Similarities between acylcarnitine profiles in large for gestational age newborns and obesity.
Ontology highlight
ABSTRACT:
SUBMITTER: Sanchez-Pintos P
PROVIDER: S-EPMC5701125 | BioStudies | 2017-01-01
REPOSITORIES: biostudies
Similar Datasets
Project description:To test whether follow-up testing for very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency uncovers a diagnosis in patients with elevations of C14:1 and C14:2 plasma acylcarnitines after a controlled fasting study performed for clinically suspected hypoglycemia and to compare the acylcarnitine profiles from fasted patients without VLCAD deficiency vs patients with known VLCAD deficiency to determine whether metabolite testing distinguishes these groups.We performed a retrospective chart review and identified 17 patients with elevated C14:1 and C14:2 plasma acylcarnitine levels after a controlled fast and with testing for VLCAD deficiency (ACADVL sequencing or fibroblast fatty acid oxidation studies). The follow-up testing in all patients was inconsistent with a diagnosis of VLCAD deficiency. We compared the plasma acylcarnitine profiles from these fasted patients vs patients with VLCAD deficiency.C14:1/C12:1 was significantly lower (P < .001) in fasted patients vs patients with VLCAD deficiency. Metabolomics analysis performed in 2 fasted patients and 1 patient with VLCAD deficiency demonstrated evidence for up-regulated lipolysis and ?-oxidation in the fasted state.Elevations of plasma C14:1 and C14:2 acylcarnitines appear to be a physiologic result of lipolysis that occurs with fasting. Both metabolomics analysis and/or C14:1/C12:1 may distinguish C14:1 elevations from physiologic fasting-induced lipolysis vs VLCAD deficiency.
2016-01-01 | S-EPMC4729603 | BioStudies
Project description:Because tandem mass spectrometry- (MS/MS-) based newborn screening identifies many suspicious cases of fatty acid oxidation and carnitine cycle disorders, a simple, noninvasive test is required to confirm the diagnosis. We have developed a novel method to evaluate the metabolic defects in peripheral blood mononuclear cells loaded with deuterium-labeled fatty acids directly using the ratios of acylcarnitines determined by flow injection MS/MS. We have identified diagnostic indices for the disorders as follows: decreased ratios of d27-C14-acylcarnitine/d31-C16-acylcarnitine and d23-C12-acylcarnitine/d31-C16-acylcarnitine for carnitine palmitoyltransferase-II (CPT-II) deficiency, decreased ratios of d23-C12-acylcarnitine/d27-C14-acylcarnitine for very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, and increased ratios of d29-C16-OH-acylcarnitine/d31-C16-acylcarnitine for trifunctional protein (TFP) deficiency, together with increased ratios of d7-C4-acylcarnitine/d31-C16-acylcarnitine for carnitine palmitoyltransferase-I deficiency. The decreased ratios of d1-acetylcarnitine/d31-C16-acylcarnitine could be indicative of ?-oxidation ability in patients with CPT-II, VLCAD, and TFP deficiencies. Overall, our data showed that the present method was valuable for establishing a rapid diagnosis of fatty acid oxidation disorders and carnitine cycle disorders and for complementing gene analysis because our diagnostic indices may overcome the weaknesses of conventional enzyme activity measurements using fibroblasts or mononuclear cells with assumedly uncertain viability.
2019-01-01 | S-EPMC6383405 | BioStudies
Project description:Previous research has indicated that long-chain fatty acids can bind myoglobin (Mb) in an oxygen-dependent manner. This suggests that oxy-Mb may play an important role in fuel delivery in Mb-rich muscle fibers (e.g. type I fibers and cardiomyocytes), and raises the possibility that Mb also serves as an acylcarnitine-binding protein. We report for the first time the putative interaction and affinity characteristics for different chain lengths of both fatty acids and acylcarnitines with oxy-Mb using molecular dynamic simulations and isothermal titration calorimetry experiments. We found that short- to medium-chain fatty acids or acylcarnitines (ranging from C2:0 to C10:0) fail to achieve a stable conformation with oxy-Mb. Furthermore, our results indicate that C12:0 is the minimum chain length essential for stable binding of either fatty acids or acylcarnitines with oxy-Mb. Importantly, the empirical lipid binding studies were consistent with structural modeling. These results reveal that: (i) the lipid binding affinity for oxy-Mb increases as the chain length increases (i.e. C12:0 to C18:1), (ii) the binding affinities of acylcarnitines are higher when compared with their respective fatty acid counterparts, and (iii) both fatty acids and acylcarnitines bind to oxy-Mb in 1:1 stoichiometry. Taken together, our results support a model in which oxy-Mb is a novel regulator of long-chain acylcarnitine and fatty acid pools in Mb-rich tissues. This has important implications for physiological fuel management during exercise, and relevance to pathophysiological conditions (e.g. fatty acid oxidation disorders and cardiac ischemia) where long-chain acylcarnitine accumulation is evident.
2016-01-01 | S-EPMC5122780 | BioStudies
Project description:Patients with beta-thalassemia major (BTM) suffer from fatigue, poor physical fitness, muscle weakness, lethargy, and cardiac complications which are related to an energy crisis. Carnitine and acylcarnitine derivatives play important roles in fatty acid oxidation, and deregulation of carnitine and acylcarnitine metabolism may lead to an energy crisis. The present study aimed to investigate carnitine and acylcarnitine metabolites to gain an insight into the pathophysiology of BTM. Dried blood spots of 45 patients with BTM and 96 age-matched healthy controls were analyzed for free carnitine and 24 acylcarnitines by using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Although medium chain acylcarnitine levels were similar in the patients with BTM and healthy controls, free carnitine, short chain acylcarnitines, long chain acylcarnitines, and total acylcarnitine levels were significantly lower in patients with BTM than in the healthy controls (P?<?0.05). Moreover, an impaired fatty acid oxidation rate was observed in the patients with BTM, as manifested by decreased fatty acid oxidation indicator ratios, namely C2/C0 and (C2?+?C3)/C0. Furthermore, an increase in the C0/(C16?+?C18) ratio indicated reduced carnitine palmitoyltransferase-1 (CPT-1) activity in the patients with BTM compared with that in the healthy controls. Thus, a low level of free carnitine and acylcarnitines together with impaired CPT-1 activity contribute to energy crisis-related complications in the patients with BTM.
2018-01-01 | S-EPMC6057484 | BioStudies
Project description:In human immunodeficiency virus (HIV)-negative individuals, a plasma metabolite profile, characterized by higher levels of branched-chain amino acids (BCAA), aromatic amino acids, and C3/C5 acylcarnitines, is associated with insulin resistance and increased risk of diabetes. We sought to characterize the metabolite profile accompanying insulin resistance in HIV-positive persons to assess whether the same or different bioenergetics pathways might be implicated. We performed an observational cohort study of 70 nondiabetic, HIV-positive individuals (50% with body mass index ≥30 kg/m2) on efavirenz, tenofovir, and emtricitabine with suppressed HIV-1 RNA levels (<50 copies/mL) for at least 2 years and a CD4+ count over 350 cells/μL. We measured fasting insulin resistance using the homeostatic model assessment 2, plasma free fatty acids (FFA) using gas chromatography, and amino acids, acylcarnitines, and organic acids using liquid chromatography/mass spectrometry. We assessed the relationship of plasma metabolites with insulin resistance using multivariable linear regression. The median age was 45 years, median CD4+ count was 701 cells/μL, and median hemoglobin A1c was 5.2%. Insulin resistance was associated with higher plasma C3 acylcarnitines (p = .01), but not BCAA or C5 acylcarnitines. However, insulin resistance was associated with lower plasma levels of C18, C16, C12, and C2 acylcarnitines (p ≤ .03 for all), and lower C18 and C16 acylcarnitine:FFA ratios (p = .002, and p = .03, respectively). In HIV-positive persons, lower levels of plasma acylcarnitines, including the C2 product of complete fatty acid oxidation, are a more prominent feature of insulin resistance than changes in BCAA, suggesting impaired fatty acid uptake and/or mitochondrial oxidation is a central aspect of glucose intolerance in this population.
2018-01-01 | S-EPMC5994672 | BioStudies
Project description:Metabolic profiles have been shown to be associated to obesity status and insulin sensitivity. Dietary intakes influence metabolic pathways and therefore, different dietary patterns may relate to modifications in metabolic signatures. The objective was to verify associations between dietary patterns and metabolic profiles composed of amino acids (AAs) and acylcarnitines (ACs).210 participants were recruited in the greater Quebec City area between September 2009 and December 2011. Dietary patterns had been previously derived using principal component analysis (PCA). The Prudent dietary pattern was characterised by higher intakes of vegetables, fruits, whole grain products, non-hydrogenated fat and lower intakes of refined grain products, whereas the Western dietary pattern was associated with higher intakes of refined grain products, desserts, sweets and processed meats. Targeted metabolites were quantified in 37 participants with the Biocrates Absolute IDQ p150 (Biocrates Life Sciences AG, Austria) mass spectrometry method (including 14 amino acids and 41 acylcarnitines).PCA analysis with metabolites including AAs and ACs revealed two main components explaining the most variance in overall data (13.8%). PC1 was composed mostly of medium- to long-chain ACs (C16:2, C14:2, C14:2-OH, C16, C14:1-OH, C14:1, C10:2, C5-DC/C6-OH, C12, C18:2, C10, C4:1-DC/C6, C8:1 and C2) whereas PC2 included certain AAs and short-chain ACs (xLeu, Met, Arg, Phe, Pro, Orn, His, C0, C3, C4 and C5). The Western dietary pattern correlated negatively with PC1 and positively with PC2 (r?=?-0.34, p?=?0.05 and r?=?0.38, p?=?0.03, respectively), independently of age, sex and BMI.These findings suggest that the Western dietary pattern is associated with a specific metabolite signature characterized by increased levels of AAs including branched-chain AAs (BCAAs) and short-chain ACs.
2013-01-01 | S-EPMC3874609 | BioStudies
Project description:The period around bariatric surgery offers a unique opportunity to characterize metabolism responses to dynamic shifts in energy, gut function, and anesthesia. We analyzed plasma acylcarnitines in obese women (n = 17) sampled in the overnight fasted/postabsorptive state approximately 1-2 wk before surgery (condition A), the morning of surgery (prior restriction to a 48-h clear liquid diet coupled in some cases a standard polyethylene glycol gut evacuation: condition B), and following induction of anesthesia (condition C). Comparisons tested if 1) plasma acylcarnitine derivatives reflective of fatty acid oxidation (FAO) and xenometabolism would be significantly increased and decreased, respectively, by preoperative gut preparation/negative energy balance (condition A vs. B), and 2) anesthesia would acutely depress markers of FAO. Acylcarnitines associated with fat mobilization and FAO were significantly increased in condition B: long-chain acylcarnitines (i.e., C18:1, ~70%), metabolites from active but incomplete FAO [i.e., C14:1 (161%) and C14:2 (102%)] and medium- to short-chain acylcarnitines [i.e., C2 (91%), R-3-hydroxybutyryl-(245%), C6 (45%), and cis-3,4-methylene-heptanoyl-(17%), etc.]. Branched-chain amino acid markers displayed disparate patterns [i.e., isobutyryl-(40% decreased) vs. isovaleryl carnitine (51% increased)]. Anesthesia reduced virtually every acylcarnitine. These results are consistent with a fasting-type metabolic phenotype coincident with the presurgical "gut preparation" phase of bariatric surgery, and a major and rapid alteration of both fat and amino acid metabolism with onset of anesthesia. Whether presurgical or anesthesia-associated metabolic shifts in carnitine and fuel metabolism impact patient outcomes or surgical risks remains to be evaluated experimentally.
1000-01-01 | S-EPMC5814600 | BioStudies
Project description:<p><strong>INTRODUCTION:</strong> Restricted or enhanced intrauterine growth is associated with elevated risks of early and late metabolic problems in humans. Metabolomics based on amino acid and carnitine/acylcarnitine profile may have a role in fetal and early postnatal energy metabolism. In this study, the relationship between intrauterine growth status and early metabolomics profile was evaluated.</p><p><strong>MATERIALS AND METHODS:</strong> A single center retrospective cohort study was conducted. Newborn infants were enrolled into the study and they were grouped according to their birth weight percentile as small for gestational age (SGA), appropriate for gestational age (AGA) and large for gestational age (LGA) infants. In all infants amino acid and carnitine/acylcarnitine profile with liquid chromatography-tandem mass spectrometry (LC-MS/MS) were recorded and compared between groups.</p><p><strong>RESULTS:</strong> LGA infants had higher levels of glutamic acid and lower levels of ornithine, alanine and glycine (p<0.05) when compared to AGA infants. SGA infants had higher levels of alanine and glycine levels when compared with AGA and LGA infants. Total carnitine, C0, C2, C4, C5, C10:1, C18:1, C18:2, C14-OH and C18:2-OH levels were significantly higher and C3 and C6-DC levels were lower in SGA infants (p<0.05). LGA infants had higher C3 and C5:1 level; and lower C18:2 and C16:1-OH levels (p<0.05). There were positive correlations between free carnitine and phenylalanine, arginine, methionine, alanine and glycine levels (p<0.05). Also a positive correlation between ponderal index and C3, C5-DC, C14, C14:1; and a negative correlation between ponderal index and ornithine, alanine, glycine, C16:1-OH, C18:2 were shown.</p><p><strong>CONCLUSION:</strong> We demonstrated differences in metabolomics possibly reflecting the energy metabolism in newborn infants with intrauterine growth problems in the early postnatal period. These differences might be the footprints of metabolic disturbances in future adulthood.</p>
2021-04-28 | MTBLS2376 | MetaboLights
Project description:Inefficient muscle long-chain fatty acid (LCFA) combustion is associated with insulin resistance, but molecular links between mitochondrial fat catabolism and insulin action remain controversial. We hypothesized that plasma acylcarnitine profiling would identify distinct metabolite patterns reflective of muscle fat catabolism when comparing individuals bearing a missense G304A uncoupling protein 3 (UCP3 g/a) polymorphism to controls, because UCP3 is predominantly expressed in skeletal muscle and g/a individuals have reduced whole-body fat oxidation. MS analyses of 42 carnitine moieties in plasma samples from fasting type 2 diabetics (n = 44) and nondiabetics (n = 12) with or without the UCP3 g/a polymorphism (n = 28/genotype: 22 diabetic, 6 nondiabetic/genotype) were conducted. Contrary to our hypothesis, genotype had a negligible impact on plasma metabolite patterns. However, a comparison of nondiabetics vs. type 2 diabetics revealed a striking increase in the concentrations of fatty acylcarnitines reflective of incomplete LCFA beta-oxidation in the latter (i.e. summed C10- to C14-carnitine concentrations were approximately 300% of controls; P = 0.004). Across all volunteers (n = 56), acetylcarnitine rose and propionylcarnitine decreased with increasing hemoglobin A1c (r = 0.544, P < 0.0001; and r = -0.308, P < 0.05, respectively) and with increasing total plasma acylcarnitine concentration. In proof-of-concept studies, we made the novel observation that C12-C14 acylcarnitines significantly stimulated nuclear factor kappa-B activity (up to 200% of controls) in RAW264.7 cells. These results are consistent with the working hypothesis that inefficient tissue LCFA beta-oxidation, due in part to a relatively low tricarboxylic acid cycle capacity, increases tissue accumulation of acetyl-CoA and generates chain-shortened acylcarnitine molecules that activate proinflammatory pathways implicated in insulin resistance.
1000-01-01 | S-EPMC2714383 | BioStudies
Project description:Insulin resistance may be linked to incomplete fatty acid ?-oxidation and the subsequent increase in acylcarnitine species in different tissues including skeletal muscle. It is not known if acylcarnitines participate in muscle insulin resistance or simply reflect dysregulated metabolism. The aims of this study were to determine whether acylcarnitines can elicit muscle insulin resistance and to better understand the link between incomplete muscle fatty acid ?-oxidation, oxidative stress, inflammation, and insulin-resistance development. Differentiated C2C12, primary mouse, and human myotubes were treated with acylcarnitines (C4:0, C14:0, C16:0) or with palmitate with or without carnitine acyltransferase inhibition by mildronate. Treatment with C4:0, C14:0, and C16:0 acylcarnitines resulted in 20-30% decrease in insulin response at the level of Akt phosphorylation and/or glucose uptake. Mildronate reversed palmitate-induced insulin resistance concomitant with an ?25% decrease in short-chain acylcarnitine and acetylcarnitine secretion. Although proinflammatory cytokines were not affected under these conditions, oxidative stress was increased by 2-3 times by short- or long-chain acylcarnitines. Acylcarnitine-induced oxidative stress and insulin resistance were reversed by treatment with antioxidants. Results are consistent with the conclusion that incomplete muscle fatty acid ?-oxidation causes acylcarnitine accumulation and associated oxidative stress, raising the possibility that these metabolites play a role in muscle insulin resistance.
1000-01-01 | S-EPMC4285541 | BioStudies