Nonalcoholic fatty liver disease (i.e., increased intrahepatic triglyceride IHTG content), predisposes to type 2 diabetes and cardiovascular disease. Adipose tissue lipolysis and hepatic de novo ...lipogenesis (DNL) are the main pathways contributing to IHTG. We hypothesized that dietary macronutrient composition influences the pathways, mediators, and magnitude of weight gain-induced changes in IHTG.
We overfed 38 overweight subjects (age 48 ± 2 years, BMI 31 ± 1 kg/m
, liver fat 4.7 ± 0.9%) 1,000 extra kcal/day of saturated (SAT) or unsaturated (UNSAT) fat or simple sugars (CARB) for 3 weeks. We measured IHTG (
H-MRS), pathways contributing to IHTG (lipolysis (
H
glycerol) and DNL (
H
O) basally and during euglycemic hyperinsulinemia), insulin resistance, endotoxemia, plasma ceramides, and adipose tissue gene expression at 0 and 3 weeks.
Overfeeding SAT increased IHTG more (+55%) than UNSAT (+15%,
< 0.05). CARB increased IHTG (+33%) by stimulating DNL (+98%). SAT significantly increased while UNSAT decreased lipolysis. SAT induced insulin resistance and endotoxemia and significantly increased multiple plasma ceramides. The diets had distinct effects on adipose tissue gene expression.
Macronutrient composition of excess energy influences pathways of IHTG: CARB increases DNL, while SAT increases and UNSAT decreases lipolysis. SAT induced the greatest increase in IHTG, insulin resistance, and harmful ceramides. Decreased intakes of SAT could be beneficial in reducing IHTG and the associated risk of diabetes.
Lipids have many central physiological roles including as structural components of cell membranes, energy storage sources and intermediates in signaling pathways. Lipid-related disturbances are known ...to underlie many diseases and their co-morbidities. The emergence of lipidomics has empowered researchers to study lipid metabolism at the cellular as well as physiological levels at a greater depth than was previously possible. The key challenges ahead in the field of lipidomics in medical research lie in the development of experimental protocols and in silico techniques needed to study lipidomes at the systems level. Clinical questions where lipidomics may have an impact in healthcare settings also need to be identified, both from the health outcomes and health economics perspectives. This article is part of a Special Issue entitled: BBALIP_Lipidomics Opinion Articles edited by Sepp Kohlwein.
•Lipidomics is a key platform for the study of lipid metabolism in health and disease.•Multiple suitable techniques for the global measurement of molecular lipids exist.•New experimental protocols are needed to study lipidomes at physiological level.•Better in silico tools are needed to study lipids at the systems level.
Adipose tissue plays a pivotal role in storing excess fat and its composition reflects the history of person's lifestyle and metabolic health. Broad profiling of lipids with mass spectrometry has ...potential for uncovering new knowledge on the pathology of obesity, metabolic syndrome, diabetes and other related conditions. Here, we developed a lipidomic method for analyzing human subcutaneous adipose biopsies. We applied the method to four body areas to understand the differences in lipid composition between these areas. Adipose tissue biopsies from 10 participants were analyzed using ultra-high-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. The sample preparation optimization included the optimization of the lipid extraction, the sample amount and the sample dilution factor to detect lipids in an appropriate concentration range. Lipidomic analyses were performed for adipose tissue collected from the abdomen, breast, thigh and lower back. Differences in lipid levels between tissues were visualized with heatmaps. Lipidomic analysis on human adipose biopsies lead to the identification of 186lipids in 2 mg of sample. Technical variation of the lipid-class specific internal standards were below 5%, thus indicating acceptable repeatability. Triacylglycerols were highly represented in the adipose tissue samples, and lipids from 13 lipid classes were identified. Long polyunsaturated triacylglycerols in higher levels in thigh (q<0.05), when compared with the abdomen, breast and lower back, indicating that the lipidome was area-specific. The method presented here is suitable for the analysis of lipid profiles in 2 mg of adipose tissue. The amount of fat across the body is important for health but we argue that also the distribution and the particular profile of the lipidome may be relevant for metabolic outcomes. We suggest that the method presented in this paper could be useful for detecting such aberrations.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•We report a reliable, fast and repeatable method to separate steroid isomers.•We compare two different drift gases in order to achieve optimum separation.•Different drift gas pressures were studied ...for optimum separation.•The separation efficiencies of the steroid isomers are increased by derivatization.
Ion mobility mass spectrometry performed in a compact traveling wave cell (TWIM-MS) is shown to provide a reliable, fast and repeatable method to separate derivatized steroid isomers. Three steroid isomer pairs were analyzed in their native form and as their p-toluenesulfonyl isocyanate derivatives. The native steroids were separated from each other, but no separation could be attained for the isomers. The derivatized steroid isomers were, however, properly separated by TWIM-MS with peak-to-peak resolutions close to or as high as baseline resolution (Rp−p=0.77–1.08).
We assessed whether blood lipid metabolites and their changes associate with various cardiometabolic, endocrine, bone- and energy-related comorbidities of Relative Energy Deficiency in Sport (RED-S) ...in female elite endurance athletes. Thirty-eight Scandinavian female elite athletes underwent a day-long exercise test. Five blood samples were obtained during the day - at fasting state and before and after two standardized exercise tests. Clinical biomarkers were assessed at fasting state, while untargeted lipidomics was undertaken using all blood samples. Linear and logistic regression was used to assess associations between lipidomic features and clinical biomarkers. Overrepresentations of findings with P < 0.05 from these association tests were assessed using Fisher's exact tests. Self-organizing maps and a trajectory clustering algorithm were utilized to identify informative clusters in the population. Twenty associations P
< 0.05 were detected between lipidomic features and clinical biomarkers. Notably, cortisol demonstrated an overrepresentation of associations with P < 0.05 compared to other traits (P
= 1.9×10
). Mean lipid trajectories were created for 201 named features for the cohort and subsequently by stratifying participants by their energy availability and menstrual dysfunction status. This exploratory analysis of lipid trajectories indicates that participants with menstrual dysfunction might have decreased adaptive response to exercise interventions.
•We report two sensitive and fast methods for the analysis of biological samples.•25-Hydroxyvitamin D3 was identified in mouse brain samples for the first time.•Oxidative stressed cell line samples ...were compared to non-stressed control samples.•The role of oxysterols in the formation of α-syn aggregates cannot be ruled out.
We have developed an ultra-high-performance liquid chromatography-atmospheric pressure photoionization-tandem mass spectrometric (UHPLC-APPI–MS/MS) method for the simultaneous quantitative analyses of several oxysterols and vitamin D metabolites in mouse brain and cell line samples. An UHPLC-APPI-high resolution mass spectrometric (UHPLC-APPI-HRMS) method that uses a quadrupole-time of flight mass spectrometer was also developed for confirmatory analysis and for the identification of non-targeted oxysterols. Both methods showed good quantitative performance. Furthermore, APPI provides high ionization efficiency for determining oxysterols and vitamin D related compounds without the time consuming derivatization step needed in the conventionally used electrospray ionization method to achieve acceptable sensitivity. Several oxysterols were quantified in mouse brain and cell line samples. Additionally, 25-hydroxyvitamin D3 was detected in mouse brain samples for the first time.
Diabetic cardiovascular autonomic neuropathy (CAN) is associated with increased mortality and morbidity. To explore metabolic mechanisms associated with CAN we investigated associations between serum ...metabolites and CAN in persons with type 1 diabetes (T1D).
Cardiovascular reflex tests (CARTs) (heart rate response to: deep breathing; lying-to-standing test; and the Valsalva maneuver) were used to diagnose CAN in 302 persons with T1D. More than one pathological CARTs defined the CAN diagnosis. Serum metabolomics and lipidomic profiles were analyzed with two complementary non-targeted mass-spectrometry methods. Cross-sectional associations between metabolites and CAN were assessed by linear regression models adjusted for relevant confounders.
Participants were median (IQR) aged 55(49, 63) years, 48% males with diabetes duration 39(32, 47) years, HbA
63(55,69) mmol/mol and 34% had CAN. A total of 75 metabolites and 106 lipids were analyzed. In crude models, the CAN diagnosis was associated with higher levels of hydroxy fatty acids (2,4- and 3,4-dihydroxybutanoic acids, 4-deoxytetronic acid), creatinine, sugar derivates (ribitol, ribonic acid, myo-inositol), citric acid, glycerol, phenols, phosphatidylcholines and lower levels of free fatty acids and the amino acid methionine (p<0.05). Upon adjustment, positive associations with the CAN diagnoses were retained for hydroxy fatty acids, tricarboxylic acid (TCA) cycle-based sugar derivates, citric acid, and phenols (P<0.05).
Metabolic pathways, including the TCA cycle, hydroxy fatty acids, phosphatidylcholines and sugar derivatives are associated with the CAN diagnosis in T1D. These pathway may be part of the pathogeneses leading to CAN and may be modifiable risk factors for the complication.
Several small molecule biomarkers have been reported in the literature for prediction and diagnosis of (pre)diabetes, its co-morbidities, and complications. Here, we report the development and ...validation of a novel, quantitative method for the determination of a selected panel of 34 metabolite biomarkers from human plasma. We selected a panel of metabolites indicative of various clinically-relevant pathogenic stages of diabetes. We combined these candidate biomarkers into a single ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method and optimized it, prioritizing simplicity of sample preparation and time needed for analysis, enabling high-throughput analysis in clinical laboratory settings. We validated the method in terms of limits of detection (LOD) and quantitation (LOQ), linearity (R2), and intra- and inter-day repeatability of each metabolite. The method’s performance was demonstrated in the analysis of selected samples from a diabetes cohort study. Metabolite levels were associated with clinical measurements and kidney complications in type 1 diabetes (T1D) patients. Specifically, both amino acids and amino acid-related analytes, as well as specific bile acids, were associated with macro-albuminuria. Additionally, specific bile acids were associated with glycemic control, anti-hypertensive medication, statin medication, and clinical lipid measurements. The developed analytical method is suitable for robust determination of selected plasma metabolites in the diabetes clinic.
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;
= 30), children who developed at least one islet autoantibody but did not progress to T1D during the follow-up (P1Ab;
= 33), and their age-matched controls (CTR;
= 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.
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