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Espoo, Finland

Nordby P.,Copenhagen University | Prats C.,Copenhagen University | Kristensen D.,Copenhagen University | Ekroos K.,Zora Biosciences | And 6 more authors.
European Journal of Applied Physiology | Year: 2010

Human muscle is studied during glycogen depletion and repletion to understand the influence of exercise and muscle glycogen on total ceramide content. In addition, fiber-type-specific ceramide storage is investigated. Ten healthy males (26.4 ± 0.9 years, BMI 24.4 ± 0.7 kg m-2 and VO2max 57 ± 2 mL O2 min-1 kg -1) participated in the study. On the first day, one leg was glycogen-depleted (DL) by exhaustive intermittent exercise followed by low carbohydrate diet. Next day, in the overnight fasted condition, muscle biopsies were excised from vastus lateralis before and after exhaustive exercise from both DL and control leg (CL). Muscle glycogen was analyzed biochemically and total muscle ceramide content by 2D quantitative lipidomic approach. Furthermore, fiber-type ceramide content was determined by fluorescence immunohistochemistry. Basal muscle glycogen was decreased (P < 0.05) with 50 ± 6% in DL versus CL. After exhaustive exercise, muscle glycogen was similar in CL and DL 139 ± 38 and 110 ± 31 mmol kg-1, respectively. Total muscle ceramide 58 ± 1 pmol mg-1 was not influenced by glycogen or exercise. Ceramide content was consistently higher (P < 0.001) in type I than in type II muscle fibers. In conclusion, human skeletal muscle, ceramide content is higher in type I than in type II. Despite rather large changes in muscle glycogen induced by prior depletion, exercise to exhaustion and repletion, total muscle ceramide concentration remained unchanged. © Springer-Verlag 2010. Source

Zora Biosciences | Date: 2015-04-02

The present invention inter alia provides a method, and use thereof, of predicting CV complications such as AMI, ACS, stroke, and CV death by determining the concentrations of at least one ceramide of Group A and at least one ceramide of Group B in a biological sample and comparing those concentrations to a control. Finding a decreased concentration of at least one Group A ceramide and an increased concentration of at least one Group B ceramide indicates that the subject has an increased risk of developing one or more CV complications. Also provided are a newly identified subset of ceramide molecules, labelled versions thereof, and kits and compositions comprising the same for use in predicting and/or diagnosing CV complications.

Hoeks J.,Maastricht University | Mensink M.,Wageningen University | Hesselink M.K.C.,Maastricht University | Ekroos K.,Zora Biosciences | Schrauwen P.,Maastricht University
Journal of Clinical Endocrinology and Metabolism | Year: 2012

Context: Animal studies revealed that medium-chain fatty acids (MCFA), due to their metabolic characteristics, are not stored in skeletal muscle and may therefore not give rise to potentially hazardous lipid species impeding insulin signaling. Objective: We here hypothesized that infusion of medium-chain triacylglycerols (MCT) in healthy lean subjects does not lead to ectopic fat accumulation and hence does not result in lipid-induced insulin resistance. Design and Methods: Nine healthy lean male subjects underwent a 6-h hyperinsulinemic-euglycemic clamp with simultaneous infusion of 1) a 100% long-chain triacylglycerols (LCT) emulsion, 2) a 50/50% MCT/LCT emulsion, or 3) glycerol in a randomized crossover design. Muscle biopsies were taken before and after each clamp. Results: MCT/LCT infusion raised plasma free fatty acid levels to a similar level compared with LCT infusion alone. Despite elevated free fatty acid levels, intramyocellular triacylglycerol (IMTG) levels were not affected by the MCT/LCT emulsion, whereas LCT infusion resulted in an approximately 1.6-fold increase in IMTG. These differences in muscle fat accumulation did not result in significant differences in lipid-induced insulin resistance between LCT (-28%,P=0.003) and MCT/LCT (-20%, P < 0.001). Total skeletal muscle ceramide content as well as lactosyl- and glucosylceramide levels were not affected by any of the interventions. In addition, the distribution pattern of all ceramide species remained unaltered. Conclusions: Although we confirm that MCFA do not lead to ceramide and IMTG accumulation in skeletal muscle tissue in humans, they do induce insulin resistance. These results indicate that, in humans, MCFA may not be beneficial in preventing peripheral insulin resistance. Copyright © 2012 by The Endocrine Society. Source

Schweiger R.,Tel Aviv University | Kaufman S.,Tel Aviv University | Laaksonen R.,Zora Biosciences | Laaksonen R.,University of Tampere | And 8 more authors.
American Journal of Human Genetics | Year: 2016

Estimation of heritability is fundamental in genetic studies. Recently, heritability estimation using linear mixed models (LMMs) has gained popularity because these estimates can be obtained from unrelated individuals collected in genome-wide association studies. Typically, heritability estimation under LMMs uses the restricted maximum likelihood (REML) approach. Existing methods for the construction of confidence intervals and estimators of SEs for REML rely on asymptotic properties. However, these assumptions are often violated because of the bounded parameter space, statistical dependencies, and limited sample size, leading to biased estimates and inflated or deflated confidence intervals. Here, we show that the estimation of confidence intervals by state-of-the-art methods is inaccurate, especially when the true heritability is relatively low or relatively high. We further show that these inaccuracies occur in datasets including thousands of individuals. Such biases are present, for example, in estimates of heritability of gene expression in the Genotype-Tissue Expression project and of lipid profiles in the Ludwigshafen Risk and Cardiovascular Health study. We also show that often the probability that the genetic component is estimated as 0 is high even when the true heritability is bounded away from 0, emphasizing the need for accurate confidence intervals. We propose a computationally efficient method, ALBI (accurate LMM-based heritability bootstrap confidence intervals), for estimating the distribution of the heritability estimator and for constructing accurate confidence intervals. Our method can be used as an add-on to existing methods for estimating heritability and variance components, such as GCTA, FaST-LMM, GEMMA, or EMMAX. © 2016 American Society of Human Genetics. Source

Janis M.T.,Zora Biosciences | Tarasov K.,Zora Biosciences | Ta H.X.,Zora Biosciences | Suoniemi M.,Zora Biosciences | And 13 more authors.
Atherosclerosis | Year: 2013

Objectives: Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) has been proposed to be a potential new therapeutic target for treatment of hypercholesterolaemia. However, little is known about the effects of PCSK9 inhibition on the lipidome. Methods: We performed molecular lipidomic analyses of plasma samples obtained from PCSK9-deficient mice, and serum of human carriers of a loss-of-function variant in the PCSK9 gene (R46L). Results: In both mouse and man, PCSK9 deficiency caused a decrease in several cholesteryl esters (CE) and short fatty acid chain containing sphingolipid species such as CE 16:0, glucosyl/galactosylceramide (Glc/GalCer) d18:1/16:0, and lactosylceramide (LacCer) d18:1/16:0. In mice, the changes in lipid concentrations were most prominent when animals were given regular chow diet. In man, a number of molecular lipid species was shown to decrease significantly even when LDL-cholesterol was non-significantly reduced by 10% only. Western diet attenuated the lipid lowering potency of PCSK9 deficiency in mice. Conclusions: Plasma molecular lipid species may be utilized for characterizing novel compounds inhibiting PCSK9 and as sensitive efficacy markers of the PCSK9 inhibition. © 2013 Elsevier Ireland Ltd. Source

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