Type 2 diabetes (T2D) and cardiovascular disease (CVD) represent significant disease burdens for most societies and susceptibility to these diseases is strongly influenced by diet and lifestyle. ...Physiological changes associated with T2D or CVD, such has high blood pressure and cholesterol and glucose levels in the blood, are often apparent prior to disease incidence. Here we integrated genetics, lipidomics, and standard clinical diagnostics to assess future T2D and CVD risk for 4,067 participants from a large prospective population-based cohort, the Malmö Diet and Cancer-Cardiovascular Cohort. By training Ridge regression-based machine learning models on the measurements obtained at baseline when the individuals were healthy, we computed several risk scores for T2D and CVD incidence during up to 23 years of follow-up. We used these scores to stratify the participants into risk groups and found that a lipidomics risk score based on the quantification of 184 plasma lipid concentrations resulted in a 168% and 84% increase of the incidence rate in the highest risk group and a 77% and 53% decrease of the incidence rate in lowest risk group for T2D and CVD, respectively, compared to the average case rates of 13.8% and 22.0%. Notably, lipidomic risk correlated only marginally with polygenic risk, indicating that the lipidome and genetic variants may constitute largely independent risk factors for T2D and CVD. Risk stratification was further improved by adding standard clinical variables to the model, resulting in a case rate of 51.0% and 53.3% in the highest risk group for T2D and CVD, respectively. The participants in the highest risk group showed significantly altered lipidome compositions affecting 167 and 157 lipid species for T2D and CVD, respectively. Our results demonstrated that a subset of individuals at high risk for developing T2D or CVD can be identified years before disease incidence. The lipidomic risk, which is derived from only one single mass spectrometric measurement that is cheap and fast, is informative and could extend traditional risk assessment based on clinical assays.
Abstract
The human plasma lipidome captures risk for cardiometabolic diseases. To discover new lipid-associated variants and understand the link between lipid species and cardiometabolic disorders, ...we perform univariate and multivariate genome-wide analyses of 179 lipid species in 7174 Finnish individuals. We fine-map the associated loci, prioritize genes, and examine their disease links in 377,277 FinnGen participants. We identify 495 genome-trait associations in 56 genetic loci including 8 novel loci, with a considerable boost provided by the multivariate analysis. For 26 loci, fine-mapping identifies variants with a high causal probability, including 14 coding variants indicating likely causal genes. A phenome-wide analysis across 953 disease endpoints reveals disease associations for 40 lipid loci. For 11 coronary artery disease risk variants, we detect strong associations with lipid species. Our study demonstrates the power of multivariate genetic analysis in correlated lipidomics data and reveals genetic links between diseases and lipid species beyond the standard lipids.
Lipidomics has become an indispensable method for the quantitative assessment of lipid metabolism in basic, clinical, and pharmaceutical research. It allows for the generation of information-dense ...datasets in a large variety of experimental setups and model organisms. Previous studies, mostly conducted in mice (Mus musculus), have shown a remarkable specificity of the lipid compositions of different cell types, tissues, and organs. However, a systematic analysis of the overall variation of the mouse lipidome is lacking. To fill this gap, in the present study, the effect of diet, sex, and genotype on the lipidomes of mouse tissues, organs, and bodily fluids has been investigated. Baseline quantitative lipidomes consisting of 796 individual lipid molecules belonging to 24 lipid classes are provided for 10 different sample types. Furthermore, the susceptibility of lipidomes to the tested parameters is assessed, providing insights into the organ-specific lipidomic plasticity and flexibility. This dataset provides a valuable resource for basic and pharmaceutical researchers working with murine models and complements existing proteomic and transcriptomic datasets. It will inform experimental design and facilitate interpretation of lipidomic datasets.
Blood plasma has gained protagonism in lipidomics studies due to its availability, uncomplicated collection and preparation, and informative readout of physiological status. At the same time, it is ...also technically challenging to analyze due to its complex lipid composition affected by many factors, which can hamper the throughput and/or lipidomics coverage. To tackle these issues, we developed a comprehensive, high throughput, and quantitative mass spectrometry‐based shotgun lipidomics platform for blood plasma lipid analyses. The main hallmarks of this technology are (i) it is comprehensive, covering 22 quantifiable different lipid classes encompassing more than 200 lipid species; (ii) it is amenable to high‐throughput, with less than 5 min acquisition time allowing the complete analysis of 200 plasma samples per day; (iii) it achieves absolute quantification, by inclusion of internal standards for every lipid class measured; (iv) it is highly reproducible, achieving an average coefficient of variation of <10% (intra‐day), approx. 10% (inter‐day), and approx. 15% (inter‐site) for most lipid species; (v) it is easily transferable allowing the direct comparison of data acquired in different sites. Moreover, we thoroughly assessed the influence of blood stabilization with different anticoagulants and freeze‐thaw cycles to exclude artifacts generated by sample preparation. Practical applications: This shotgun lipidomics platform can be implemented in different laboratories without compromising reproducibility, allowing multi‐site studies and inter‐laboratory comparisons. This possibility combined with the high‐throughput, broad lipidomic coverage and absolute quantification are important aspects for clinical applications and biomarker research. This MS‐based automated shotgun lipidomics platform for comprehensive analysis of the blood plasma lipidome (covering 22 lipid classes) achieves high inter‐day and inter‐site reproducibility and accuracy and enables unprecedented large scale lipidomics studies.
Membrane lipidome of an epithelial cell line Sampaio, Julio L; Gerl, Mathias J; Klose, Christian ...
Proceedings of the National Academy of Sciences - PNAS,
02/2011, Letnik:
108, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Tissue differentiation is an important process that involves major cellular membrane remodeling. We used Madin-Darby canine kidney cells as a model for epithelium formation and investigated the ...remodeling of the total cell membrane lipidome during the transition from a nonpolarized morphology to an epithelial morphology and vice versa. To achieve this, we developed a shotgun-based lipidomics workflow that enabled the absolute quantification of mammalian membrane lipidomes with minimal sample processing from low sample amounts. Epithelial morphogenesis was accompanied by a major shift from sphingomyelin to glycosphingolipid, together with an increase in plasmalogen, phosphatidylethanolamine, and cholesterol content, whereas the opposite changes took place during an epithelial-to-mesenchymal transition. Moreover, during polarization, the sphingolipids became longer, more saturated, and more hydroxylated as required to generate an apical membrane domain that serves as a protective barrier for the epithelial sheet.
Platinum and platinum-based alloys are used as the electrode material in cochlear implants because of the biocompatibility and the favorable electrochemical properties. Still, these implants can fail ...over time. The present study was conducted to shed light on the effects of microstructure on the electrochemical degradation of platinum. After three days of stimulation with a square wave signal, corrosive attack appeared on the platinum surface. The influence of mechanical deformation, in particular rolling, on the corrosion resistance of platinum was also prominent. The cyclic voltammetry showed a clear dependence on the electrolyte used, which was interpreted as an influence of the buffer in the artificial perilymph used. In addition, the polarization curves showed a shift with grain size that was not expected. This could be attributed to the defects present on the surface. These findings are crucial for the manufacture of cochlear implants to ensure their long-term functionality.
Mass spectrometry-based shotgun lipidomics has enabled the quantitative and comprehensive assessment of cellular lipid compositions. The yeast Saccharomyces cerevisiae has proven to be a particularly ...valuable experimental system for studying lipid-related cellular processes. Here, by applying our shotgun lipidomics platform, we investigated the influence of a variety of commonly used growth conditions on the yeast lipidome, including glycerophospholipids, triglycerides, ergosterol as well as complex sphingolipids. This extensive dataset allowed for a quantitative description of the intrinsic flexibility of a eukaryotic lipidome, thereby providing new insights into the adjustments of lipid biosynthetic pathways. In addition, we established a baseline for future lipidomic experiments in yeast. Finally, flexibility of lipidomic features is proposed as a new parameter for the description of the physiological state of an organism.
The plasma membrane (PM) is composed of a complex lipid mixture that forms heterogeneous membrane environments. Yet, how small-scale lipid organization controls physiological events at the PM remains ...largely unknown. Here, we show that ORP-related Osh lipid exchange proteins are critical for the synthesis of phosphatidylinositol (4,5)-bisphosphate PI(4,5)P2, a key regulator of dynamic events at the PM. In real-time assays, we find that unsaturated phosphatidylserine (PS) and sterols, both Osh protein ligands, synergistically stimulate phosphatidylinositol 4-phosphate 5-kinase (PIP5K) activity. Biophysical FRET analyses suggest an unconventional co-distribution of unsaturated PS and phosphatidylinositol 4-phosphate (PI4P) species in sterol-containing membrane bilayers. Moreover, using in vivo imaging approaches and molecular dynamics simulations, we show that Osh protein-mediated unsaturated PI4P and PS membrane lipid organization is sensed by the PIP5K specificity loop. Thus, ORP family members create a nanoscale membrane lipid environment that drives PIP5K activity and PI(4,5)P2 synthesis that ultimately controls global PM organization and dynamics.
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•The Osh lipid exchange proteins are required to maintain PI(4,5)P2 levels in the PM•Unsaturated PS and sterols synergistically stimulate PIP5K activity•The specificity loop conserved in PIP5Ks serves as a lipid sensor•A simulation model of the PIP5K specificity loop embedded in a lipid bilayer
Nishimura et al. show that the Osh lipid exchange proteins are required for PI(4,5)P2 synthesis, a key regulator of global plasma membrane organization and function. The Osh proteins form a unique membrane lipid environment with unsaturated phosphatidylserine and sterols that specifies PIP 5-kinase activity at the plasma membrane.
Two and a half years prior to China’s M7.9 Wenchuan earthquake of May 2008, at least 300 million metric tons of water accumulated with additional seasonal water level changes in the Minjiang River ...Valley at the eastern margin of the Longmen Shan. This article shows that static surface loading in the Zipingpu water reservoir induced Coulomb failure stresses on the nearby Beichuan thrust fault system at <17 km depth. Triggering stresses exceeded levels of daily lunar and solar tides and perturbed a fault area measuring 416 ± 96 km2. These stress perturbations, in turn, likely advanced the clock of the mainshock and directed the initial rupture propagation upward towards the reservoir on the "Coulomb-like" Beichuan fault with rate- and state-dependent frictional behavior. Static triggering perturbations produced up to 60 years (0.6%) of equivalent tectonic loading, and show strong correlations to the coseismic slip. Moreover, correlations between clock advancement and coseismic slip, observed during the mainshock beneath the reservoir, are strongest for a longer seismic cycle (10kyr) of M > 7 earthquakes. Finally, the daily event rate of the micro-seismicity (M ≥ 0.5) correlates well with the static stress perturbations, indicating destabilization.
Obesity is associated with changes in the plasma lipids. Although simple lipid quantification is routinely used, plasma lipids are rarely investigated at the level of individual molecules. We aimed ...at predicting different measures of obesity based on the plasma lipidome in a large population cohort using advanced machine learning modeling. A total of 1,061 participants of the FINRISK 2012 population cohort were randomly chosen, and the levels of 183 plasma lipid species were measured in a novel mass spectrometric shotgun approach. Multiple machine intelligence models were trained to predict obesity estimates, i.e., body mass index (BMI), waist circumference (WC), waist-hip ratio (WHR), and body fat percentage (BFP), and validated in 250 randomly chosen participants of the Malmö Diet and Cancer Cardiovascular Cohort (MDC-CC). Comparison of the different models revealed that the lipidome predicted BFP the best (R2 = 0.73), based on a Lasso model. In this model, the strongest positive and the strongest negative predictor were sphingomyelin molecules, which differ by only 1 double bond, implying the involvement of an unknown desaturase in obesity-related aberrations of lipid metabolism. Moreover, we used this regression to probe the clinically relevant information contained in the plasma lipidome and found that the plasma lipidome also contains information about body fat distribution, because WHR (R2 = 0.65) was predicted more accurately than BMI (R2 = 0.47). These modeling results required full resolution of the lipidome to lipid species level, and the predicting set of biomarkers had to be sufficiently large. The power of the lipidomics association was demonstrated by the finding that the addition of routine clinical laboratory variables, e.g., high-density lipoprotein (HDL)- or low-density lipoprotein (LDL)- cholesterol did not improve the model further. Correlation analyses of the individual lipid species, controlled for age and separated by sex, underscores the multiparametric and lipid species-specific nature of the correlation with the BFP. Lipidomic measurements in combination with machine intelligence modeling contain rich information about body fat amount and distribution beyond traditional clinical assays.
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