Browsing by Subject "lipidomics"

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  • Salminen, Liina; Braicu, Elena Ioana; Laaperi, Mitja; Jylha, Antti; Oksa, Sinikka; Hietanen, Sakari; Sehouli, Jalid; Kulbe, Hagen; du Bois, Andreas; Mahner, Sven; Harter, Philipp; Carpen, Olli; Huhtinen, Kaisa; Hynninen, Johanna; Hilvo, Mika (2021)
    Simple Summary Most ovarian cancer patients initially show a response to primary treatments, but the development of refractory disease is a major problem. Currently, there are no blood-based prognostic biomarkers, and the prognosis of a patient is determined by the International Federation of Gynecology and Obstetrics (FIGO) stage and residual disease after cytoreductive surgery. In this study, we developed and validated a novel test based on the ratio of two circulatory lipids that enables the prognostic stratification of ovarian cancer patients at the time of diagnosis, prior to any oncological treatments. The translational relevance of this test is to find those patients with poor prognosis early on, and to identify patients that are at high risk of recurrence despite complete cytoreduction. Thus, the test enables the early direction of novel targeted therapies to those ovarian cancer patients at greatest risk of recurrence and death. Epithelial ovarian cancer (EOC) generally responds well to oncological treatments, but the eventual development of a refractory disease is a major clinical problem. Presently, there are no prognostic blood-based biomarkers for the stratification of EOC patients at the time of diagnosis. We set out to assess and validate the prognostic utility of a novel two-lipid signature, as the lipidome is known to be markedly aberrant in EOC patients. The study consisted of 499 women with histologically confirmed EOC that were prospectively recruited at the university hospitals in Turku (Finland) and Charite (Berlin, Germany). Lipidomic screening by tandem liquid chromatography-mass spectrometry (LC-MS/MS) was performed for all baseline serum samples of these patients, and additionally for 20 patients of the Turku cohort at various timepoints. A two-lipid signature, based on the ratio of the ceramide Cer(d18:1/18:0) and phosphatidylcholine PC(O-38:4), showed consistent prognostic performance in all investigated study cohorts. In the Turku cohort, the unadjusted hazard ratios (HRs) per standard deviation (SD) (95% confidence interval) were 1.79 (1.40, 2.29) for overall and 1.40 (1.14, 1.71) for progression-free survival. In a Charite cohort incorporating only stage III completely resected patients, the corresponding HRs were 1.59 (1.08, 2.35) and 1.53 (1.02, 2.30). In linear-mixed models predicting progression of the disease, the two-lipid signature showed higher performance (beta per SD increase 1.99 (1.38, 2.97)) than cancer antigen 125 (CA-125, 1.78 (1.13, 2.87)). The two-lipid signature was able to identify EOC patients with an especially poor prognosis at the time of diagnosis, and also showed promise for the detection of disease relapse.
  • Yetukuri, Laxman; Soderlund, Sanni; Koivuniemi, Artturi; Seppanen-Laakso, Tuulikki; Niemela, Perttu S.; Hyvonen, Marja; Taskinen, Marja-Riitta; Vattulainen, Ilpo Tapio; Jauhiainen, Matti; Oresic, Matej (2010)
  • Lamichhane, Santosh; Ahonen, Linda; Dyrlund, Thomas Sparholt; Dickens, Alex M.; Siljander, Heli; Hyöty, Heikki; Ilonen, Jorma; Toppari, Jorma; Veijola, Riitta; Hyötyläinen, Tuulia; Knip, Mikael; Oresic, Matej (2019)
    Previous studies suggest that children who progress to type 1 diabetes (T1D) later in life already have an altered serum lipid molecular profile at birth. Here, we compared cord blood lipidome across the three study groups: children who progressed to T1D (PT1D; n = 30), children who developed at least one islet autoantibody but did not progress to T1D during the follow-up (P1Ab; n = 33), and their age-matched controls (CTR; n = 38). We found that phospholipids, specifically sphingomyelins, were lower in T1D progressors when compared to P1Ab and the CTR. Cholesterol esters remained higher in PT1D when compared to other groups. A signature comprising five lipids was predictive of the risk of progression to T1D, with an area under the receiver operating characteristic curve (AUROC) of 0.83. Our findings provide further evidence that the lipidomic profiles of newborn infants who progress to T1D later in life are different from lipidomic profiles in P1Ab and CTR.
  • Kiamehr, Mostafa; Heiskanen, Laura; Laufer, Thomas; Duesterloh, Aneta; Kahraman, Mustafa; Kakela, Reijo; Laaksonen, Reijo; Aalto-Setala, Katriina (2019)
    Aim: Primary human hepatocytes (PHHs) undergo dedifferentiation upon the two-dimensional (2D) culture, which particularly hinders their utility in long-term in vitro studies. Lipids, as a major class of biomolecules, play crucial roles in cellular energy storage, structure, and signaling. Here, for the first time, we mapped the alterations in the lipid profile of the dedifferentiating PHHs and studied the possible role of lipids in the loss of the phenotype of PHHs. Simultaneously, differentially expressed miRNAs associated with changes in the lipids and fatty acids (FAs) of the dedifferentiating PHHs were investigated. Methods: PHHs were cultured in monolayer and their phenotype was monitored morphologically, genetically, and biochemically for five days. The lipid and miRNA profile of the PHHs were analyzed by mass spectrometry and Agilent microarray, respectively. In addition, 24 key genes involved in the metabolism of lipids and FAs were investigated by qPCR. Results: The typical morphology of PHHs was lost from day 3 onward. Additionally, ALB and CYP genes were downregulated in the cultured PHHs. Lipidomics revealed a clear increase in the saturated fatty acids (SFA) and monounsaturated fatty acids (MUFA) containing lipids, but a decrease in the polyunsaturated fatty acids (PUFA) containing lipids during the dedifferentiation of PHHs. In line with this, FASN, SCD, ELOVL1, ELOVL3, and ELOVL7 were upregulated but ELOVL2 was downregulated in the dedifferentiated PHHs. Furthermore, differentially expressed miRNAs were identified, and the constantly upregulated miR-27a and miR-21, and downregulated miR-30 may have regulated the synthesis, accumulation and secretion of PHH lipids during the dedifferentiation. Conclusion: Our results showed major alterations in the molecular lipid species profiles, lipid-metabolizing enzyme expression as wells as miRNA profiles of the PHHs during their prolonged culture, which in concert could play important roles in the PHHs' loss of phenotype. These findings promote the understanding from the dedifferentiation process and could help in developing optimal culture conditions, which better meet the needs of the PHHs and support their original phenotype.
  • Braicu, Elena Ioana; Darb-Esfahani, Silvia; Schmitt, Wolfgang D.; Koistinen, Kaisa M.; Heiskanen, Laura; Pöhö, Päivi; Budczies, Jan; Kuhberg, Marc; Dietel, Manfred; Frezza, Christian; Denkert, Carsten; Sehouli, Jalid; Hilvo, Mika (2017)
    Ovarian cancer is a very severe type of disease with poor prognosis. Treatment of ovarian cancer is challenging because of the lack of tests for early detection and effective therapeutic targets. Thus, new biomarkers are needed for both diagnostics and better understanding of the cellular processes of the disease. Small molecules, consisting of metabolites or lipids, have shown emerging potential for ovarian cancer diagnostics. Here we performed comprehensive lipidomic profiling of serum and tumor tissue samples from high-grade serous ovarian cancer patients to find lipids that were altered due to cancer and also associated with progression of the disease. Ovarian cancer patients exhibited an overall reduction of most lipid classes in their serum as compared to a control group. Despite the overall reduction, there were also specific lipids showing elevation, and especially alterations in ceramide and triacylglycerol lipid species were dependent on their fatty acyl side chain composition. Several lipids showed progressive alterations in patients with more advanced disease and poorer overall survival, and outperformed CA-125 as prognostic markers. The abundance of many serum lipids correlated with their abundance in tumor tissue samples. Furthermore, we found a negative correlation of serum lipids with 3-hydroxybutyric acid, suggesting an association between decreased lipid levels and fatty acid oxidation. In conclusion, here we present a comprehensive analysis of lipid metabolism alterations in ovarian cancer patients, with clinical implications.
  • Sylvänne, Tuulia (Helsingfors universitet, 2013)
    Lipoproteins play a central role in the disease mechanisms of cardiovascular diseases (CVD) and therefore they have been studied widely. They carry several classes of apolipoproteins where apo-A1 and apo-B are the major classes. The sucrose based sequential lipoprotein isolation method can retrieve the lipoprotein fractions suitable for lipidomics analyses. The main lipoprotein classes are very low-density lipoprotein (VLDL), low-density lipoprotein (LDL) and high density lipoprotein (HDL) that can be isolated easily by their density from human blood plasma or serum. Lipidomics analyses can quantify lipids that lipoproteins carry in the circulation. Mainly they carry cholesterol and its esterified forms, glycerolipids, small amounts of sphingolipids and phospholipids form their monolayer membrane. The isolation method was set-up together with scaled-down sample volumes. The protein and lipid content of the main lipoprotein fractions were evaluated by electrophoresis analysis, various enzymatic assays and lipidomics analyses. The total protein and apolipoprotein content was found to be similar as in the literature. Apo-B was found to be the main apolipoprotein in the VLDL and the LDL fractions whereas apo-A1 was the main apolipoprotein in the HDL fractions. Triglycerides (TG) were measured by enzymatic analysis and TG was mainly found in LDL and VLDL. The lipidomics analyses demonstrated the lipid content of the lipoproteins were similar as in the literature with minor changes. The main lipid class found in all the lipoproteins was cholesteryl esters (CE) followed by phosphatidylcholines (PC) that are commonly found in cell membranes. Sphingolipids such as ceramides were also detected in lipid class level only in small quantities in the lipoprotein fractions. The low initial sample volume did not correlate linearly with higher sample volume and low sample volume is not recommended to use in this specific isolation method. Based on the results of the comprehensive screening of isolated lipoproteins the isolation method was successfully established.
  • Kuang, Alan; Erlund, Iris; Herder, Christian; Westerhuis, Johan A.; Tuomilehto, Jaakko; Cornelis, Marilyn C. (2018)
    Coffee is widely consumed and contains many bioactive compounds, any of which may impact pathways related to disease development. Our objective was to identify individual lipid changes in response to coffee drinking. We profiled the lipidome of fasting serum samples collected from a previously reported single blinded, three-stage clinical trial. Forty-seven habitual coffee consumers refrained from drinking coffee for 1 month, consumed 4 cups of coffee/day in the second month and 8 cups/day in the third month. Samples collected after each coffee stage were subject to quantitative lipidomic profiling using ion-mobility spectrometry-mass spectrometry. A total of 853 lipid species mapping to 14 lipid classes were included for univariate analysis. Three lysophosphatidylcholine (LPC) species including LPC (20:4), LPC (22:1) and LPC (22:2), significantly decreased after coffee intake (p <0.05 and q <0.05). An additional 72 species mapping to the LPC, free fatty acid, phosphatidylcholine, cholesteryl ester and triacylglycerol classes of lipids were nominally associated with coffee intake (p <0.05 and q > 0.05); 58 of these decreased after coffee intake. In conclusion, coffee intake leads to lower levels of specific LPC species with potential impacts on glycerophospholipid metabolism more generally.
  • Tigistu-Sahle, Feven (Helsingfors universitet, 2012)
    In addition to being structural components of biological membranes and energy storage of cells, lipids have recently been found to participate as essential players in cell signaling, subcellular transport mechanisms, adjusting functions of integral proteins, and regulation of cell growth and apoptosis. In this study electrospray ionization mass spectrometry (ESI-MS) techniques were used to analyze the phospholipid composition of human bone marrow derived mesenchymal stem cells (BMSC). Numerous chemically distinct lipid species were quantified and the changes in their relative amounts i.e. in the cell’s lipid profile after sequential passaging were followed until senescence (usually from passage 4 up to passage 10, in some cases until p14). Subsequently, the total lipids extracted from the cell pellets were analyzed by triple quadrupole ESI-MS equipment and using lipid-class specific scanning modes. The BMSC lines studied originated from ten donors, five of which were young and five elderly individuals. In culture, the BMSC from both young and aged donors showed time-dependent changes in their phospholipid profiles. The clearest marker findings among individual lipid species were that in phosphatidylcholines (PC) and phosphatidylethanolamines (PE), the species 38:4 (acyl chain pair 18:0/20:4n-6) largely increased towards the late passages, which was seen in the BMSC derived from both the young or aged donors. Thus the reserves of 20:4n-6, the precursor of the eicosanoids having antiproliferative, apoptotic and inflammatory cellular reactions, were increased towards late passages. At phospholipid class level, lysophosphatidylcholine (LysoPC) and phosphatidylinositol (PI) totals, and the ratio of total PI to total phosphatidylserine (PI:PS) were increased from early to latest passages. The results provide new lipid biomarkers to be used for stem cell quality control. The accumulation of polyunsaturated lipid species containing 20:4n-6 or the increase of PI: PS ratio could be potential markers for cell aging and the cells’ poor viability and functionality. The results can be used to develop efficient stem cell therapies and improve patient safety.
  • Wood, Paul; Siljander, Heli Tuija Annika; Knip, Jan Mikael (2017)
    Aim: There are currently limited lipidomics data for human umbilical cord blood. Therefore, the lipidomes of cord sera from six newborns and sera from six nonpregnant females were compared. Materials & methods: Sera lipidomics analyses were conducted using a high-resolution mass spectrometry analytical platform. Results: Cord serum contained a diverse array of glycerophospholipids, albeit generally at lower concentrations than monitored in adult serum. The unexpected observations were that cord serum contained several neurosteroid sulfates and bile acid sulfates that were not detectable in adult serum. Conclusion: Our data are the first to demonstrate that cord serum contains bile acid sulfates that are synthesized early in the hydroxylase, neutral and acidic pathways of primary bile acid biosynthesis and support previous publications of cord blood perfluoralkyl toxins in newborns. Lay abstract: Umbilical cord blood offers the potential to increase our understanding of fetal development during pregnancy and during development after delivery. Our studies of complex sterols in umbilical cord blood (bile acid sulfates) suggest that with further studies these may be useful biomarkers of abnormal fetal liver development.
  • Munsch-Alatossava, Patricia; Käkelä, Reijo; Ibarra, Dominique; Youbi-Idrissi, Mohammed; Alatossava, Tapani (2018)
    Cold storage aims to preserve the quality and safety of raw milk from farms to dairies; unfortunately, low temperatures also promote the growth of psychrotrophic bacteria, some of which produce heat-stable enzymes that cause spoilage of milk or dairy products. Previously, N-2 gas flushing of raw milk has demonstrated significant potential as a method to hinder bacterial growth at both laboratory and pilot plant scales. Using a mass spectrometry-based lipidomics approach, we examined the impact of cold storage [at 6 degrees C for up to 7 days, the control condition (C)], on the relative amounts of major phospholipids (phosphatidylethanolamine/PE, phosphatidylcholine/PC, phosphatidylserine/PS, phosphatidylinositol/PI, and sphingomyelin/SM) in three bovine raw milk samples, and compared it to the condition that received additional N-2 gas flushing (N). As expected, bacterial growth was hindered by the N-2-based treatment (over 4 log-units lower at day 7) compared to the non-treated control condition. At the end of the cold storage period, the control condition (C7) revealed higher hydrolysis of PC, SM, PE, and PS (the major species reached 27.2, 26.7, 34.6, and 9.9 mu M, respectively), compared to the N-2-flushed samples (N7) (the major species reached 55.6, 35.9, 54.0, and 18.8 mu M, respectively). C7 samples also exhibited a three-fold higher phosphatidic acid (PA) content (6.8 mu M) and a five-fold higher content (17.3 mu M) of lysophospholipids (LPE, LPC, LPS, and LPI) whereas both lysophospholipids and PA remained at their initial levels for 7 days in N7 samples. Taking into consideration the significant phospholipid losses in the controls, the lipid profiling results together with the microbiological data suggest a major role of phospholipase (PLase) C (PLC) in phospholipolysis during cold storage. However, the experimental data also indicate that bacterial sphingomyelinase C, together with PLases PLD and PLA contributed to the degradation of phospholipids present in raw milk as well, and potential contributions from PLB activity cannot be excluded. Altogether, this lipidomics study highlights the beneficial effects of N-2 flushing treatment on the quality and safety of raw milk through its ability to effectively hinder phospholipolysis during cold storage.
  • Ruuth, Maija; Äikäs, Lauri; Tigistu-Sahle, Feven; Käkelä, Reijo; Lindholm, Harri; Simonen, Piia; Kovanen, Petri T.; Gylling, Helena; Öörni, Katariina (2020)
    OBJECTIVE: Plant stanol ester supplementation (2-3 g plant stanols/d) reduces plasma LDL (low-density lipoprotein) cholesterol concentration by 9% to 12% and is, therefore, recommended as part of prevention and treatment of atherosclerotic cardiovascular disease. In addition to plasma LDL-cholesterol concentration, also qualitative properties of LDL particles can influence atherogenesis. However, the effect of plant stanol ester consumption on the proatherogenic properties of LDL has not been studied. APPROACH AND RESULTS: Study subjects (n=90) were randomized to consume either a plant stanol ester-enriched spread (3.0 g plant stanols/d) or the same spread without added plant stanol esters for 6 months. Blood samples were taken at baseline and after the intervention. The aggregation susceptibility of LDL particles was analyzed by inducing aggregation of isolated LDL and following aggregate formation. LDL lipidome was determined by mass spectrometry. Binding of serum lipoproteins to proteoglycans was measured using a microtiter well-based assay. LDL aggregation susceptibility was decreased in the plant stanol ester group, and the median aggregate size after incubation for 2 hours decreased from 1490 to 620 nm,P=0.001. Plant stanol ester-induced decrease in LDL aggregation was more extensive in participants having body mass index CONCLUSIONS: Consumption of plant stanol esters decreases the aggregation susceptibility of LDL particles by modifying LDL lipidome. The resulting improvement of LDL quality may be beneficial for cardiovascular health. REGISTRATION: URL: Unique identifier: NCT01315964. GRAPHIC ABSTRACT: A graphic abstract is available for this article.
  • Ruhanen, Hanna; Perttila, Julia; Holtta-Vuori, Maarit; Zhou, You; Yki-Jarvinen, Hannele; Ikonen, Elina; Kakela, Reijo; Olkkonen, Vesa M. (2014)
  • Avela, Henri (Helsingin yliopisto, 2019)
    Lipidomics is a quickly growing trend in metabolomics research: not only seen as passive cell membrane building blocks, lipids contribute actively to cell signaling and identification, thus seen as potential biomarkers (e.g. for early stage cancer diagnostics). The literature part includes a review of 63 articles on UHPLC/MS-methods in the time frame of 2017-05/2019. The following literature is focused especially on glycerophospholipids (GPs). In addition, an overview to basic glycerolipids (GLs) and sphingolipids (SPs) is established, which evidently affects the emphasis and narration of lipid class representations in this review. Chromatographic methods in lipidomics are used to achieve either very selective or all-encompassing analyses for lipid classes. Since HPLC/MS is an insufficient method for fully encompassing low-abundance lipids, UHPLC/MS was mostly used for metabolic profiling where its large analyte range due to high sensitivity, separation efficiency and resolution excels in performance compared to other methods. Imaging techniques have further diverted towards DIMS and other novel non-chromatographic methods, e.g. Raman techniques with single cell resolution. The field of mass-spectral lipidomics is divided between studies using isotope-labeled standards or fully standardless algorithm-based analyses, furthermore, machine learning and statistical analysis has increased. The experimental part focused on LC-IMS-MS and plasma-based in-house database method development for targeted analysis of ascites. Method development included optimization of the chromatography, adduct species selection and data-independent/-dependent fragmentation. Totally, 130 potential species from the LIPID MAPS database were used for the identification at the minimum score of 79% for identification in the Qualitative Workflows with retention times (RTs) and Mass Profiler-program with collision cross-sections (CCSs). Plasma sample analyses resulted in the documentation of 70 RTs and 36 CCS values. Two lipid extraction methods (Folch and BUME) with pre-sampling surrogates and post-sampling internal standards were compared with each other. The process resulted in confirming the BUME method in lipidomics to be superior in ecology-, workload-, health- and extraction-related properties. The lipidome of ascites has rarely been studied due to its availability only in diseased patients. Also, limiting factors for these studies are the logistics to realise such a representative analysis.
  • Ján, Labuda; Richard P., Bowater; Miroslav, Fojta; Günter, Gauglitz; Zdeněk, Glatz; Ivan, Hapala; Jan, Havliš; Ferenc, Kilar; Aniko, Kilar; Lenka, Malinovská; Siren, Heli Marja Marita; Petr, Skládal; Federico, Torta; Martin, Valachovič; Michaela, Wimmerová; Zbyněk, Zdráhal; David Brynn, Hibbert (2018)
    Recommendations are given concerning the terminology of methods of bioanalytical chemistry. With respect to dynamic development particularly in the analysis and investigation of biomacromolecules, terms related to bioanalytical samples, enzymatic methods, immunoanalytical methods, methods used in genomics and nucleic acid analysis, proteomics, metabolomics, glycomics, lipidomics, and biomolecules interaction studies are introduced.
  • Velagapudi, Vidya R.; Hezaveh, Rahil; Reigstad, Christopher S.; Gopalacharyulu, Peddinti; Yetukuri, Laxman; Islam, Sama; Felin, Jenny; Perkins, Rosie; Boren, Jan; Oresic, Matej; Backhed, Fredrik (2010)
  • Qadri, Sami; Lallukka-Brück, Susanna; Luukkonen, Panu K.; Zhou, You; Gastaldelli, Amalia; Orho-Melander, Marju; Sammalkorpi, Henna; Juuti, Anne; Penttilä, Anne K.; Perttilä, Julia; Hakkarainen, Antti; Lehtimäki, Tiina E.; Oresic, Matej; Hyötyläinen, Tuulia; Hodson, Leanne; Olkkonen, Vesa M.; Yki-Järvinen, Hannele (2020)
    Background & Aims The I148M variant in PNPLA3 is the major genetic risk factor for non-alcoholic fatty liver disease (NAFLD). The liver is enriched with polyunsaturated triglycerides (PUFA-TGs) in PNPLA3-I148M carriers. Gene expression data indicate that PNPLA3 is liver-specific in humans, but whether it functions in adipose tissue (AT) is unknown. We investigated whether PNPLA3-I148M modifies AT metabolism in human NAFLD. Methods Profiling of the AT lipidome and fasting serum non-esterified fatty acid (NEFA) composition was conducted in 125 volunteers (PNPLA3(148MM/MI), n = 63; PNPLA3(148II), n = 62). AT fatty acid composition was determined in 50 volunteers homozygous for the variant (PNPLA3(148MM), n = 25) or lacking the variant (PNPLA3(148II), n = 25). Whole-body insulin sensitivity of lipolysis was determined using [H-2(5)]glycerol, and PNPLA3 mRNA and protein levels were measured in subcutaneous AT and liver biopsies in a subset of the volunteers. Results PUFA-TGs were significantly increased in AT in carriers versus non-carriers of PNPLA3-I148M. The variant did not alter the rate of lipolysis or the composition of fasting serum NEFAs. PNPLA3 mRNA was 33-fold higher in the liver than in AT (P <.0001). In contrast, PNPLA3 protein levels per tissue protein were three-fold higher in AT than the liver (P <.0001) and nine-fold higher when related to whole-body AT and liver tissue masses (P <.0001). Conclusions Contrary to previous assumptions, PNPLA3 is highly abundant in AT. PNPLA3-I148M locally remodels AT TGs to become polyunsaturated as it does in the liver, without affecting lipolysis or composition of serum NEFAs. Changes in AT metabolism do not contribute to NAFLD in PNPLA3-I148M carriers.