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Arthritis Research & Therapy Dec 2023Currently, it is not possible to predict whether patients with hyperuricemia (HUA) will develop gout and how this progression may be affected by urate-lowering treatment...
BACKGROUND
Currently, it is not possible to predict whether patients with hyperuricemia (HUA) will develop gout and how this progression may be affected by urate-lowering treatment (ULT). Our study aimed to evaluate differences in plasma lipidome between patients with asymptomatic HUA detected ≤ 40 years (HUA ≤ 40) and > 40 years, gout patients with disease onset ≤ 40 years (Gout ≤ 40) and > 40 years, and normouricemic healthy controls (HC).
METHODS
Plasma samples were collected from 94 asymptomatic HUA (77% HUA ≤ 40) subjects, 196 gout patients (59% Gout ≤ 40), and 53 HC. A comprehensive targeted lipidomic analysis was performed to semi-quantify 608 lipids in plasma. Univariate and multivariate statistics and advanced visualizations were applied.
RESULTS
Both HUA and gout patients showed alterations in lipid profiles with the most significant upregulation of phosphatidylethanolamines and downregulation of lysophosphatidylcholine plasmalogens/plasmanyls. More profound changes were observed in HUA ≤ 40 and Gout ≤ 40 without ULT. Multivariate statistics differentiated HUA ≤ 40 and Gout ≤ 40 groups from HC with an overall accuracy of > 95%.
CONCLUSION
Alterations in the lipidome of HUA and Gout patients show a significant impact on lipid metabolism. The most significant glycerophospholipid dysregulation was found in HUA ≤ 40 and Gout ≤ 40 patients, together with a correction of this imbalance with ULT.
Topics: Humans; Hyperuricemia; Uric Acid; Lipidomics; Gout; Gout Suppressants
PubMed: 38042879
DOI: 10.1186/s13075-023-03204-6 -
Scientific Reports Aug 2023While TIA patients have transient symptoms, they should not be underestimated, as they could have an underlying pathology that may lead to a subsequent stroke: stroke...
While TIA patients have transient symptoms, they should not be underestimated, as they could have an underlying pathology that may lead to a subsequent stroke: stroke recurrence (SR). Previously, it has been described the involvement of lipids in different vascular diseases. The aim of the current study was to perform a lipidomic analysis to identify differences in the lipidomic profile between patients with SR and patients without. Untargeted lipidomic analysis was performed in plasma samples of 460 consecutive TIA patients recruited < 24 h after the onset of symptoms. 37 (8%) patients suffered SR at 90 days. Lipidomic profiling disclosed 7 lipid species differentially expressed between groups: 5 triacylglycerides (TG), 1 diacylglyceride (DG), and 1 alkenyl-PE (plasmalogen) [specifically, TG(56:1), TG(63:0), TG(58:2), TG(50:5), TG(53:7, DG(38:5)) and PE(P-18:0/18:2)]. 6 of these 7 lipid species belonged to the glycerolipid family and a plasmalogen, pointing to bioenergetics pathways, as well as oxidative stress response. In this context, it was proposed the PE(P-18:0/18:2) as potential biomarker of SR condition.The observed changes in lipid patterns suggest pathophysiological mechanisms associated with lipid droplets metabolism and antioxidant protection that is translated to plasma level as consequence of a more intensive or high-risk ischemic condition related to SR.
Topics: Humans; Male; Female; Middle Aged; Aged; Aged, 80 and over; Stroke; Recurrence; Follow-Up Studies; Lipids; Lipidomics
PubMed: 37607967
DOI: 10.1038/s41598-023-40838-7 -
Aging Cell Aug 2023"Lipid raft aging" in nerve cells represents an early event in the development of aging-related neurodegenerative diseases, such as Alzheimer's disease. Lipid rafts are...
"Lipid raft aging" in nerve cells represents an early event in the development of aging-related neurodegenerative diseases, such as Alzheimer's disease. Lipid rafts are key elements in synaptic plasticity, and their modification with aging alters interactions and distribution of signaling molecules, such as glutamate receptors and ion channels involved in memory formation, eventually leading to cognitive decline. In the present study, we have analyzed, in vivo, the effects of dietary supplementation of n-3 LCPUFA on the lipid structure, membrane microviscosity, domain organization, and partitioning of ionotropic and metabotropic glutamate receptors in hippocampal lipid raffs in female mice. The results revealed several lipid signatures of "lipid rafts aging" in old mice fed control diets, consisting in depletion of n-3 LCPUFA, membrane unsaturation, along with increased levels of saturates, plasmalogens, and sterol esters, as well as altered lipid relevant indexes. These changes were paralleled by increased microviscosity and changes in the raft/non-raft (R/NR) distribution of AMPA-R and mGluR5. Administration of the n-3 LCPUFA diet caused the partial reversion of fatty acid alterations found in aged mice and returned membrane microviscosity to values found in young animals. Paralleling these findings, lipid rafts accumulated mGluR5, NMDA-R, and ASIC2, and increased their R/NR proportions, which collectively indicate changes in synaptic plasticity. Unexpectedly, this diet also modified the lipidome and dimension of lipid rafts, as well as the domain redistribution of glutamate receptors and acid-sensing ion channels involved in hippocampal synaptic plasticity, likely modulating functionality of lipid rafts in memory formation and reluctance to age-associated cognitive decline.
Topics: Female; Mice; Animals; Fatty Acids; Fatty Acids, Unsaturated; Hippocampus; Membrane Microdomains; Diet
PubMed: 37254617
DOI: 10.1111/acel.13867 -
Med (New York, N.Y.) Mar 2024A healthy lifestyle is associated with a lower premature mortality risk and with longer life expectancy. However, the metabolic pathways of a healthy lifestyle and how...
BACKGROUND
A healthy lifestyle is associated with a lower premature mortality risk and with longer life expectancy. However, the metabolic pathways of a healthy lifestyle and how they relate to mortality and longevity are unclear. We aimed to identify and replicate a healthy lifestyle metabolomic signature and examine how it is related to total and cause-specific mortality risk and longevity.
METHODS
In four large cohorts with 13,056 individuals and 28-year follow-up, we assessed five healthy lifestyle factors, used liquid chromatography mass spectrometry to profile plasma metabolites, and ascertained deaths with death certificates. The unique healthy lifestyle metabolomic signature was identified using an elastic regression. Multivariable Cox regressions were used to assess associations of the signature with mortality and longevity.
FINDINGS
The identified healthy lifestyle metabolomic signature was reflective of lipid metabolism pathways. Shorter and more saturated triacylglycerol and diacylglycerol metabolite sets were inversely associated with the healthy lifestyle score, whereas cholesteryl ester and phosphatidylcholine plasmalogen sets were positively associated. Participants with a higher healthy lifestyle metabolomic signature had a 17% lower risk of all-cause mortality, 19% for cardiovascular disease mortality, and 17% for cancer mortality and were 25% more likely to reach longevity. The healthy lifestyle metabolomic signature explained 38% of the association between the self-reported healthy lifestyle score and total mortality risk and 49% of the association with longevity.
CONCLUSIONS
This study identifies a metabolomic signature that measures adherence to a healthy lifestyle and shows prediction of total and cause-specific mortality and longevity.
FUNDING
This work was funded by the NIH, CIHR, AHA, Novo Nordisk Foundation, and SciLifeLab.
Topics: Humans; Longevity; Prospective Studies; Risk Factors; Cohort Studies; Healthy Lifestyle
PubMed: 38366602
DOI: 10.1016/j.medj.2024.01.010 -
Metabolomics : Official Journal of the... Dec 2023Regular physical activity and dietary variety are modifiable and influential factors of health outcomes. However, the cumulative effects of these behaviors are not well... (Randomized Controlled Trial)
Randomized Controlled Trial
A lipidomic and metabolomic signature of a very low-carbohydrate high-fat diet and high-intensity interval training: an additional analysis of a randomized controlled clinical trial.
INTRODUCTION
Regular physical activity and dietary variety are modifiable and influential factors of health outcomes. However, the cumulative effects of these behaviors are not well understood. Metabolomics may have a promising research potential to extend our knowledge and use it in the attempts to find a long-term and sustainable personalized approach in exercise and diet recommendations.
OBJECTIVE
The main aim was to investigate the effect of the 12 week very low carbohydrate high fat (VLCHF) diet and high-intensity interval training (HIIT) on lipidomic and metabolomic profiles in individuals with overweight and obesity.
METHODS
The participants (N = 91) were randomly allocated to HIIT (N = 22), VLCHF (N = 25), VLCHF + HIIT (N = 25) or control (N = 19) groups for 12 weeks. Fasting plasma samples were collected before the intervention and after 4, 8 and 12 weeks. The samples were then subjected to untargeted lipidomic and metabolomic analyses using reversed phase ultra-high-performance liquid chromatography coupled to high-resolution mass spectrometry.
RESULTS
The VLCHF diet affected plasma lipids considerably while the effect of HIIT was unremarkable. Already after 4 weeks of intervention substantial changes of plasma lipids were found in both VLCHF diet groups. The changes persisted throughout the entire 12 weeks of the VLCHF diet. Specifically, acyl carnitines, plasmalogens, fatty acyl esters of hydroxy fatty acid, sphingomyelin, ceramides, cholesterol esters, fatty acids and 4-hydroxybutyric were identified as lipid families that increased in the VLCHF diet groups whereas lipid families of triglycerides and glycerophospholipids decreased. Additionally, metabolomic analysis showed a decrease of theobromine.
CONCLUSIONS
This study deciphers the specific responses to a VLCHF diet, HIIT and their combination by analysing untargeted lipidomic and metabolomic profile. VLCHF diet caused divergent changes of plasma lipids and other metabolites when compared to the exercise and control group which may contribute to a better understanding of metabolic changes and the appraisal of VLCHF diet benefits and harms.
CLINICAL TRIAL REGISTRY NUMBER
NCT03934476, registered 1st May 2019 https://clinicaltrials.gov/ct2/show/NCT03934476?term=NCT03934476&draw=2&rank=1 .
Topics: Humans; Lipidomics; Diet, High-Fat; High-Intensity Interval Training; Metabolomics; Triglycerides; Carbohydrates
PubMed: 38141101
DOI: 10.1007/s11306-023-02071-1 -
Cardiovascular Diabetology Jan 2024Legume consumption has been linked to a reduced risk of type 2 diabetes (T2D) and cardiovascular disease (CVD), while the potential association between plasma...
BACKGROUND
Legume consumption has been linked to a reduced risk of type 2 diabetes (T2D) and cardiovascular disease (CVD), while the potential association between plasma metabolites associated with legume consumption and the risk of cardiometabolic diseases has never been explored. Therefore, we aimed to identify a metabolite signature of legume consumption, and subsequently investigate its potential association with the incidence of T2D and CVD.
METHODS
The current cross-sectional and longitudinal analysis was conducted in 1833 PREDIMED study participants (mean age 67 years, 57.6% women) with available baseline metabolomic data. A subset of these participants with 1-year follow-up metabolomics data (n = 1522) was used for internal validation. Plasma metabolites were assessed through liquid chromatography-tandem mass spectrometry. Cross-sectional associations between 382 different known metabolites and legume consumption were performed using elastic net regression. Associations between the identified metabolite profile and incident T2D and CVD were estimated using multivariable Cox regression models.
RESULTS
Specific metabolic signatures of legume consumption were identified, these included amino acids, cortisol, and various classes of lipid metabolites including diacylglycerols, triacylglycerols, plasmalogens, sphingomyelins and other metabolites. Among these identified metabolites, 22 were negatively and 18 were positively associated with legume consumption. After adjustment for recognized risk factors and legume consumption, the identified legume metabolite profile was inversely associated with T2D incidence (hazard ratio (HR) per 1 SD: 0.75, 95% CI 0.61-0.94; p = 0.017), but not with CVD incidence risk (1.01, 95% CI 0.86-1.19; p = 0.817) over the follow-up period.
CONCLUSIONS
This study identified a set of 40 metabolites associated with legume consumption and with a reduced risk of T2D development in a Mediterranean population at high risk of cardiovascular disease.
TRIAL REGISTRATION
ISRCTN35739639.
Topics: Humans; Female; Aged; Male; Diabetes Mellitus, Type 2; Fabaceae; Cardiovascular Diseases; Cross-Sectional Studies; Diet, Mediterranean; Risk Factors
PubMed: 38245716
DOI: 10.1186/s12933-023-02111-z -
Scientific Reports Apr 2024Alzheimer's disease (AD) is a neurodegenerative disease that commonly causes dementia. Identifying biomarkers for the early detection of AD is an emerging need, as brain...
Alzheimer's disease (AD) is a neurodegenerative disease that commonly causes dementia. Identifying biomarkers for the early detection of AD is an emerging need, as brain dysfunction begins two decades before the onset of clinical symptoms. To this end, we reanalyzed untargeted metabolomic mass spectrometry data from 905 patients enrolled in the AD Neuroimaging Initiative (ADNI) cohort using MS-DIAL, with 1,304,633 spectra of 39,108 unique biomolecules. Metabolic profiles of 93 hydrophilic metabolites were determined. Additionally, we integrated targeted lipidomic data (4873 samples from 1524 patients) to explore candidate biomarkers for predicting progressive mild cognitive impairment (pMCI) in patients diagnosed with AD within two years using the baseline metabolome. Patients with lower ergothioneine levels had a 12% higher rate of AD progression with the significance of P = 0.012 (Wald test). Furthermore, an increase in ganglioside (GM3) and decrease in plasmalogen lipids, many of which are associated with apolipoprotein E polymorphism, were confirmed in AD patients, and the higher levels of lysophosphatidylcholine (18:1) and GM3 d18:1/20:0 showed 19% and 17% higher rates of AD progression, respectively (Wald test: P = 3.9 × 10 and 4.3 × 10). Palmitoleamide, oleamide, diacylglycerols, and ether lipids were also identified as significantly altered metabolites at baseline in patients with pMCI. The integrated analysis of metabolites and genomics data showed that combining information on metabolites and genotypes enhances the predictive performance of AD progression, suggesting that metabolomics is essential to complement genomic data. In conclusion, the reanalysis of multiomics data provides new insights to detect early development of AD pathology and to partially understand metabolic changes in age-related onset of AD.
Topics: Humans; Alzheimer Disease; Neurodegenerative Diseases; Multiomics; Neuroimaging; Biomarkers; Lipids; Cognitive Dysfunction; Disease Progression
PubMed: 38565541
DOI: 10.1038/s41598-024-56837-1 -
Diabetologia Jan 2024High-throughput metabolomics technologies in a variety of study designs have demonstrated a consistent metabolomic signature of overweight and type 2 diabetes. However,...
AIMS/HYPOTHESIS
High-throughput metabolomics technologies in a variety of study designs have demonstrated a consistent metabolomic signature of overweight and type 2 diabetes. However, the extent to which these metabolomic patterns can be reversed with weight loss and diabetes remission has been weakly investigated. We aimed to characterise the metabolomic consequences of a weight-loss intervention in individuals with type 2 diabetes.
METHODS
We analysed 574 fasted serum samples collected within an existing RCT (the Diabetes Remission Clinical Trial [DiRECT]) (N=298). In the trial, participating primary care practices were randomly assigned (1:1) to provide either a weight management programme (intervention) or best-practice care by guidelines (control) treatment to individuals with type 2 diabetes. Here, metabolomics analysis was performed on samples collected at baseline and 12 months using both untargeted MS and targeted H-NMR spectroscopy. Multivariable regression models were fitted to evaluate the effect of the intervention on metabolite levels.
RESULTS
Decreases in branched-chain amino acids, sugars and LDL triglycerides, and increases in sphingolipids, plasmalogens and metabolites related to fatty acid metabolism were associated with the intervention (Holm-corrected p<0.05). In individuals who lost more than 9 kg between baseline and 12 months, those who achieved diabetes remission saw greater reductions in glucose, fructose and mannose, compared with those who did not achieve remission.
CONCLUSIONS/INTERPRETATION
We have characterised the metabolomic effects of an integrated weight management programme previously shown to deliver weight loss and diabetes remission. A large proportion of the metabolome appears to be modifiable. Patterns of change were largely and strikingly opposite to perturbances previously documented with the development of type 2 diabetes.
DATA AVAILABILITY
The data used for analysis are available on a research data repository ( https://researchdata.gla.ac.uk/ ) with access given to researchers subject to appropriate data sharing agreements. Metabolite data preparation, data pre-processing, statistical analyses and figure generation were performed in R Studio v.1.0.143 using R v.4.0.2. The R code for this study has been made publicly available on GitHub at: https://github.com/lauracorbin/metabolomics_of_direct .
Topics: Humans; Diabetes Mellitus, Type 2; Glucose; Metabolome; Metabolomics; Weight Loss; Randomized Controlled Trials as Topic
PubMed: 37878066
DOI: 10.1007/s00125-023-06019-x -
Frontiers in Nutrition 2023Breastfed infants have lower disease risk compared to formula-fed infants, however, the mechanisms behind this protection are unknown. Human milk has a complex lipidome...
BACKGROUND
Breastfed infants have lower disease risk compared to formula-fed infants, however, the mechanisms behind this protection are unknown. Human milk has a complex lipidome which may have many critical roles in health and disease risk. However, human milk lipidomics is challenging, and research is still required to fully understand the lipidome and to interpret and translate findings. This study aimed to address key human milk lipidome knowledge gaps and discuss possible implications for early life health.
METHODS
Human milk samples from two birth cohorts, the Barwon Infant Study ( = 312) and University of Western Australia birth cohort ( = 342), were analysed using four liquid chromatography-mass spectrometry (LC-MS) methods (lipidome, triacylglycerol, total fatty acid, alkylglycerol). Bovine, goat, and soy-based infant formula, and bovine and goat milk were analysed for comparison. Composition was explored as concentrations, relative abundance, and infant lipid intake. Statistical analyses included principal component analysis, mixed effects modelling, and correlation, with false discovery rate correction, to explore human milk lipidome longitudinal trends and inter and intra-individual variation, differences between sample types, lipid intakes, and correlations between infant plasma and human milk lipids.
RESULTS
Lipidomics analysis identified 979 lipids. The human milk lipidome was distinct from that of infant formula and animal milk. Ether lipids were of particular interest, as they were significantly higher, in concentration and relative abundance, in human milk than in formula and animal milk, if present in the latter samples at all. Many ether lipids were highest in colostrum, and some changed significantly through lactation. Significant correlations were identified between human milk and infant circulating lipids (40% of which were ether lipids), and specific ether lipid intake by exclusively breastfed infants was 200-fold higher than that of an exclusively formula-fed infant.
CONCLUSION
There are marked differences between the lipidomes of human milk, infant formula, and animal milk, with notable distinctions between ether lipids that are reflected in the infant plasma lipidome. These findings have potential implications for early life health, and may reveal why breast and formula-fed infants are not afforded the same protections. Comprehensive lipidomics studies with outcomes are required to understand the impacts on infant health and tailor translation.
PubMed: 37712002
DOI: 10.3389/fnut.2023.1227340 -
PNAS Nexus Jun 2024Plasmalogens are glycerophospholipids with a vinyl ether linkage at the sn-1 position of the glycerol backbone. Despite being suggested as antioxidants due to the high...
Plasmalogens are glycerophospholipids with a vinyl ether linkage at the sn-1 position of the glycerol backbone. Despite being suggested as antioxidants due to the high reactivity of their vinyl ether groups with reactive oxygen species, our study reveals the generation of subsequent reactive oxygen and electrophilic lipid species from oxidized plasmalogen intermediates. By conducting a comprehensive analysis of the oxidation products by liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS), we demonstrate that singlet molecular oxygen [O (Δ)] reacts with the vinyl ether bond, producing hydroperoxyacetal as a major primary product (97%) together with minor quantities of dioxetane (3%). Furthermore, we show that these primary oxidized intermediates are capable of further generating reactive species including excited triplet carbonyls and O (Δ) as well as electrophilic phospholipid and fatty aldehyde species as secondary reaction products. The generation of excited triplet carbonyls from dioxetane thermal decomposition was confirmed by light emission measurements in the visible region using dibromoanthracene as a triplet enhancer. Moreover, O (Δ) generation from dioxetane and hydroperoxyacetal was evidenced by detection of near-infrared light emission at 1,270 nm and chemical trapping experiments. Additionally, we have thoroughly characterized alpha-beta unsaturated phospholipid and fatty aldehydes by LC-HRMS analysis using two probes that specifically react with aldehydes and alpha-beta unsaturated carbonyls. Overall, our findings demonstrate the generation of excited molecules and electrophilic lipid species from oxidized plasmalogen species unveiling the potential prooxidant nature of plasmalogen-oxidized products.
PubMed: 38894877
DOI: 10.1093/pnasnexus/pgae216