene expression, lipid uptake, ROS, and inflammation were analyzed in bone-marrow derived macrophages from vimentin-deficient (Vim(-/-)) and wild-type (Vim(-/-)) mice. Atherosclerosis was induced in Ldlr(-/-) mice transplanted with a PCSK9 gain-of-function virus. The mice were fed an atherogenic diet for 12-15 weeks. We observed impaired uptake of native LDL but increased uptake of oxLDL in Vim(-/-) macrophages. FACS analysis revealed increased surface expression of the scavenger receptor CD36 on Vim(-/-) macrophages. Vim(-/-) macrophages also displayed increased markers of oxidative stress, activity of the transcription factor NF-kappa B, secretion of proinflammatory cytokines and GLUT1-mediated glucose uptake. Vim(-/- )mice displayed decreased atherogenesis despite increased vascular inflammation and increased CD36 expression on macrophages in two mouse models of atherosclerosis. We demonstrate that vimentin has a strong suppressive effect on oxidative stress and that Vim(-/-) mice display increased vascular inflammation with increased CD36 expression on macrophages despite decreased subendothelial lipid accumulation. Thus, vimentin has a key role in regulating inflammation in macrophages during atherogenesis.

  • 19. Heinonen, Sini
    et al.
    Muniandy, Maheswary
    Buzkova, Jana
    Mardinoglu, Adil
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab. Chalmers University of Technology, Sweden.
    Rodriguez, Amaia
    Fruhbeck, Gema
    Hakkarainen, Antti
    Lundbom, Jesper
    Lundbom, Nina
    Kaprio, Jaakko
    Rissanen, Aila
    Pietilainen, Kirsi H.
    Mitochondria-related transcriptional signature is downregulated in adipocytes in obesity: a study of young healthy MZ twins2017Inngår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 60, nr 1, s. 169-181Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Low mitochondrial activity in adipose tissue is suggested to be an underlying factor in obesity and its metabolic complications. We aimed to find out whether mitochondrial measures are downregulated in obesity also in isolated adipocytes. We studied young adult monozygotic (MZ) twin pairs discordant (n = 14, intrapair difference Delta BMI ae<yen> 3 kg/m(2)) and concordant (n = 5, Delta BMI < 3 kg/m(2)) for BMI, identified from ten birth cohorts of 22- to 36-year-old Finnish twins. Abdominal body fat distribution (MRI), liver fat content (magnetic resonance spectroscopy), insulin sensitivity (OGTT), high-sensitivity C-reactive protein, serum lipids and adipokines were measured. Subcutaneous abdominal adipose tissue biopsies were obtained to analyse the transcriptomics patterns of the isolated adipocytes as well as of the whole adipose tissue. Mitochondrial DNA transcript levels in adipocytes were measured by quantitative real-time PCR. Western blots of oxidative phosphorylation (OXPHOS) protein levels in adipocytes were performed in obese and lean unrelated individuals. The heavier (BMI 29.9 +/- 1.0 kg/m(2)) co-twins of the discordant twin pairs had more subcutaneous, intra-abdominal and liver fat and were more insulin resistant (p < 0.01 for all measures) than the lighter (24.1 +/- 0.9 kg/m(2)) co-twins. Altogether, 2538 genes in adipocytes and 2135 in adipose tissue were significantly differentially expressed (nominal p < 0.05) between the co-twins. Pathway analysis of these transcripts in both isolated adipocytes and adipose tissue revealed that the heavier co-twins displayed reduced expression of genes relating to mitochondrial pathways, a result that was replicated when analysing the pathways behind the most consistently downregulated genes in the heavier co-twins (in at least 12 out of 14 pairs). Consistently upregulated genes in adipocytes were related to inflammation. We confirmed that mitochondrial DNA transcript levels (12S RNA, 16S RNA, COX1, ND5, CYTB), expression of mitochondrial ribosomal protein transcripts and a major mitochondrial regulator PGC-1 alpha (also known as PPARGC1A) were reduced in the heavier co-twins' adipocytes (p < 0.05). OXPHOS protein levels of complexes I and III in adipocytes were lower in obese than in lean individuals. Subcutaneous abdominal adipocytes in obesity show global expressional downregulation of oxidative pathways, mitochondrial transcripts and OXPHOS protein levels and upregulation of inflammatory pathways. The datasets analysed and generated during the current study are available in the figshare repository.

  • 20. Huvila, J.
    et al.
    Laajala, T. D.
    Edqvist, P. -H
    Mardinoglu, Adil
    KTH, Centra, Science for Life Laboratory, SciLifeLab. Department of Biology and Biological Engineering, Chalmers University of Technology, 41296 Gothenburg, Sweden.
    Talve, L.
    Pontén, F.
    Grénman, S.
    Carpén, O.
    Aittokallio, T.
    Auranen, A.
    Combined ASRGL1 and p53 immunohistochemistry as an independent predictor of survival in endometrioid endometrial carcinoma2018Inngår i: Gynecologic Oncology, ISSN 0090-8258, E-ISSN 1095-6859, Vol. 149, nr 1, s. 173-180Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: In clinical practise, prognostication of endometrial cancer is based on clinicopathological risk factors. The use of immunohistochemistry-based markers as prognostic tools is generally not recommended and a systematic analysis of their utility as a panel is lacking. We evaluated whether an immunohistochemical marker panel could reliably assess endometrioid endometrial cancer (EEC) outcome independent of clinicopathological information. Methods: A cohort of 306 EEC specimens was profiled using tissue microarray (TMA). Cost- and time-efficient immunohistochemical analysis of well-established tissue biomarkers (ER, PR, HER2, Ki-67, MLH1 and p53) and two new biomarkers (L1CAM and ASRGL1) was carried out. Statistical modelling with embedded variable selection was applied on the staining results to identify minimal prognostic panels with maximal prognostic accuracy without compromising generalizability. Results: A panel including p53 and ASRGL1 immunohistochemistry was identified as the most accurate predictor of relapse-free and disease-specific survival. Within this panel, patients were allocated into high- (5.9%), intermediate- (29.5%) and low- (64.6%) risk groups where high-risk patients had a 30-fold risk (P < 0.001) of dying of EEC compared to the low-risk group. Conclusions: P53 and ASRGL1 immunoprofiling stratifies EEC patients into three risk groups with significantly different outcomes. This simple and easily applicable panel could provide a useful tool in EEC risk stratification and guiding the allocation of treatment modalities. 

  • 21. Karnevi, E.
    et al.
    Dror, L. B.
    Mardinoglu, Adil
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Systembiologi.
    Elebro, J.
    Heby, M.
    Olofsson, S. -E
    Nodin, B.
    Eberhard, J.
    Gallagher, W.
    Uhlén, Mathias
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap.
    Jirström, K.
    Translational study reveals a two-faced role of RBM3 in pancreatic cancer and suggests its potential value as a biomarker for improved patient stratification2018Inngår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 9, nr 5, s. 6188-6200Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Periampullary adenocarcinoma, including pancreatic cancer, is a heterogeneous group of tumors with dismal prognosis, partially due to lack of reliable targetable and predictive biomarkers. RNA-binding motif protein 3 (RBM3) has previously been shown to be an independent prognostic and predictive biomarker in several types of cancer. Herein, we examined the prognostic value of RBM3 in periampullary adenocarcinoma, as well as the effects following RBM3 suppression in pancreatic cancer cells in vitro. RBM3 mRNA levels were examined in 176 pancreatic cancer patients from The Cancer Genome Atlas. Immunohistochemical expression of RBM3 was analyzed in tissue microarrays with primary tumors and paired lymph node metastases from 175 consecutive patients with resected periampullary adenocarcinoma. Pancreatic cancer cells were transfected with anti-RBM3 siRNA in vitro and the influence on cell viability following chemotherapy, transwell migration and invasion was assessed. The results demonstrated that high mRNA-levels of RBM3 were significantly associated with a reduced overall survival (p = 0.026). RBM3 protein expression was significantly higher in lymph node metastases than in primary tumors (p = 0.005). High RBM3 protein expression was an independent predictive factor for the effect of adjuvant chemotherapy and an independent negative prognostic factor in untreated patients (p for interaction = 0.003). After siRNA suppression of RBM3 in vitro, pancreatic cancer cells displayed reduced migration and invasion compared to control, as well as a significantly increased resistance to chemotherapy. In conclusion, the strong indication of a positive response predictive effect of RBM3 expression in pancreatic cancer may be highly relevant in the clinical setting and merits further validation.

  • 22.
    Klevstig, Martina
    et al.
    Univ Gothenburg, Sahlgrenska Univ Hosp, Wallenberg Lab, Dept Mol & Clin Med, Gothenburg, Sweden..
    Arif, Muhammad
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Systembiologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Mannila, Maria
    Karolinska Inst, Karolinska Univ Hosp, BioClin, Cardiovasc Med Unit,Dept Med,Ctr Mol Med, Stockholm, Sweden..
    Svedlund, Sara
    Sahlgrens Univ Hosp, Dept Clin Physiol, Gothenburg, Sweden..
    Mardani, Ismena
    Univ Gothenburg, Sahlgrenska Univ Hosp, Wallenberg Lab, Dept Mol & Clin Med, Gothenburg, Sweden..
    Stahlman, Marcus
    Univ Gothenburg, Sahlgrenska Univ Hosp, Wallenberg Lab, Dept Mol & Clin Med, Gothenburg, Sweden..
    Andersson, Linda
    Univ Gothenburg, Sahlgrenska Univ Hosp, Wallenberg Lab, Dept Mol & Clin Med, Gothenburg, Sweden..
    Lindbom, Malin
    Univ Gothenburg, Sahlgrenska Univ Hosp, Wallenberg Lab, Dept Mol & Clin Med, Gothenburg, Sweden..
    Miljanovic, Azra
    Univ Gothenburg, Sahlgrenska Univ Hosp, Wallenberg Lab, Dept Mol & Clin Med, Gothenburg, Sweden..
    Franco-Cereceda, Anders
    Karolinska Univ Hosp, Dept Cardiothorac Surg & Anaesthesia, Stockholm, Sweden..
    Eriksson, Per
    Karolinska Inst, Karolinska Univ Hosp, BioClin, Cardiovasc Med Unit,Dept Med,Ctr Mol Med, Stockholm, Sweden..
    Jeppsson, Anders
    Univ Gothenburg, Sahlgrenska Univ Hosp, Wallenberg Lab, Dept Mol & Clin Med, Gothenburg, Sweden..
    Gan, Li -Ming
    Univ Gothenburg, Sahlgrenska Univ Hosp, Wallenberg Lab, Dept Mol & Clin Med, Gothenburg, Sweden.;AstraZeneca R&D, Cardiovasc Renal & Metab IMED Biotech Unit, Molndal, Sweden..
    Levin, Malin
    Univ Gothenburg, Sahlgrenska Univ Hosp, Wallenberg Lab, Dept Mol & Clin Med, Gothenburg, Sweden..
    Mardinoglu, Adil
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Ehrenborg, Ewa
    Karolinska Inst, Karolinska Univ Hosp, BioClin, Cardiovasc Med Unit,Dept Med,Ctr Mol Med, Stockholm, Sweden..
    Boren, Jan
    Univ Gothenburg, Sahlgrenska Univ Hosp, Wallenberg Lab, Dept Mol & Clin Med, Gothenburg, Sweden..
    Cardiac expression of the microsomal triglyceride transport protein protects the heart function during ischemia2019Inngår i: Journal of Molecular and Cellular Cardiology, ISSN 0022-2828, E-ISSN 1095-8584, Vol. 137, s. 1-8Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aims: The microsomal triglyceride transport protein (MTTP) is critical for assembly and secretion of apolipoprotein B (apoB)-containing lipoproteins and is most abundant in the liver and intestine. Surprisingly, MTTP is also expressed in the heart. Here we tested the functional relevance of cardiac MTTP expression. Materials and methods: We combined clinical studies, advanced expression analysis of human heart biopsies and analyses in genetically modified mice lacking cardiac expression of the MTTP-A isoform of MTTP. Results: Our results indicate that lower cardiac MTTP expression in humans is associated with structural and perfusion abnormalities in patients with ischemic heart disease. MTTP-A deficiency in mice heart does not affect total MTTP expression, activity or lipid concentration in the heart. Despite this, MTTP-A deficient mice displayed impaired cardiac function after a myocardial infarction. Expression analysis of MTTP indicates that MTTP expression is linked to cardiac function and responses in the heart. Conclusions: Our results indicate that MTTP may play an important role for the heart function in conjunction to ischemic events.

  • 23.
    Lee, Sunjae
    et al.
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab. Korea Adv Inst Sci & Technol, South Korea.
    Mardinoglu, Adil
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab. Chalmers, Sweden.
    Zhang, Cheng
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Lee, Doheon
    Nielsen, Jens
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab. Chalmers, Sweden.
    Dysregulated signaling hubs of liver lipid metabolism reveal hepatocellular carcinoma pathogenesis2016Inngår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 44, nr 12, s. 5529-5539Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Hepatocellular carcinoma (HCC) has a high mortality rate and early detection of HCC is crucial for the application of effective treatment strategies. HCC is typically caused by either viral hepatitis infection or by fatty liver disease. To diagnose and treat HCC it is necessary to elucidate the underlying molecular mechanisms. As a major cause for development of HCC is fatty liver disease, we here investigated anomalies in regulation of lipid metabolism in the liver. We applied a tailored network-based approach to identify signaling hubs associated with regulation of this part of metabolism. Using transcriptomics data of HCC patients, we identified significant dysregulated expressions of lipid-regulated genes, across many different lipid metabolic pathways. Our findings, however, show that viral hepatitis causes HCC by a distinct mechanism, less likely involving lipid anomalies. Based on our analysis we suggest signaling hub genes governing overall catabolic or anabolic pathways, as novel drug targets for treatment of HCC that involves lipid anomalies.

  • 24.
    Lee, Sunjae
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Zhang, Cheng
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Arif, Muhammad
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Systembiologi.
    Liu, Zhengtao
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Benfeitas, Rui
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Bidkhori, Gholamreza
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Deshmukh, Sumit
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Shobky, Mohamed AI
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Lovric, Alen
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Boren, Jan
    Nielsen, Jens
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Uhlén, Mathias
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Mardinoglu, Adil
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    TCSBN: a database of tissue and cancer specific biological networks2017Inngår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 46, nr D1, s. D595-D600Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Biological networks provide new opportunities for understanding the cellular biology in both health and disease states. We generated tissue specific integrated networks (INs) for liver, muscle and adipose tissues by integratingmetabolic, regulatory and protein-protein interaction networks. We also generated human co-expression networks (CNs) for 46 normal tissues and 17 cancers to explore the functional relationships between genes as well as their relationships with biological functions, and investigate the overlap between functional and physical interactions provided by CNs and INs, respectively. These networks can be employed in the analysis of omics data, provide detailed insight into disease mechanisms by identifying the key biological components and eventually can be used in the development of efficient treatment strategies. Moreover, comparative analysis of the networks may allow for the identification of tissue-specific targets that can be used in the development of drugs with the minimum toxic effect to other human tissues. These context-specific INs and CNs are presented in an interactive website http://inetmodels.com without any limitation.

    Fulltekst (pdf)
    fulltext
  • 25.
    Lee, Sunjae
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Zhang, Cheng
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Liu, Zhengtao
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Klevstig, Martina
    Mukhopadhyay, Bani
    Bergentall, Mattias
    Cinar, Resat
    Ståhlman, Marcus
    Sikanic, Natasa
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap.
    Park, Joshua K.
    Deshmukh, Sumit
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap.
    Harzandi, Azadeh M.
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Kuijpers, Tim
    KTH.
    Grotli, Morten
    Elsässer, Simon J.
    Piening, Brian D.
    Snyder, Michael
    Smith, Ulf
    Nielsen, Jens
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Bäckhed, Fredrik
    Kunos, George
    Uhlén, Mathias
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Boren, Jan
    Mardinoglu, Adil
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Network analyses identify liver-specific targets for treating liver diseases2017Inngår i: Molecular Systems Biology, ISSN 1744-4292, E-ISSN 1744-4292Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We performed integrative network analyses to identify targets that can be used for effectively treating liver diseases with minimal side effects. We first generated co-expression networks (CNs) for 46 human tissues and liver cancer to explore the functional relationships between genes and examined the overlap between functional and physical interactions. Since increased de novo lipogenesis is a characteristic of nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC), we investigated the liver-specific genes co-expressed with fatty acid synthase (FASN). CN analyses predicted that inhibition of these liver-specific genes decreases FASN expression. Experiments in human cancer cell lines, mouse liver samples, and primary human hepatocytes validated our predictions by demonstrating functional relationships between these liver genes, and showing that their inhibition decreases cell growth and liver fat content. In conclusion, we identified liver-specific genes linked to NAFLD pathogenesis, such as pyruvate kinase liver and red blood cell (PKLR), or to HCC pathogenesis, such as PKLR, patatin-like phospholipase domain containing 3 (PNPLA3), and proprotein convertase subtilisin/kexin type 9 (PCSK9), all of which are potential targets for drug development.

    Fulltekst (pdf)
    fulltext
  • 26.
    Liu, Z.
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab. Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China.
    Mardinoglu, A.
    KTH, Centra, Science for Life Laboratory, SciLifeLab. Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.
    Que, S.
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Letter: dose-response analysis revealed closer relationship between obesity and perioperative outcomes in patients after liver transplantation2018Inngår i: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 47, nr 2, s. 310-312Artikkel i tidsskrift (Fagfellevurdert)
  • 27.
    Liu, Zhengtao
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab. Key Laboratory of Combined Multi-Organ Transplantation Ministry of Public Health First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China.
    Que, Shuping
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Mardinoglu, Adil
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.
    Rediscussion on Linearity Between Fibrosis Stages and Mortality Risk in Nonalcoholic Fatty Liver Disease Patients2017Inngår i: Hepatology, ISSN 0270-9139, E-ISSN 1527-3350, Vol. 66, nr 4, s. 1357-1358Artikkel i tidsskrift (Fagfellevurdert)
  • 28.
    Liu, Zhengtao
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Zhang, Cheng
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Lee, Sunjae
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Kim, Woonghee
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Systembiologi.
    Klevstig, Martina
    Harzandi, Azadeh M.
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Sikanic, Natasa
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap.
    Arif, Muhammad
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Systembiologi.
    Ståhlman, Marcus
    Nielsen, Jens
    Uhlén, Mathias
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Boren, Jan
    Mardinoglu, Adil
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Pyruvate kinase L/R is a regulator of lipid metabolism and mitochondrial function2019Inngår i: Metabolic engineering, ISSN 1096-7176, E-ISSN 1096-7184Artikkel i tidsskrift (Fagfellevurdert)
  • 29.
    Lovric, Alen
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Graner, Marit
    Univ Helsinki, Heart & Lung Ctr, Div Cardiol, Cent Hosp, Helsinki, Finland.;Univ Helsinki, Helsinki, Finland..
    Bjornson, Elias
    Chalmers Univ Technol, Dept Biol & Biol Engn, Gothenburg, Sweden.;Univ Gothenburg, Wallenberg Lab, Dept Mol & Clin Med, Gothenburg, Sweden.;Sahlgrens Univ Hosp, Gothenburg, Sweden..
    Arif, Muhammad
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Benfeitas, Rui
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Nyman, Kristofer
    Univ Helsinki, Helsinki, Finland.;Univ Helsinki, HUS Med Imaging Ctr, Dept Radiol, Cent Hosp, Helsinki, Finland..
    Stahlman, Marcus
    Univ Gothenburg, Wallenberg Lab, Dept Mol & Clin Med, Gothenburg, Sweden.;Sahlgrens Univ Hosp, Gothenburg, Sweden..
    Pentikainen, Markku O.
    Univ Helsinki, Heart & Lung Ctr, Div Cardiol, Cent Hosp, Helsinki, Finland.;Univ Helsinki, Helsinki, Finland..
    Lundborn, Jesper
    Univ Helsinki, Helsinki, Finland.;Univ Helsinki, HUS Med Imaging Ctr, Dept Radiol, Cent Hosp, Helsinki, Finland..
    Hakkarainen, Antti
    Univ Helsinki, Helsinki, Finland.;Univ Helsinki, HUS Med Imaging Ctr, Dept Radiol, Cent Hosp, Helsinki, Finland..
    Siren, Reijo
    Univ Helsinki, Helsinki, Finland.;Hlth Care Ctr City Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland..
    Nieminen, Markku S.
    Univ Helsinki, Heart & Lung Ctr, Div Cardiol, Cent Hosp, Helsinki, Finland.;Univ Helsinki, Helsinki, Finland..
    Lundborns, Nina
    Univ Helsinki, Helsinki, Finland.;Univ Helsinki, HUS Med Imaging Ctr, Dept Radiol, Cent Hosp, Helsinki, Finland..
    Lauermas, Kirsi
    Univ Helsinki, Helsinki, Finland.;Univ Helsinki, HUS Med Imaging Ctr, Dept Radiol, Cent Hosp, Helsinki, Finland..
    Taskinen, Marja-Riitta
    Univ Helsinki, Heart & Lung Ctr, Div Cardiol, Cent Hosp, Helsinki, Finland.;Univ Helsinki, Helsinki, Finland..
    Mardinoglu, Adil
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Boren, Jan
    Univ Gothenburg, Wallenberg Lab, Dept Mol & Clin Med, Gothenburg, Sweden.;Sahlgrens Univ Hosp, Gothenburg, Sweden..
    Characterization of different fat depots in NAFLD using inflammation-associated proteome, lipidome and metabolome2018Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, artikkel-id 14200Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    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.

  • 30. Lundgren, Sebastian
    et al.
    Fagerström-Vahman, Helena
    Zhang, Cheng
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Ben-Dror, Liv
    Mardinoglu, Adil
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Uhlén, Mathias
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Nodin, Björn
    Jirström, Karin
    Discovery of KIRREL as a biomarker for prognostic stratification of patients within melanoma2019Inngår i: Biomarker Research, ISSN 0961-088X, E-ISSN 1475-925XArtikkel i tidsskrift (Fagfellevurdert)
    Fulltekst (pdf)
    fulltext
  • 31.
    Mahdessian, Diana
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Cellulär och klinisk proteomik.
    Sullivan, D. P.
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Cellulär och klinisk proteomik.
    Danielsson, Frida
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Cellulär och klinisk proteomik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Arif, Muhammad
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Systembiologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Zhang, Cheng
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Systembiologi.
    Åkesson, Lovisa
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Cellulär och klinisk proteomik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Gnann, Christian
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Cellulär och klinisk proteomik. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Shutten, Rutger
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH).
    Thul, Peter
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Cellulär och klinisk proteomik.
    Carja, Oana
    Department of Genetics, Stanford University, Stanford, CA 94305, USA. ; Chan Zuckerberg Biohub, San Francisco, San Francisco, CA 94158, USA..
    Ayoglu, Burcu
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Cellulär och klinisk proteomik.
    Mardinoglu, Adil
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Systembiologi. Centre for Host–Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, SE1 9RT, United Kingdom.
    Pontén, Fredrik
    Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, SE-751 85 Uppsala, Sweden.
    Uhlén, Mathias
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Systembiologi.
    Lindskog, Cecilia
    Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, SE-751 85 Uppsala, Sweden..
    Lundberg, Emma
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Cellulär och klinisk proteomik. Department of Genetics, Stanford University, Stanford, CA 94305, USA. ; Chan Zuckerberg Biohub, San Francisco, San Francisco, CA 94158, USA..
    Spatiotemporal dissection of the cell cycle regulated human proteomeManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Here we present a spatiotemporal dissection of proteome single cell heterogeneity in human cells, performed with subcellular resolution over the course of a cell cycle. We identify 17% of the human proteome to display cell-to-cell variability, of which we could attribute 25% as correlated to cell cycle progression, and present the first evidence of cell cycle association for 258 proteins. A key finding is that the variance, of many of the cell cycle associated proteins, is only partially explained by the cell cycle, which hints at cross-talk between the cell cycle and other signaling pathways. We also demonstrate that several of the identified cell cycle regulated proteins may be clinically significant in proliferative disorders. This spatially resolved proteome map of the cell cycle, integrated into the Human Protein Atlas, serves as a valuable resource to accelerate the molecular knowledge of the cell cycle and opens up novel avenues for the understanding of cell proliferation.

  • 32.
    Mardinoglu, Adil
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Bjornson, Elias
    Zhang, Cheng
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Klevstig, Martina
    Soderlund, Sanni
    Stahlman, Marcus
    Adiels, Martin
    Hakkarainen, Antti
    Lundbom, Nina
    Kilicarslan, Murat
    Hallstrom, Bjorn M.
    Lundbom, Jesper
    Verges, Bruno
    Barrett, Peter Hugh R.
    Watts, Gerald F.
    Serlie, Mireille J.
    Nielsen, Jens
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Uhlén, Mathias
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Smith, Ulf
    Marschall, Hanns-Ulrich
    Taskinen, Marja-Riitta
    Boren, Jan
    Personal model-assisted identification of NAD(+) and glutathione metabolism as intervention target in NAFLD2017Inngår i: Molecular Systems Biology, ISSN 1744-4292, E-ISSN 1744-4292, Vol. 13, nr 3, artikkel-id 916Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    To elucidate the molecular mechanisms underlying non-alcoholic fatty liver disease (NAFLD), we recruited 86 subjects with varying degrees of hepatic steatosis (HS). We obtained experimental data on lipoprotein fluxes and used these individual measurements as personalized constraints of a hepatocyte genome-scale metabolic model to investigate metabolic differences in liver, taking into account its interactions with other tissues. Our systems level analysis predicted an altered demand for NAD(+) and glutathione (GSH) in subjects with high HS. Our analysis and metabolomic measurements showed that plasma levels of glycine, serine, and associated metabolites are negatively correlated with HS, suggesting that these GSH metabolism precursors might be limiting. Quantification of the hepatic expression levels of the associated enzymes further pointed to altered de novo GSH synthesis. To assess the effect of GSH and NAD(+) repletion on the development of NAFLD, we added precursors for GSH and NAD(+) biosynthesis to the Western diet and demonstrated that supplementation prevents HS in mice. In a proof-of-concept human study, we found improved liver function and decreased HS after supplementation with serine (a precursor to glycine) and hereby propose a strategy for NAFLD treatment.

  • 33.
    Mardinoglu, Adil
    et al.
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab. Chalmers University of Technology, Sweden.
    Boren, Jan
    AUP1 (Ancient Ubiquitous Protein 1): A Molecular Link Between Hepatic Lipid Mobilization and VLDL Secretion2017Inngår i: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 37, nr 4, s. 609-610Artikkel i tidsskrift (Fagfellevurdert)
  • 34.
    Mardinoglu, Adil
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Boren, Jan
    Smith, Ulf
    Confounding Effects of Metformin on the Human Gut Microbiome in Type 2 Diabetes2016Inngår i: Cell Metabolism, ISSN 1550-4131, E-ISSN 1932-7420, Vol. 23, nr 1, s. 10-12Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    Type 2 diabetes (T2D) is associated with dysbiosis of the gut microbiota, though diabetes treatment regimens, including metformin, may confound the results. Forslund et al. (2015) identify distinct disease and drug signatures and highlight the importance of adjusting for treatment when investigating how T2D influences the human gut microbiome.

  • 35.
    Mardinoglu, Adil
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab. Chalmers Univ Technol, Dept Biol & Biol Engn, Gothenburg, Sweden..
    Boren, Jan
    Univ Gothenburg, Dept Mol & Clin Med, Gothenburg, Sweden.;Sahlgrens Univ Hosp, Gothenburg, Sweden..
    Smith, Ulf
    Univ Gothenburg, Dept Mol & Clin Med, Gothenburg, Sweden.;Sahlgrens Univ Hosp, Gothenburg, Sweden..
    Uhlén, Mathias
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Nielsen, Jens
    KTH, Centra, Science for Life Laboratory, SciLifeLab. Chalmers Univ Technol, Dept Biol & Biol Engn, Gothenburg, Sweden..
    Systems biology in hepatology: approaches and applications2018Inngår i: Nature Reviews. Gastroenterology & Hepatology, ISSN 1759-5045, E-ISSN 1759-5053, Vol. 15, nr 6, s. 365-377Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Detailed insights into the biological functions of the liver and an understanding of its crosstalk with other human tissues and the gut microbiota can be used to develop novel strategies for the prevention and treatment of liver-associated diseases, including fatty liver disease, cirrhosis, hepatocellular carcinoma and type 2 diabetes mellitus. Biological network models, including metabolic, transcriptional regulatory, protein-protein interaction, signalling and co-expression networks, can provide a scaffold for studying the biological pathways operating in the liver in connection with disease development in a systematic manner. Here, we review studies in which biological network models were used to integrate multiomics data to advance our understanding of the pathophysiological responses of complex liver diseases. We also discuss how this mechanistic approach can contribute to the discovery of potential biomarkers and novel drug targets, which might lead to the design of targeted and improved treatment strategies. Finally, we present a roadmap for the successful integration of models of the liver and other human tissues with the gut microbiota to simulate whole-body metabolic functions in health and disease.

  • 36.
    Mardinoglu, Adil
    et al.
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi.
    Bosley, Jim
    Integrated Network Modeling for Novel Target Searches and Better Predictive Models2016Inngår i: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 43, s. S88-S88Artikkel i tidsskrift (Fagfellevurdert)
  • 37.
    Mardinoglu, Adil
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Gogg, Silvia
    Lotta, Luca A.
    Stancakova, Alena
    Nerstedt, Annika
    Boren, Jan
    Blueher, Matthias
    Ferrannini, Ele
    Langenberg, Claudia
    Wareham, Nicholas J.
    Laakso, Markku
    Smith, Ulf
    Elevated Plasma Levels of 3-Hydroxyisobutyric Acid Are Associated With Incident Type 2 Diabetes2018Inngår i: EBioMedicine, E-ISSN 2352-3964, Vol. 27, s. 151-155Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    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.

  • 38.
    Mardinoglu, Adil
    et al.
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab. Chalmers University of Technology, Sweden.
    Heiker, John T.
    Gaertner, Daniel
    Bjornson, Elias
    Schoen, Michael R.
    Flehmig, Gesine
    Kloeting, Nora
    Krohn, Knut
    Fasshauer, Mathias
    Stumvoll, Michael
    Nielsen, Jens
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab. Chalmers University of Technology, Sweden.
    Blueher, Matthias
    Extensive weight loss reveals distinct gene expression changes in human subcutaneous and visceral adipose tissue2015Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, artikkel-id 14841Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Weight loss has been shown to significantly improve Adipose tissue (AT) function, however changes in AT gene expression profiles particularly in visceral AT (VAT) have not been systematically studied. Here, we tested the hypothesis that extensive weight loss in response to bariatric surgery (BS) causes AT gene expression changes, which may affect energy and lipid metabolism, inflammation and secretory function of AT. We assessed gene expression changes by whole genome expression chips in AT samples obtained from six morbidly obese individuals, who underwent a two step BS strategy with sleeve gastrectomy as initial and a Roux-en-Y gastric bypass as second step surgery after 12 +/- 2 months. Global gene expression differences in VAT and subcutaneous (S) AT were analyzed through the use of genome-scale metabolic model (GEM) for adipocytes. Significantly altered gene expressions were PCR-validated in 16 individuals, which also underwent a two-step surgery intervention. We found increased expression of cell death-inducing DFFA-like effector a (CIDEA), involved in formation of lipid droplets in both fat depots in response to significant weight loss. We observed that expression of the genes associated with metabolic reactions involved in NAD+, glutathione and branched chain amino acid metabolism are significantly increased in AT depots after surgery-induced weight loss.

  • 39.
    Mardinoglu, Adil
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Nielsen, Jens
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Editorial: The Impact of Systems Medicine on Human Health and Disease2016Inngår i: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 7, artikkel-id 552Artikkel i tidsskrift (Annet vitenskapelig)
  • 40.
    Mardinoglu, Adil
    et al.
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab. Chalmers University of Technology, Sweden.
    Shoaie, Saeed
    Bergentall, Mattias
    Ghaffari, Pouyan
    Zhang, Cheng
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Larsson, Erik
    Backhed, Fredrik
    Nielsen, Jens
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab. Chalmers University of Technology, Sweden.
    The gut microbiota modulates host amino acid and glutathione metabolism in mice2015Inngår i: Molecular Systems Biology, ISSN 1744-4292, E-ISSN 1744-4292, Vol. 11, nr 10, artikkel-id 834Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The gut microbiota has been proposed as an environmental factor that promotes the progression of metabolic diseases. Here, we investigated how the gut microbiota modulates the global metabolic differences in duodenum, jejunum, ileum, colon, liver, and two white adipose tissue depots obtained from conventionally raised (CONV-R) and germ-free (GF) mice using gene expression data and tissue-specific genome-scale metabolic models (GEMs). We created a generic mouse metabolic reaction (MMR) GEM, reconstructed 28 tissue-specific GEMs based on proteomics data, and manually curated GEMs for small intestine, colon, liver, and adipose tissues. We used these functional models to determine the global metabolic differences between CONV-R and GF mice. Based on gene expression data, we found that the gut microbiota affects the host amino acid (AA) metabolism, which leads to modifications in glutathione metabolism. To validate our predictions, we measured the level of AAs and N-acetylated AAs in the hepatic portal vein of CONV-R and GF mice. Finally, we simulated the metabolic differences between the small intestine of the CONV-R and GF mice accounting for the content of the diet and relative gene expression differences. Our analyses revealed that the gut microbiota influences host amino acid and glutathione metabolism in mice.

  • 41.
    Mardinoglu, Adil
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab. Chalmers Univ Technol, Dept Biol & Biol Engn, S-41260 Gothenburg, Sweden..
    Stancakova, Alena
    Univ Eastern Finland, Inst Clin Med, Internal Med, Kuopio 70210, Finland.;Kuopio Univ Hosp, SF-70210 Kuopio, Finland..
    Lotta, Luca A.
    Univ Cambridge, MRC, Epidemiol Unit, Cambridge CB2 0QQ, England..
    Kuusisto, Johanna
    Univ Eastern Finland, Inst Clin Med, Internal Med, Kuopio 70210, Finland.;Kuopio Univ Hosp, SF-70210 Kuopio, Finland..
    Boren, Jan
    Univ Gothenburg, Dept Mol & Clin Med, S-41345 Gothenburg, Sweden.;Sahlgrens Univ Hosp, S-41345 Gothenburg, Sweden..
    Blueher, Matthias
    Univ Leipzig, Dept Med, D-04103 Leipzig, Germany..
    Wareham, Nicholas J.
    Univ Cambridge, MRC, Epidemiol Unit, Cambridge CB2 0QQ, England..
    Ferrannini, Ele
    CNR, Inst Clin Physiol, I-56126 Pisa, Italy..
    Groop, Per Henrik
    Folkhalsan Res Ctr, Biomedicum, Folkhalsan Inst Genet, Helsinki 00290, Finland.;Univ Helsinki, Abdominal Ctr Nephrol, Helsinki 00029, Finland.;Helsinki Univ Hosp, Helsinki 00029, Finland.;Baker IDI Heart & Diabet Inst, Melbourne, Vic 3004, Australia..
    Laakso, Markku
    Univ Eastern Finland, Inst Clin Med, Internal Med, Kuopio 70210, Finland.;Kuopio Univ Hosp, SF-70210 Kuopio, Finland..
    Langenberg, Claudia
    Univ Cambridge, MRC, Epidemiol Unit, Cambridge CB2 0QQ, England..
    Smith, Ulf
    Univ Gothenburg, Dept Mol & Clin Med, S-41345 Gothenburg, Sweden.;Sahlgrens Univ Hosp, S-41345 Gothenburg, Sweden..
    Plasma Mannose Levels Are Associated with Incident Type 2 Diabetes and Cardiovascular Disease2017Inngår i: Cell Metabolism, ISSN 1550-4131, E-ISSN 1932-7420, Vol. 26, nr 2, s. 281-283Artikkel i tidsskrift (Fagfellevurdert)
  • 42.
    Mardinoglu, Adil
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Uhlen, Mathias
    Boren, Jan
    Broad Views of Non-alcoholic Fatty Liver Disease2018Inngår i: CELL SYSTEMS, ISSN 2405-4712, Vol. 6, nr 1, s. 7-9Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    Multi-omics multi-tissue data are used to interpret genome-wide association study results from mice to identify key driver genes of non-alcoholic fatty liver disease. Non-alcoholic fatty liver disease (NAFLD) is the accumulation of fat (steatosis) in the liver due to causes other than excessive alcohol consumption. The disease may progress to more severe forms of liver diseases, including non-alcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma. In this issue of Cell Systems, Krishnan et al. (2018) reveal mechanisms underlying NAFLD by generating multi-omics data using liver and adipose tissues obtained from the Hybrid Mouse Diversity Panel, consisting of 113 mouse strains with various degrees of NAFLD. The study identified key driver genes of NAFLD that can be used in the development of efficient treatment strategies and illustrates the potential utility of systematic analysis of multi-layer biological networks.

  • 43.
    Mardinoglu, Adil
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Ural, Dilek
    Koc Univ, Sch Med, TR-34450 Istanbul, Turkey..
    Zeybel, Mujdat
    Koc Univ, Sch Med, Dept Gastroenterol & Hepatol, TR-34450 Istanbul, Turkey..
    Yuksel, Hatice Hilal
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Uhlén, Mathias
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för bioteknologi (BIO), Centra, Albanova VinnExcellence Center for Protein Technology, ProNova. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap.
    Boren, Jan
    Univ Gothenburg, Dept Mol & Clin Med, S-41345 Gothenburg, Sweden.;Sahlgrenska Univ Hosp Gothenburg, S-41345 Gothenburg, Sweden..
    The Potential Use of Metabolic Cofactors in Treatment of NAFLD2019Inngår i: Nutrients, ISSN 2072-6643, E-ISSN 2072-6643, Vol. 11, nr 7, artikkel-id 1578Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Non-alcoholic fatty liver disease (NAFLD) is caused by the imbalance between lipid deposition and lipid removal from the liver, and its global prevalence continues to increase dramatically. NAFLD encompasses a spectrum of pathological conditions including simple steatosis and non-alcoholic steatohepatitis (NASH), which can progress to cirrhosis and liver cancer. Even though there is a multi-disciplinary effort for development of a treatment strategy for NAFLD, there is not an approved effective medication available. Single or combined metabolic cofactors can be supplemented to boost the metabolic processes altered in NAFLD. Here, we review the dosage and usage of metabolic cofactors including l-carnitine, Nicotinamide riboside (NR), l-serine, and N-acetyl-l-cysteine (NAC) in human clinical studies to improve the altered biological functions associated with different human diseases. We also discuss the potential use of these substances in treatment of NAFLD and other metabolic diseases including neurodegenerative and cardiovascular diseases of which pathogenesis is linked to mitochondrial dysfunction.

  • 44.
    Mardinoglu, Adil
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Wu, Hao
    Björnson, Elias
    Zhang, Cheng
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Hakkarainen, Antti
    Rasanen, Sari M.
    Lee, Sunjae
    Mancina, Rosellina M.
    Bergentall, Mattias
    Pietilainen, Kirsi H.
    Söderlund, Sanni
    Matikainen, Niina
    Stahlman, Marcus
    Bergh, Per-Olof
    Adiels, Martin
    Piening, Brian D.
    Graner, Marit
    Lundbom, Nina
    Williams, Kevin J.
    Romeo, Stefano
    Nielsen, Jens
    Snyder, Michael
    Uhlén, Mathias
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Bergström, Göran
    Perkins, Rosie
    Marschall, Hanns-Ulrich
    Backhed, Fredrik
    Taskinen, Marja-Riitta
    Boren, Jan
    An Integrated Understanding of the Rapid Metabolic Benefits of a Carbohydrate-Restricted Diet on Hepatic Steatosis in Humans2018Inngår i: Cell Metabolism, ISSN 1550-4131, E-ISSN 1932-7420, Vol. 27, nr 3, s. 559-571.e1-e5Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    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.

  • 45. Pagoni, A.
    et al.
    Marinelli, L.
    Di Stefano, A.
    Ciulla, M.
    Turkez, H.
    Mardinoglu, Adil
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Systembiologi. KTH, Centra, Science for Life Laboratory, SciLifeLab. King's College London, London, SE1 9RT, United Kingdom.
    Vassiliou, S.
    Cacciatore, I.
    Novel anti-Alzheimer phenol-lipoyl hybrids: Synthesis, physico-chemical characterization, and biological evaluation2020Inngår i: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 186, artikkel-id 111880Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    To date, drugs that hit a single target are inadequate for the treatment of neurodegenerative diseases, such as Alzheimer's or Parkinson's diseases. The development of multitarget ligands, able to interact with the different pathways involved in the progession of these disorders, represents a great challenge for medicinal chemists. In this context, we report here the synthesis and biological evaluation of phenol-lipoyl hybrids (SV1-13), obtained via a linking strategy, to take advantage of the synergistic effect due to the antioxidant portions and anti-amyloid properties of the single constituents present in the hybrid molecule. Biological results showed that SV5 and SV10 possessed the best protective activity against Aβ1-42 induced neurotoxicity in differentiated SH-SY5Y cells. SV9 and SV10 showed remarkable antioxidant properties due to their ability to counteract the damage caused by H2O2 in SHSY-5Y-treated cells. Hovewer, SV5, showing moderate antioxidant and good neuroprotective activities, resulted the best candidate for further experiments since it also resulted stable both simulated and plasma fluids.

  • 46.
    Robinson, Jonathan L.
    et al.
    Chalmers Univ Technol, Dept Biol & Biol Engn, Kemivagen 10, SE-41258 Gothenburg, Sweden.;Chalmers Univ Technol, Wallenberg Ctr Prot Res, Kemivagen 10, SE-41258 Gothenburg, Sweden..
    Kocabas, Pinar
    Chalmers Univ Technol, Dept Biol & Biol Engn, Kemivagen 10, SE-41258 Gothenburg, Sweden.;Chalmers Univ Technol, Wallenberg Ctr Prot Res, Kemivagen 10, SE-41258 Gothenburg, Sweden..
    Wang, Hao
    Chalmers Univ Technol, Dept Biol & Biol Engn, Kemivagen 10, SE-41258 Gothenburg, Sweden.;Univ Gothenburg, Wallenberg Ctr Mol & Translat Med, Kemivagen 10, SE-41258 Gothenburg, Sweden.;Chalmers Univ Technol, Sci Life Lab, Natl Bioinformat Infrastruct Sweden, Dept Biol & Biol Engn, Kemivagen 10, SE-41258 Gothenburg, Sweden..
    Cholley, Pierre-Etienne
    Chalmers Univ Technol, Sci Life Lab, Natl Bioinformat Infrastruct Sweden, Dept Biol & Biol Engn, Kemivagen 10, SE-41258 Gothenburg, Sweden..
    Cook, Daniel
    Chalmers Univ Technol, Dept Biol & Biol Engn, Kemivagen 10, SE-41258 Gothenburg, Sweden..
    Nilsson, Avlant
    Chalmers Univ Technol, Dept Biol & Biol Engn, Kemivagen 10, SE-41258 Gothenburg, Sweden..
    Anton, Mihail
    Chalmers Univ Technol, Sci Life Lab, Natl Bioinformat Infrastruct Sweden, Dept Biol & Biol Engn, Kemivagen 10, SE-41258 Gothenburg, Sweden..
    Ferreira, Raphael
    Chalmers Univ Technol, Dept Biol & Biol Engn, Kemivagen 10, SE-41258 Gothenburg, Sweden..
    Domenzain, Ivan
    Chalmers Univ Technol, Dept Biol & Biol Engn, Kemivagen 10, SE-41258 Gothenburg, Sweden.;Chalmers Univ Technol, Wallenberg Ctr Prot Res, Kemivagen 10, SE-41258 Gothenburg, Sweden..
    Billa, Virinchi
    Chalmers Univ Technol, Dept Biol & Biol Engn, Kemivagen 10, SE-41258 Gothenburg, Sweden..
    Limeta, Angelo
    Chalmers Univ Technol, Dept Biol & Biol Engn, Kemivagen 10, SE-41258 Gothenburg, Sweden..
    Hedin, Alex
    Chalmers Univ Technol, Dept Biol & Biol Engn, Kemivagen 10, SE-41258 Gothenburg, Sweden..
    Gustafsson, Johan
    Chalmers Univ Technol, Dept Biol & Biol Engn, Kemivagen 10, SE-41258 Gothenburg, Sweden.;Chalmers Univ Technol, Wallenberg Ctr Prot Res, Kemivagen 10, SE-41258 Gothenburg, Sweden..
    Kerkhoven, Eduard J.
    Chalmers Univ Technol, Dept Biol & Biol Engn, Kemivagen 10, SE-41258 Gothenburg, Sweden..
    Svensson, L. Thomas
    Chalmers Univ Technol, Sci Life Lab, Natl Bioinformat Infrastruct Sweden, Dept Biol & Biol Engn, Kemivagen 10, SE-41258 Gothenburg, Sweden..
    Palsson, Bernhard O.
    Tech Univ Denmark, Novo Nordisk Fdn, Ctr Biosustainabil, DK-2800 Lyngby, Denmark.;Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA.;Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA..
    Mardinoglu, Adil
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Systembiologi. Kings Coll London, Fac Dent Oral & Craniofacial Sci, Ctr Host Microbiome Interact, London WC2R 2LS, England..
    Hansson, Lena
    Chalmers Univ Technol, Sci Life Lab, Natl Bioinformat Infrastruct Sweden, Dept Biol & Biol Engn, Kemivagen 10, SE-41258 Gothenburg, Sweden.;Novo Nordisk Res Ctr Oxford, Oxford OX3 7FZ, England..
    Uhlén, Mathias
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Centra, Wallenberg Center for Protein Research. Tech Univ Denmark, Novo Nordisk Fdn, Ctr Biosustainabil, DK-2800 Lyngby, Denmark..
    Nielsen, Jens
    Chalmers Univ Technol, Dept Biol & Biol Engn, Kemivagen 10, SE-41258 Gothenburg, Sweden.;Chalmers Univ Technol, Wallenberg Ctr Prot Res, Kemivagen 10, SE-41258 Gothenburg, Sweden.;Tech Univ Denmark, Novo Nordisk Fdn, Ctr Biosustainabil, DK-2800 Lyngby, Denmark.;BioInnovat Inst, Ole Maaloes Vej 3, DK-2200 Copenhagen, Denmark..
    An atlas of human metabolism2020Inngår i: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145, Vol. 13, nr 624, artikkel-id eaaz1482Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    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.

  • 47.
    Rosario, Dorines
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Benfeitas, Rui
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Bidkhori, Gholamreza
    KTH, Centra, Science for Life Laboratory, SciLifeLab. Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Zhang, Cheng
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Uhlén, Mathias
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Shoaie, Saeed
    Kings Coll London, Ctr Host Microbiome Interact, Dent Inst, London, England.;Karolinska Inst, Ctr Translat Microbiome Res, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
    Mardinoglu, Adil
    KTH, Centra, Science for Life Laboratory, SciLifeLab. Chalmers Univ Technol, Dept Biol & Biol Engn, Gothenburg, Sweden..
    Understanding the Representative Gut Microbiota Dysbiosis in Metformin-Treated Type 2 Diabetes Patients Using Genome-Scale Metabolic Modeling2018Inngår i: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 9, artikkel-id 775Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Dysbiosis in the gut microbiome composition may be promoted by therapeutic drugs such as metformin, the world's most prescribed antidiabetic drug. Under metformin treatment, disturbances of the intestinal microbes lead to increased abundance of Escherichia spp., Akkermansia muciniphila, Subdoligranulum variabile and decreased abundance of Intestinibacter bartlettii. This alteration may potentially lead to adverse effects on the host metabolism, with the depletion of butyrate producer genus. However, an increased production of butyrate and propionate was verified in metformin-treated Type 2 diabetes (T2D) patients. The mechanisms underlying these nutritional alterations and their relation with gut microbiota dysbiosis remain unclear. Here, we used Genomescale Metabolic Models of the representative gut bacteria Escherichia spp., I. bartlettii, A. muciniphila, and S. variabile to elucidate their bacterial metabolism and its effect on intestinal nutrient pool, including macronutrients (e.g., amino acids and short chain fatty acids), minerals and chemical elements (e.g., iron and oxygen). We applied flux balance analysis (FBA) coupled with synthetic lethality analysis interactions to identify combinations of reactions and extracellular nutrients whose absence prevents growth. Our analyses suggest that Escherichia sp. is the bacteria least vulnerable to nutrient availability. We have also examined bacterial contribution to extracellular nutrients including short chain fatty acids, amino acids, and gasses. For instance, Escherichia sp. and S. variabile may contribute to the production of important short chain fatty acids (e.g., acetate and butyrate, respectively) involved in the host physiology under aerobic and anaerobic conditions. We have also identified pathway susceptibility to nutrient availability and reaction changes among the four bacteria using both FBA and flux variability analysis. For instance, lipopolysaccharide synthesis, nucleotide sugar metabolism, and amino acid metabolism are pathways susceptible to changes in Escherichia sp. and A. muciniphila. Our observations highlight important commensal and competing behavior, and their association with cellular metabolism for prevalent gut microbes. The results of our analysis have potential important implications for development of new therapeutic approaches in T2D patients through the development of prebiotics, probiotics, or postbiotics.

    Fulltekst (pdf)
    fulltext
  • 48.
    Sahebekhtiari, Navid
    et al.
    Univ Helsinki, Diabet & Obes Res Program, Res Programs Unit, Obes Res Unit, FIN-00014 Helsinki, Finland. araswat, Mayank; Joenvaara, Sakari; Renkonen, Risto.
    Saraswat, Mayank
    Joenvaara, Sakari
    Jokinen, Riikka
    Lovric, Alen
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Kaye, Sanna
    Mardinoglu, Adil
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Rissanen, Aila
    Kaprio, Jaakko
    Renkonen, Risto
    Pietilainen, Kirsi H.
    Plasma Proteomics Analysis Reveals Dysregulation of Complement Proteins and Inflammation in Acquired Obesity-A Study on Rare BMI-Discordant Monozygotic Twin Pairs2019Inngår i: PROTEOMICS - Clinical Applications, ISSN 1862-8346, E-ISSN 1862-8354, Vol. 13, nr 4, artikkel-id 1800173Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    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.

  • 49.
    Sayitoglu, Ece Canan
    et al.
    Nova Southeastern Univ, Dr Kiran C Patel Coll Allopath Med, Ft Lauderdale, FL 33314 USA.;Nova Southeastern Univ, NSU Cell Therapy Inst, Ft Lauderdale, FL 33314 USA..
    Georgoudaki, Anna-Maria
    Nova Southeastern Univ, Dr Kiran C Patel Coll Allopath Med, Ft Lauderdale, FL 33314 USA.;Nova Southeastern Univ, NSU Cell Therapy Inst, Ft Lauderdale, FL 33314 USA.;Karolinska Univ Hosp Huddinge, Karolinska Inst, Ctr Hematol & Regenerat Med, Stockholm, Sweden..
    Chrobok, Michael
    Karolinska Univ Hosp Huddinge, Karolinska Inst, Ctr Hematol & Regenerat Med, Stockholm, Sweden..
    Ozkazanc, Didem
    Sabanci Univ, Fac Engn & Nat Sci, Istanbul, Turkey..
    Josey, Benjamin J.
    Nova Southeastern Univ, Dr Kiran C Patel Coll Allopath Med, Ft Lauderdale, FL 33314 USA.;Nova Southeastern Univ, NSU Cell Therapy Inst, Ft Lauderdale, FL 33314 USA..
    Arif, Muhammad
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Systembiologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Kusser, Kim
    Nova Southeastern Univ, Translat Res & Econ Dev, Ft Lauderdale, FL 33314 USA..
    Hartman, Michelle
    Nova Southeastern Univ, Translat Res & Econ Dev, Ft Lauderdale, FL 33314 USA..
    Chinn, Tamara M.
    Nova Southeastern Univ, Dr Kiran C Patel Coll Osteopath Med, Ft Lauderdale, FL 33314 USA..
    Potens, Renee
    Nova Southeastern Univ, NSU Cell Therapy Inst, Ft Lauderdale, FL 33314 USA..
    Pamukcu, Cevriye
    Sabanci Univ, Fac Engn & Nat Sci, Istanbul, Turkey..
    Krueger, Robin
    Nova Southeastern Univ, Translat Res & Econ Dev, Ft Lauderdale, FL 33314 USA..
    Zhang, Cheng
    Kings Coll London, Fac Dent Oral & Craniofacial Sci, Ctr Host Microbiome Interact, London, England..
    Mardinoglu, Adil
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Systembiologi.
    Alici, Evren
    Temple, Harry Thomas
    Nova Southeastern Univ, Dr Kiran C Patel Coll Allopath Med, Dept Surg, Ft Lauderdale, FL 33314 USA..
    Sutlu, Tolga
    Bogazici Univ, Dept Mol Biol & Genet, Istanbul, Turkey..
    Duru, Adil Doganay
    Nova Southeastern Univ, Dr Kiran C Patel Coll Allopath Med, Ft Lauderdale, FL 33314 USA.;Nova Southeastern Univ, NSU Cell Therapy Inst, Ft Lauderdale, FL 33314 USA.;Karolinska Inst, Dept Med Solna, Sci Life Lab, Stockholm, Sweden..
    Boosting Natural Killer Cell-Mediated Targeting of Sarcoma Through DNAM-1 and NKG2D2020Inngår i: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 11, artikkel-id 40Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Sarcomas are malignancies of mesenchymal origin that occur in bone and soft tissues. Many are chemo- and radiotherapy resistant, thus conventional treatments fail to increase overall survival. Natural Killer (NK) cells exert anti-tumor activity upon detection of a complex array of tumor ligands, but this has not been thoroughly explored in the context of sarcoma immunotherapy. In this study, we investigated the NK cell receptor/ligand immune profile of primary human sarcoma explants. Analysis of tumors from 32 sarcoma patients identified the proliferative marker PCNA and DNAM-1 ligands CD112 and/or CD155 as commonly expressed antigens that could be efficiently targeted by genetically modified (GM) NK cells. Despite the strong expression of CD112 and CD155 on sarcoma cells, characterization of freshly dissociated sarcomas revealed a general decrease in tumor-infiltrating NK cells compared to the periphery, suggesting a defect in the endogenous NK cell response. We also applied a functional screening approach to identify relevant NK cell receptor/ligand interactions that induce efficient anti-tumor responses using a panel NK-92 cell lines GM to over-express 12 different activating receptors. Using GM NK-92 cells against primary sarcoma explants (n = 12) revealed that DNAM-1 over-expression on NK-92 cells led to efficient degranulation against all tested explants (n = 12). Additionally, NKG2D over-expression showed enhanced responses against 10 out of 12 explants. These results show that DNAM-1(+) or NKG2D(+) GM NK-92 cells may be an efficient approach in targeting sarcomas. The degranulation capacity of GM NK-92 cell lines was also tested against various established tumor cell lines, including neuroblastoma, Schwannoma, melanoma, myeloma, leukemia, prostate, pancreatic, colon, and lung cancer. Enhanced degranulation of DNAM-1(+) or NKG2D(+) GM NK-92 cells was observed against the majority of tumor cell lines tested. In conclusion, DNAM-1 or NKG2D over-expression elicited a dynamic increase in NK cell degranulation against all sarcoma explants and cancer cell lines tested, including those that failed to induce a notable response in WT NK-92 cells. These results support the broad therapeutic potential of DNAM-1(+) or NKG2D(+) GM NK-92 cells and GM human NK cells for the treatment of sarcomas and other malignancies.

  • 50. Sen, P.
    et al.
    Mardinogulu, Adil
    KTH, Centra, Science for Life Laboratory, SciLifeLab. Chalmers University of Technology, Sweden.
    Nielsen, J.
    Selection of complementary foods based on optimal nutritional values2017Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, nr 1, artikkel-id 5413Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Human milk is beneficial for growth and development of infants. Several factors result in mothers ceasing breastfeeding which leads to introduction of breast-milk substitutes (BMS). In some communities traditional foods are given as BMS, in others they are given as complementary foods during weaning. Improper food selection at this stage is associated with a high prevalence of malnutrition in children under 5 years. Here we listed the traditional foods from four continents and compared them with human milk based on their dietary contents. Vitamins such as thiamine (~[2-10] folds), riboflavin (~[4-10] folds) and ascorbic acid (<2 folds) contents of Asian and African foods were markedly lower. In order to extend the search for foods that includes similar dietary constituents as human milk, we designed a strategy of screening 8654 foods. 12 foods were identified and these foods were evaluated for their ability to meet the daily nutritional requirement of breastfed and non-breastfed infants during their first year of life. Genome-scale models of infant's hepatocytes, adipocytes and myocytes were then used to simulate in vitro growth of tissues when subjected to these foods. Key findings were that pork ham cured, fish pudding, and egg lean white induced better tissue growth, and quark with fruit, cheese quarg 45% and cheese cream 60% had similar lactose content as human milk.

12 1 - 50 of 67
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