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Reuter, Stephanie E., Allan M. Evans, Randall J. Faull, Donald H. Chace, and Gianfranco Fornasini. "Impact of haemodialysis on individual endogenous plasma acylcarnitine concentrations in end-stage renal disease." Annals of Clinical Biochemistry: International Journal of Laboratory Medicine 42, no. 5 (September 1, 2005): 387–93. http://dx.doi.org/10.1258/0004563054889954.
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Background: Patients with end-stage renal disease (ESRD) undergoing long-term haemodialysis exhibit low L-carnitine and elevated acylcarnitine concentrations. This study evaluated endogenous concentrations of an array of acylcarnitines (carbon chain length up to 18) in healthy individuals and ESRD patients receiving haemodialysis, and examined the impact of a single haemodialysis session on acylcarnitine concentrations. Methods: Blood samples were collected from 60 healthy subjects and 50 ESRD patients undergoing haemodialysis (pre- and post-dialysis samples). Plasma samples were analysed for individual acylcarnitine concentrations by electrospray MS/MS. Results: Of the 31 acylcarnitines, 29 were significantly ( P<0.05) elevated in ESRD patients compared with healthy controls; in particular, C5 and C8:1 concentrations were substantially elevated. For acylcarnitines with a carbon chain length less than eight, plasma acylcarnitine concentrations decreased significantly over the course of a single dialysis session; however, post-dialysis concentrations invariably remained significantly higher than those in healthy subjects. Dialytic removal of acylcarnitines diminished once the acyl chain length exceeded eight carbons. Conclusions: The accumulation of acylcarnitines during long-term haemodialysis suggests that removal by haemodialysis is less efficient than removal from the body by the healthy kidney. Removal is significantly correlated to acyl chain length, most likely due to the increased molecular weight and lipophilicity that accompanies increased chain length.
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Guasch-Ferré, Marta, Miguel Ruiz-Canela, Jun Li, Yan Zheng, Mònica Bulló, Dong D. Wang, Estefanía Toledo, et al. "Plasma Acylcarnitines and Risk of Type 2 Diabetes in a Mediterranean Population at High Cardiovascular Risk." Journal of Clinical Endocrinology & Metabolism 104, no. 5 (November 13, 2018): 1508–19. http://dx.doi.org/10.1210/jc.2018-01000.
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Abstract Context The potential associations between acylcarnitine profiles and incidence of type 2 diabetes (T2D) and whether acylcarnitines can be used to improve diabetes prediction remain unclear. Objective To evaluate the associations between baseline and 1-year changes in acylcarnitines and their diabetes predictive ability beyond traditional risk factors. Design, Setting, and Participants We designed a case-cohort study within the PREDIMED Study including all incident cases of T2D (n = 251) and 694 randomly selected participants at baseline (follow-up, 3.8 years). Plasma acylcarnitines were measured using a targeted approach by liquid chromatography–tandem mass spectrometry. We tested the associations between baseline and 1-year changes in individual acylcarnitines and T2D risk using weighted Cox regression models. We used elastic net regressions to select acylcarnitines for T2D prediction and compute a weighted score using a cross-validation approach. Results An acylcarnitine profile, especially including short- and long-chain acylcarnitines, was significantly associated with a higher risk of T2D independent of traditional risk factors. The relative risks of T2D per SD increment of the predictive model scores were 4.03 (95% CI, 3.00 to 5.42; P < 0.001) for the conventional model and 4.85 (95% CI, 3.65 to 6.45; P < 0.001) for the model including acylcarnitines, with a hazard ratio of 1.33 (95% CI, 1.08 to 1.63; P < 0.001) attributed to the acylcarnitines. Including the acylcarnitines into the model did not significantly improve the area under the receiver operator characteristic curve (0.86 to 0.88, P = 0.61). A 1-year increase in C4OH-carnitine was associated with higher risk of T2D [per SD increment, 1.44 (1.03 to 2.01)]. Conclusions An acylcarnitine profile, mainly including short- and long-chain acylcarnitines, was significantly associated with higher T2D risk in participants at high cardiovascular risk. The inclusion of acylcarnitines into the model did not significantly improve the T2D prediction C-statistics beyond traditional risk factors, including fasting glucose.
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Li, Shangfu, Dan Gao, and Yuyang Jiang. "Function, Detection and Alteration of Acylcarnitine Metabolism in Hepatocellular Carcinoma." Metabolites 9, no. 2 (February 21, 2019): 36. http://dx.doi.org/10.3390/metabo9020036.
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Acylcarnitines play an essential role in regulating the balance of intracellular sugar and lipid metabolism. They serve as carriers to transport activated long-chain fatty acids into mitochondria for β-oxidation as a major source of energy for cell activities. The liver is the most important organ for endogenous carnitine synthesis and metabolism. Hepatocellular carcinoma (HCC), a primary malignancy of the live with poor prognosis, may strongly influence the level of acylcarnitines. In this paper, the function, detection and alteration of acylcarnitine metabolism in HCC were briefly reviewed. An overview was provided to introduce the metabolic roles of acylcarnitines involved in fatty acid β-oxidation. Then different analytical platforms and methodologies were also briefly summarised. The relationship between HCC and acylcarnitine metabolism was described. Many of the studies reported that short, medium and long-chain acylcarnitines were altered in HCC patients. These findings presented current evidence in support of acylcarnitines as new candidate biomarkers for studies on the pathogenesis and development of HCC. Finally we discussed the challenges and perspectives of exploiting acylcarnitine metabolism and its related metabolic pathways as a target for HCC diagnosis and prognosis.
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Dave, Amanda M., Thiago C. Genaro-Mattos, Zeljka Korade, and Eric S. Peeples. "Neonatal Hypoxic-Ischemic Brain Injury Alters Brain Acylcarnitine Levels in a Mouse Model." Metabolites 12, no. 5 (May 22, 2022): 467. http://dx.doi.org/10.3390/metabo12050467.
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Hypoxic-ischemic brain injury (HIBI) leads to depletion of ATP, mitochondrial dysfunction, and enhanced oxidant formation. Measurement of acylcarnitines may provide insight into mitochondrial dysfunction. Plasma acylcarnitine levels are altered in neonates after an HIBI, but individual acylcarnitine levels in the brain have not been evaluated. Additionally, it is unknown if plasma acylcarnitines reflect brain acylcarnitine changes. In this study, postnatal day 9 CD1 mouse pups were randomized to HIBI induced by carotid artery ligation, followed by 30 min at 8% oxygen, or to sham surgery and normoxia, with subgroups for tissue collection at 30 min, 24 h, or 72 h after injury (12 animals/group). Plasma, liver, muscle, and brain (dissected into the cortex, cerebellum, and striatum/thalamus) tissues were collected for acylcarnitine analysis by LC-MS. At 30 min after HIBI, acylcarnitine levels were significantly increased, but the differences resolved by 24 h. Palmitoylcarnitine was increased in the cortex, muscle, and plasma, and stearoylcarnitine in the cortex, striatum/thalamus, and cerebellum. Other acylcarnitines were elevated only in the muscle and plasma. In conclusion, although plasma acylcarnitine results in this study mimic those seen previously in humans, our data suggest that the plasma acylcarnitine profile was more reflective of muscle changes than brain changes. Acylcarnitine metabolism may be a target for therapeutic intervention after neonatal HIBI, though the lack of change after 30 min suggests a limited therapeutic window.
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Van Bocxlaer, J. F., and A. P. De Leenheer. "Solid-phase extraction technique for gas-chromatographic profiling of acylcarnitines." Clinical Chemistry 39, no. 9 (September 1, 1993): 1911–17. http://dx.doi.org/10.1093/clinchem/39.9.1911.
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Abstract We present a simple, new clean-up method for the gas-chromatographic profiling analysis of acylcarnitines. The use of a solid-phase, cation-exchange extraction combined with gas-chromatographic separation, based on the derivatization into acyloxylactones by Lowes and Rose (Analyst 1990;115:511-6), allows a selective and sensitive screening for acylcarnitines in urine. As such, a quantitative approach was developed for differential evaluation of acylcarnitines for detection of inborn errors of metabolism; the evaluation is both fast and routinely applicable in any biochemical laboratory. We validate the analysis method for acylcarnitines of various chain-lengths and present examples of its application to urine samples from diseased patients. We give special attention to the medium-chain acylcarnitines because of their association with medium-chain acylCoA dehydrogenase deficiency. Finally, the quantitative nature of the analysis allows evaluation of the acylcarnitine excretion over time.
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Schooneman, Marieke G., Niki Achterkamp, Carmen A. Argmann, Maarten R. Soeters, and Sander M. Houten. "Plasma acylcarnitines inadequately reflect tissue acylcarnitine metabolism." Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 1841, no. 7 (July 2014): 987–94. http://dx.doi.org/10.1016/j.bbalip.2014.04.001.
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An, Zhenni, Danmeng Zheng, Dongzhuo Wei, Dingwen Jiang, Xuejiao Xing, and Chang Liu. "Correlation between Acylcarnitine and Peripheral Neuropathy in Type 2 Diabetes Mellitus." Journal of Diabetes Research 2022 (February 17, 2022): 1–9. http://dx.doi.org/10.1155/2022/8115173.
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Objective. In patients with type 2 diabetes mellitus (T2DM), it is unknown whether acylcarnitine changes in the patient’s plasma as diabetic peripheral neuropathy (DPN) occurs. The purpose of the present study was to investigate the correlation between acylcarnitines and DPN in Chinese patients with T2DM. Methods. A total of 508 patients admitted to the First Affiliated Hospital of Jinzhou Medical University were included in this study, and all of whom were hospitalized for T2DM from January 2018 to December 2020. The diagnostic criteria for DPN were based on the 2017 Chinese Guidelines for the Prevention of Type 2 Diabetes. The contents of 25 acylcarnitine metabolites in fasting blood were determined by mass spectrometry. The measured acylcarnitines were classified by factor analysis, and the factors were extracted. To determine the correlation between acylcarnitines and DPN, binary logistic regression analysis was applied. Results. Among the 508 T2DM patients, 270 had DPN. Six factors were extracted from 25 acylcarnitines, and the cumulative contribution rate of variance was 61.02%. After the adjustment for other potential confounding factors, such as other carnitines and conventional risk factors, Factor 2 was positively associated with an increased risk of DPN (OR: 1.38, 95% CI: 1.13-1.69). Factor 2 contained acetylcarnitine (C2), propionylcarnitine (C3), butylcarnitine (C4), and isovalerylcarnitine (C5). Conclusions. Plasma levels of short-chain acylcarnitines (C2, C3, C4, and C5) were positively associated with DPN risk.
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Minkler, Paul E., Maria S. K. Stoll, Stephen T. Ingalls, Shuming Yang, Janos Kerner, and Charles L. Hoppel. "Quantification of Carnitine and Acylcarnitines in Biological Matrices by HPLC Electrospray Ionization– Mass Spectrometry." Clinical Chemistry 54, no. 9 (September 1, 2008): 1451–62. http://dx.doi.org/10.1373/clinchem.2007.099226.
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Abstract Background: Analysis of carnitine and acylcarnitines by tandem mass spectrometry (MS/MS) has limitations. First, preparation of butyl esters partially hydrolyzes acylcarnitines. Second, isobaric nonacylcarnitine compounds yield false-positive results in acylcarnitine tests. Third, acylcarnitine constitutional isomers cannot be distinguished. Methods: Carnitine and acylcarnitines were isolated by ion-exchange solid-phase extraction, derivatized with pentafluorophenacyl trifluoromethanesulfonate, separated by HPLC, and detected with an ion trap mass spectrometer. Carnitine was quantified with d3-carnitine as the internal standard. Acylcarnitines were quantified with 42 synthesized calibrators. The internal standards used were d6-acetyl-, d3-propionyl-, undecanoyl-, undecanedioyl-, and heptadecanoylcarnitine. Results: Example recoveries [mean (SD)] were 69.4% (3.9%) for total carnitine, 83.1% (5.9%) for free carnitine, 102.2% (9.8%) for acetylcarnitine, and 107.2% (8.9%) for palmitoylcarnitine. Example imprecision results [mean (SD)] within runs (n = 6) and between runs (n = 18) were, respectively: total carnitine, 58.0 (0.9) and 57.4 (1.7) μmol/L; free carnitine, 44.6 (1.5) and 44.3 (1.2) μmol/L; acetylcarnitine, 7.74 (0.51) and 7.85 (0.69) μmol/L; and palmitoylcarnitine, 0.12 (0.01) and 0.11 (0.02) μmol/L. Standard-addition slopes and linear regression coefficients were 1.00 and 0.9998, respectively, for total carnitine added to plasma, 0.99 and 0.9997 for free carnitine added to plasma, 1.04 and 0.9972 for octanoylcarnitine added to skeletal muscle, and 1.05 and 0.9913 for palmitoylcarnitine added to skeletal muscle. Reference intervals for plasma, urine, and skeletal muscle are provided. Conclusions: This method for analysis of carnitine and acylcarnitines overcomes the observed limitations of MS/MS methods.
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Rutkowsky, Jennifer M., Trina A. Knotts, Kikumi D. Ono-Moore, Colin S. McCoin, Shurong Huang, Dina Schneider, Shamsher Singh, Sean H. Adams, and Daniel H. Hwang. "Acylcarnitines activate proinflammatory signaling pathways." American Journal of Physiology-Endocrinology and Metabolism 306, no. 12 (June 15, 2014): E1378—E1387. http://dx.doi.org/10.1152/ajpendo.00656.2013.
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Incomplete β-oxidation of fatty acids in mitochondria is a feature of insulin resistance and type 2 diabetes mellitus (T2DM). Previous studies revealed that plasma concentrations of medium- and long-chain acylcarnitines (by-products of incomplete β-oxidation) are elevated in T2DM and insulin resistance. In a previous study, we reported that mixed d,l isomers of C12- or C14-carnitine induced an NF-κB-luciferase reporter gene in RAW 264.7 cells, suggesting potential activation of proinflammatory pathways. Here, we determined whether the physiologically relevant l-acylcarnitines activate classical proinflammatory signaling pathways and if these outcomes involve pattern recognition receptor (PRR)-associated pathways. Acylcarnitines induced the expression of cyclooxygenase-2 in a chain length-dependent manner in RAW 264.7 cells. l-C14 carnitine (5–25 μM), used as a representative acylcarnitine, stimulated the expression and secretion of proinflammatory cytokines in a dose-dependent manner. Furthermore, l-C14 carnitine induced phosphorylation of JNK and ERK, common downstream components of many proinflammatory signaling pathways including PRRs. Knockdown of MyD88, a key cofactor in PRR signaling and inflammation, blunted the proinflammatory effects of acylcarnitine. While these results point to potential involvement of PRRs, l-C14 carnitine promoted IL-8 secretion from human epithelial cells (HCT-116) lacking Toll-like receptors (TLR)2 and -4, and did not activate reporter constructs in TLR overexpression cell models. Thus, acylcarnitines have the potential to activate inflammation, but the specific molecular and tissue target(s) involved remain to be identified.
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Zhang, Ningning, Xiaopu Jia, Shuai Fan, Bin Wu, Shuqing Wang, and Bo OuYang. "NMR Characterization of Long-Chain Fatty Acylcarnitine Binding to the Mitochondrial Carnitine/Acylcarnitine Carrier." International Journal of Molecular Sciences 23, no. 9 (April 21, 2022): 4608. http://dx.doi.org/10.3390/ijms23094608.
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The mitochondrial carnitine/acylcarnitine carrier (CAC) transports short-, medium- and long-carbon chain acylcarnitines across the mitochondrial inner membrane in exchange for carnitine. How CAC recognizes the substrates with various fatty acyl groups, especially long-chain fatty acyl groups, remains unclear. Here, using nuclear magnetic resonance (NMR) technology, we have shown that the CAC protein reconstituted into a micelle system exhibits a typical six transmembrane structure of the mitochondrial carrier family. The chemical shift perturbation patterns of different fatty acylcarnitines suggested that the segment A76–G81 in CAC specifically responds to the long-chain fatty acylcarnitine. Molecular dynamics (MD) simulations of palmitoyl-L-carnitine inside the CAC channel showed the respective interaction and motion of the long-chain acylcarnitine in CAC at the cytosol-open state and matrix-open state. Our data provided a molecular-based understanding of CAC structure and transport mechanism.
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Liepinsh, Edgars, Marina Makrecka-Kuka, Kristine Volska, Janis Kuka, Elina Makarova, Unigunde Antone, Eduards Sevostjanovs, et al. "Long-chain acylcarnitines determine ischaemia/reperfusion-induced damage in heart mitochondria." Biochemical Journal 473, no. 9 (April 26, 2016): 1191–202. http://dx.doi.org/10.1042/bcj20160164.
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During ischaemia acylcarnitines accumulate in the heart mitochondria, inhibit oxidative phosphorylation and stimulate reactive oxygen species (ROS) production and therefore are harmful to mitochondria. An increase in the acylcarnitine heart content increases the infarct size (IS) whereas a decrease in the mitochondrial acylcarnitine content reduces the IS.
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Ummenhofer, Wolfgang C., and Christopher M. Bernards. "Acylcarnitine Chain Length Influences Carnitine-enhanced Drug Flux through the Spinal Meninges." Anesthesiology 86, no. 3 (March 1, 1997): 642–48. http://dx.doi.org/10.1097/00000542-199703000-00017.
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Background Palmitoyl carnitine has been shown to improve the penetration of hydrophilic drugs through the spinal meninges. Naturally occurring acylcarnitines, however, exist as a homologous series of different acyl chain lengths. The purpose of this study was to determine the most effective acylcarnitine chain length to increase meningeal permeability. Methods The transmeningeal flux of mannitol, morphine, and sufentanil through monkey spinal meninges was determined before and after adding acylcarnitines with chain lengths of 6 to 18 carbon atoms. Flux was measured using a previously established in vitro diffusion cell model. Results For mannitol, acylcarnitines generally showed a greater penetration-enhancing effect with increasing chain length, with palmitoyl carnitine (16 carbons) being the most effective compound with an increase of 244 +/- 29% (means +/- SE). Morphine flux was increased most significantly by lauroyl-(12 carbons) and myristoyl-carnitine (14 carbons) with 165 +/- 25% and 188 +/- 44% flux increases, respectively. In contrast, none of the studied acylcarnitines significantly altered the meningeal penetration of the more hydrophobic drug sufentanil. Conclusions The results suggest that, to promote hydrophilic drug penetration, acylcarnitines must surpass a critical chain length (10 carbon units) but should not exceed 16 carbon units. The activity of the acylcarnitines at the spinal meninges is reduced on either side of this range. The ability of acylcarnitines to increase the transmeningeal flux of morphine in vitro suggests that lauroyl or myristoyl carnitine may increase the spinal bioavailability of morphine after epidural administration.
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Schooneman, Marieke G., Gabriella A. M. Ten Have, Naomi van Vlies, Sander M. Houten, Nicolaas E. P. Deutz, and Maarten R. Soeters. "Transorgan fluxes in a porcine model reveal a central role for liver in acylcarnitine metabolism." American Journal of Physiology-Endocrinology and Metabolism 309, no. 3 (August 1, 2015): E256—E264. http://dx.doi.org/10.1152/ajpendo.00503.2014.
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Acylcarnitines are derived from mitochondrial acyl-CoA metabolism and have been associated with diet-induced insulin resistance. However, plasma acylcarnitine profiles have been shown to poorly reflect whole body acylcarnitine metabolism. We aimed to clarify the individual role of different organ compartments in whole body acylcarnitine metabolism in a fasted and postprandial state in a porcine transorgan arteriovenous model. Twelve cross-bred pigs underwent surgery where intravascular catheters were positioned before and after the liver, gut, hindquarter muscle compartment, and kidney. Before and after a mixed meal, we measured acylcarnitine profiles at several time points and calculated net transorgan acylcarnitine fluxes. Fasting plasma acylcarnitine concentrations correlated with net hepatic transorgan fluxes of free and C2- and C16-carnitine. Transorgan acylcarnitine fluxes were small, except for a pronounced net hepatic C2-carnitine production. The peak of the postprandial acylcarnitine fluxes was between 60 and 90 min. Acylcarnitine production or release was seen in the gut and liver and consisted mostly of C2-carnitine. Acylcarnitines were extracted by the kidney. No significant net muscle acylcarnitine flux was observed. We conclude that liver has a key role in acylcarnitine metabolism, with high net fluxes of C2-carnitine both in the fasted and fed state, whereas the contribution of skeletal muscle is minor. These results further clarify the role of different organ compartments in the metabolism of different acylcarnitine species.
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Nemchinova, N. V., T. A. Bairova, A. V. Belskikh, O. V. Bugun, and L. V. Rychkova. "Assessment of reference intervals of acylcarnitines in newborns in Siberia." Acta Biomedica Scientifica 7, no. 5-1 (December 7, 2022): 86–99. http://dx.doi.org/10.29413/abs.2022-7.5-1.10.
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Background. The incidence of diseases associated with impaired transport and oxidation of fatty acids is from 1:5,000 to 1:9,000 newborns. High morbidity, risk of death in the absence of timely correction, non-specificity of clinical manifestations define the importance of their timely laboratory diagnosis based on the determination of free carnitine and acylcarnitines in the blood. Reference values for free carnitine and acylcarnitines vary in different populations. The aim. To determine the reference intervals of free carnitine and acylcarnitines in newborns of the Irkutsk region and to compare them with similar reference intervals in newborns in other countries. Methods. The analysis of 229 samples of drу blood spots of healthy newborn children of the Irkutsk region aged from 0 to 7 days was carried out. Analysis of acylcarnitine concentrations was performed using high performance liquid chromatography with tandem mass spectrometry. Results. 2.5 and 97.5 percentiles (µmol/l) were calculateed for 13 acylcarnitines: C0 – [8.78; 38.08]; C2 – [3.55; 19.09]; C3 – [0.33; 1.96]; C4 – [0.08; 0.51]; C5 – [0.06; 0.44]; C5DC – [0.03; 0.17]; C6 – [0.01; 0.07]; C8 – [0.01; 0.07]; C10 – [0.02; 0.07]; C12 – [0.04; 0.51]; C14 – [0.07; 0.24]; C16 – [0.58; 3.25]; C18 – [0.35; 1.16]. Conclusion. Differences in acylcarnitine reference intervals were found: compared with other countries, the concentrations of reference intervals for C0, C2, C3, C5DC, C8, C10, C14, C16 and C18 were lower in our study, reference intervals for C5 and C12 were higher in our country.
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Brass, E. P., and S. P. Stabler. "Carnitine metabolism in the vitamin B-12-deficient rat." Biochemical Journal 255, no. 1 (October 1, 1988): 153–59. http://dx.doi.org/10.1042/bj2550153.
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In vitamin B-12 (cobalamin) deficiency the metabolism of propionyl-CoA and methylmalonyl-CoA are inhibited secondarily to decreased L-methylmalonyl-CoA mutase activity. Production of acylcarnitines provides a mechanism for removing acyl groups and liberating CoA under conditions of impaired acyl-CoA utilization. Carnitine metabolism was studied in the vitamin B-12-deficient rat to define the relationship between alterations in acylcarnitine generation and the development of methylmalonic aciduria. Urinary excretion of methylmalonic acid was increased 200-fold in vitamin B-12-deficient rats as compared with controls. Urinary acylcarnitine excretion was increased in the vitamin B-12-deficient animals by 70%. This increase in urinary acylcarnitine excretion correlated with the degree of metabolic impairment as measured by the urinary methylmalonic acid elimination. Urinary propionylcarnitine excretion averaged 11 nmol/day in control rats and 120 nmol/day in the vitamin B-12-deficient group. The fraction of total carnitine present as short-chain acylcarnitines in the plasma and liver of vitamin B-12-deficient rats was increased as compared with controls. When the rats were fasted for 48 h, relative or absolute increases were seen in the urine, plasma, liver and skeletal-muscle acylcarnitine content of the vitamin B-12-deficient rats as compared with controls. Thus vitamin B-12 deficiency was associated with a redistribution of carnitine towards acylcarnitines. Propionylcarnitine was a significant constituent of the acylcarnitine pool in the vitamin B-12-deficient animals. The changes in carnitine metabolism were consistent with the changes in CoA metabolism known to occur with vitamin B-12 deficiency. The vitamin B-12-deficient rat provides a model system for studying carnitine metabolism in the methylmalonic acidurias.
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Mednova, Irina A., Alexander A. Chernonosov, Marat F. Kasakin, Elena G. Kornetova, Arkadiy V. Semke, Nikolay A. Bokhan, Vladimir V. Koval, and Svetlana A. Ivanova. "Amino Acid and Acylcarnitine Levels in Chronic Patients with Schizophrenia: A Preliminary Study." Metabolites 11, no. 1 (January 5, 2021): 34. http://dx.doi.org/10.3390/metabo11010034.
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Amino acids and acylcarnitines play an important role as substrates and intermediate products in most of pathways involved in schizophrenia development such as mitochondrial dysfunction, inflammation, lipid oxidation, DNA damage, oxidative stress, and apoptosis. It seems relevant to use an integrated approach with ‘omics’ technology to study their contribution. The aim of our study was to investigate serum amino acid and acylcarnitine levels in antipsychotics-treated patients with chronic schizophrenia compared with healthy donors. We measured serum levels of 15 amino acids and 30 acylcarnitines in 37 patients with schizophrenia and 36 healthy donors by means of tandem mass spectrometry. In summary, patients with chronic schizophrenia had an altered concentration of a few amino acids and acylcarnitines in comparison to the healthy probands. Further research is needed to assess and understand the identified changes.
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Babu, Ambrin Farizah, Ville Mikael Koistinen, Soile Turunen, Gloria Solano-Aguilar, Joseph F. Urban, Iman Zarei, and Kati Hanhineva. "Identification and Distribution of Sterols, Bile Acids, and Acylcarnitines by LC–MS/MS in Humans, Mice, and Pigs—A Qualitative Analysis." Metabolites 12, no. 1 (January 7, 2022): 49. http://dx.doi.org/10.3390/metabo12010049.
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Sterols, bile acids, and acylcarnitines are key players in human metabolism. Precise annotations of these metabolites with mass spectrometry analytics are challenging because of the presence of several isomers and stereoisomers, variability in ionization, and their relatively low concentrations in biological samples. Herein, we present a sensitive and simple qualitative LC–MS/MS (liquid chromatography with tandem mass spectrometry) method by utilizing a set of pure chemical standards to facilitate the identification and distribution of sterols, bile acids, and acylcarnitines in biological samples including human stool and plasma; mouse ileum, cecum, jejunum content, duodenum content, and liver; and pig bile, proximal colon, cecum, heart, stool, and liver. With this method, we detected 24 sterol, 32 bile acid, and 27 acylcarnitine standards in one analysis that were separated within 13 min by reversed-phase chromatography. Further, we observed different sterol, bile acid, and acylcarnitine profiles for the different biological samples across the different species. The simultaneous detection and annotation of sterols, bile acids, and acylcarnitines from reference standards and biological samples with high precision represents a valuable tool for screening these metabolites in routine scientific research.
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Meadows, Jamie A., and Matthew J. Wargo. "Characterization of Pseudomonas aeruginosa Growth onO-Acylcarnitines and Identification of a Short-Chain Acylcarnitine Hydrolase." Applied and Environmental Microbiology 79, no. 11 (March 22, 2013): 3355–63. http://dx.doi.org/10.1128/aem.03943-12.
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ABSTRACTTo survive in various environments, from host tissue to soil, opportunistic bacterial pathogens must be metabolically flexible and able to use a variety of nutrient sources. We are interested inPseudomonas aeruginosa's catabolism of quaternary amine compounds that are prevalent in association with eukaryotes. Carnitine and acylcarnitines are abundant in animal tissues, particularly skeletal muscle, and are used to shuttle fatty acids in and out of the mitochondria, where they undergo β-oxidation. We previously identified the genes required for carnitine catabolism as the first four genes in the carnitine operon (caiX-cdhCAB;PA5388toPA5385). However, the last gene in the operon,PA5384, was not required for carnitine catabolism. We were interested in determining the function of PA5384. Bioinformatic analyses along with the genomic location ofPA5384led us to hypothesize a role for PA5384 in acylcarnitine catabolism. Here, we have characterized PA5384 as anl-enantiomer-specific short-chain acylcarnitine hydrolase that is required for growth and hydrolysis of acetyl- and butyrylcarnitine to carnitine and the respective short-chain fatty acid. The liberated carnitine and its downstream catabolic product, glycine betaine, are subsequently available to function as osmoprotectants in hyperosmotic environments and induce transcription of the virulence factor phospholipase C,plcH. Furthermore, we confirmed that acylcarnitines with 2- to 16-carbon chain lengths, except for octanoylcarnitine (8 carbons), can be utilized byP. aeruginosaas sole carbon and nitrogen sources. These findings expand our knowledge of short-chain acylcarnitine catabolism and also point to remaining questions related to acylcarnitine transport and hydrolysis of medium- and long-chain acylcarnitines.
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Fix, J. A., K. Engle, P. A. Porter, P. S. Leppert, S. J. Selk, C. R. Gardner, and J. Alexander. "Acylcarnitines: drug absorption-enhancing agents in the gastrointestinal tract." American Journal of Physiology-Gastrointestinal and Liver Physiology 251, no. 3 (September 1, 1986): G332—G340. http://dx.doi.org/10.1152/ajpgi.1986.251.3.g332.
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Acylcarnitines were tested as potential absorption-enhancing agents for drugs that are poorly absorbed from the gastrointestinal tract. Urethan-anesthetized Sprague-Dawley rats and conscious Beagle dogs were used. Palmitoyl-DL-carnitine was the most effective acylcarnitine tested, although significant increases in drug absorption were observed with acylcarnitines containing C12 through C18 fatty acid chains. Palmitoyl-DL-carnitine afforded significant increases in the absorption of cefoxitin, gentamicin, cytarabine, somatostatin analogue, and alpha-methyldopa. The response to palmitoyl-DL-carnitine was concentration dependent and reversible within 60-120 min. Histological examination of the intestinal tissue revealed no apparent change in mucosal structural integrity at doses of palmitoyl-DL-carnitine that resulted in increased drug absorption. The acylcarnitines were effective in increasing drug absorption from the small intestine and the rectal compartment of both rats and dogs. The data also demonstrated effectiveness with aqueous and solid dosage forms (Witepsol H-15 suppositories). The data suggest that acylcarnitines may be effective and safe absorption-enhancing agents for a variety of drugs.
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Bhattacharyya, Sudeepa, Mohamed Ali, William H. Smith, Paul E. Minkler, Maria S. Stoll, Charles L. Hoppel, and Sean H. Adams. "Anesthesia and bariatric surgery gut preparation alter plasma acylcarnitines reflective of mitochondrial fat and branched-chain amino acid oxidation." American Journal of Physiology-Endocrinology and Metabolism 313, no. 6 (December 1, 2017): E690—E698. http://dx.doi.org/10.1152/ajpendo.00222.2017.
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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.
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Schooneman, Marieke G., Frédéric M. Vaz, Sander M. Houten, and Maarten R. Soeters. "Acylcarnitines." Diabetes 62, no. 1 (December 20, 2012): 1–8. http://dx.doi.org/10.2337/db12-0466.
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Fiamoncini, Jarlei, Carina Fernandes Barbosa, José Arnoni Junior, José Araújo Junior, Cinthia Taglieri, Tiago Szego, Barbara Gelhaus, Heraldo Possolo de Souza, Hannelore Daniel, and Thais Martins de Lima. "Roux-en-Y Gastric Bypass Surgery Induces Distinct but Frequently Transient Effects on Acylcarnitine, Bile Acid and Phospholipid Levels." Metabolites 8, no. 4 (November 23, 2018): 83. http://dx.doi.org/10.3390/metabo8040083.
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Roux-en-Y gastric bypass (RYGB) is an effective method to achieve sustained weight loss, but the mechanisms responsible for RYGB effects have not yet been fully characterized. In this study, we profiled the concentrations of 143 lipid metabolites in dry blood spots (DBS) of RYGB patients. DBS from obese patients (BMI range 35–44 kg/m2) were collected 7 days before, 15 and 90 days after the surgery. LC-MS/MS was used to quantify acylcarnitines, phosphatidylcholines, sphingomyelins and bile acids. RYGB caused a rapid increase in acylcarnitine levels that proved to be only transient, contrasting with the sustained decrease in phosphatidylcholines and increase of sphingomyelins and bile acids. A PLS-DA analysis revealed a 3-component model (R2 = 0.9, Q2 = 0.74) with key metabolites responsible for the overall metabolite differences. These included the BCAA-derived acylcarnitines and sphingomyelins with 16 and 18 carbons. We found important correlations between the levels of BCAA-derived acylcarnitines and specific sphingomyelins with plasma cholesterol and triacylglycerol concentrations. Along with the marked weight loss and clinical improvements, RYGB induced specific alterations in plasma acylcarnitines, bile acid and phospholipid levels. This calls for more studies on RYGB effects aiming to elucidate the metabolic adaptations that follow this procedure.
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Song, Yiqing, Chen Lyu, Ming Li, Mohammad L. Rahman, Zhen Chen, Yeyi Zhu, Stefanie N. Hinkle, et al. "Plasma Acylcarnitines during Pregnancy and Neonatal Anthropometry: A Longitudinal Study in a Multiracial Cohort." Metabolites 11, no. 12 (December 17, 2021): 885. http://dx.doi.org/10.3390/metabo11120885.
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As surrogate readouts reflecting mitochondrial dysfunction, elevated levels of plasma acylcarnitines have been associated with cardiometabolic disorders, such as obesity, gestational diabetes, and type 2 diabetes. This study aimed to examine prospective associations of acylcarnitine profiles across gestation with neonatal anthropometry, including birthweight, birthweight z score, body length, sum of skinfolds, and sum of body circumferences. We quantified 28 acylcarnitines using electrospray ionization tandem mass spectrometry in plasma collected at gestational weeks 10–14, 15–26, 23–31, and 33–39 among 321 pregnant women from the National Institute of Child Health and Human Development (NICHD) Fetal Growth Studies-Singletons. A latent-class trajectory approach was applied to identify trajectories of acylcarnitines across gestation. We examined the associations of individual acylcarnitines and distinct trajectory groups with neonatal anthropometry using weighted generalized linear models adjusting for maternal age, race/ethnicity, education, parity, gestational age at blood collection, and pre-pregnancy body mass index (BMI). We identified three distinct trajectory groups in C2, C3, and C4 and two trajectory groups in C5, C10, C5–DC, C8:1, C10:1, and C12, respectively. Women with nonlinear decreasing C12 levels across gestation (5.7%) had offspring with significantly lower birthweight (−475 g; 95% CI, −942, −6.79), birthweight z score (−0.39, −0.71, −0.06), and birth length (−1.38 cm, −2.49, −0.27) than those with persistently stable C12 levels (94.3%) (all nominal p value < 0.05). Women with consistently higher levels of C10 (6.1%) had offspring with thicker sum of skinfolds (4.91 mm, 0.85, 8.98) than did women with lower levels (93.9%) during pregnancy, whereas women with lower C10:1 levels (12.6%) had offspring with thicker sum of skinfolds (3.23 mm, 0.19, 6.27) than did women with abruptly increasing levels (87.4%) (p < 0.05). In conclusion, this study suggests that distinctive trajectories of C10, C10:1, and C12 acylcarnitine levels throughout pregnancy were significantly associated with neonatal anthropometry.
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McCoin, Colin S., Trina A. Knotts, Kikumi D. Ono-Moore, Pieter J. Oort, and Sean H. Adams. "Long-chain acylcarnitines activate cell stress and myokine release in C2C12 myotubes: calcium-dependent and -independent effects." American Journal of Physiology-Endocrinology and Metabolism 308, no. 11 (June 1, 2015): E990—E1000. http://dx.doi.org/10.1152/ajpendo.00602.2014.
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Acylcarnitines, important lipid biomarkers reflective of acyl-CoA status, are metabolites that possess bioactive and inflammatory properties. This study examined the potential for long-chain acylcarnitines to activate cellular inflammatory, stress, and death pathways in a skeletal muscle model. Differentiated C2C12 myotubes treated with l-C14, C16, C18, and C18:1 carnitine displayed dose-dependent increases in IL-6 production with a concomitant rise in markers of cell permeability and death, which was not observed for shorter chain lengths. l-C16 carnitine, used as a representative long-chain acylcarnitine at initial extracellular concentrations ≥25 μM, increased IL-6 production 4.1-, 14.9-, and 31.4-fold over vehicle at 25, 50, and 100 μM. Additionally, l-C16 carnitine activated c-Jun NH2-terminal kinase, extracellular signal-regulated kinase, and p38 mitogen-activated protein kinase between 2.5- and 11-fold and induced cell injury and death within 6 h with modest activation of the apoptotic caspase-3 protein. l-C16 carnitine rapidly increased intracellular calcium, most clearly by 10 μM, implicating calcium as a potential mechanism for some activities of long-chain acylcarnitines. The intracellular calcium chelator BAPTA-AM blunted l-C16 carnitine-mediated IL-6 production by >65%. However, BAPTA-AM did not attenuate cell permeability and death responses, indicating that these outcomes are calcium independent. The 16-carbon zwitterionic compound amidosulfobetaine-16 qualitatively mimicked the l-C16 carnitine-associated cell stress outcomes, suggesting that the effects of high experimental concentrations of long-chain acylcarnitines are through membrane disruption. Herein, a model is proposed in which acylcarnitine cell membrane interactions take place along a spectrum of cellular concentrations encountered in physiological-to-pathophysiological conditions, thus regulating function of membrane-based systems and impacting cell biology.
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Deda, Olga, Eleftherios Panteris, Thomas Meikopoulos, Olga Begou, Thomai Mouskeftara, Efstratios Karagiannidis, Andreas S. Papazoglou, Georgios Sianos, Georgios Theodoridis, and Helen Gika. "Correlation of Serum Acylcarnitines with Clinical Presentation and Severity of Coronary Artery Disease." Biomolecules 12, no. 3 (February 23, 2022): 354. http://dx.doi.org/10.3390/biom12030354.
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Recent studies support that acylcarnitines exert a significant role in cardiovascular disease development and progression. The aim of this metabolomics-based study was to investigate the association of serum acylcarnitine levels with coronary artery disease (CAD) severity, as assessed via SYNTAX Score. Within the context of the prospective CorLipid trial (NCT04580173), the levels of 13 circulating acylcarnitines were accurately determined through a newly developed HILIC-MS/MS method in 958 patients undergoing coronary angiography in the AHEPA University Hospital of Thessaloniki, Greece. Patients presenting with acute coronary syndrome had significantly lower median acylcarnitine C8, C10, C16, C18:1 and C18:2 values, compared to patients with chronic coronary syndrome (p = 0.012, 0.007, 0.018, 0.011 and <0.001, respectively). Among CAD subgroups, median C5 levels were significantly decreased in unstable angina compared to STEMI (p = 0.026), while median C10, C16, C18:1 and C18:2 levels were higher in stable angina compared to STEMI (p = 0.019 p = 0.012, p = 0.013 and p < 0.001, respectively). Moreover, median C2, C3, C4 and C8 levels were significantly elevated in patients with diabetes mellitus (p < 0.001, <0.001, 0.029 and 0.011, respectively). Moreover, short-chain acylcarnitine C2, C4, C5 and C6 levels were elevated in patients with heavier calcification and lower left ventricular ejection fraction (LVEF) % (all p-values less than 0.05). With regard to CAD severity, median C4 and C5 levels were elevated and C16 and C18:2 levels were reduced in the high CAD complexity group with SYNTAX Score > 22 (p = 0.002, 0.024, 0.044 and 0.012, respectively), indicating a potential prognostic capability of those metabolites and of the ratio C4/C18:2 for the prediction of CAD severity. In conclusion, serum acylcarnitines could serve as clinically useful biomarkers leading to a more individualized management of patients with CAD, once further clinically oriented metabolomics-based studies provide similar evidence.
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Lyu, Chen, Yiqing Song, Ming Li, Mohammad Rahman, Yeyi Zhu, Stefanie Hinkle, Liwei Chen, et al. "Plasma Acylcarnitines During Pregnancy and Neonatal Anthropometry: A Longitudinal Study in a Multiracial Cohort." Current Developments in Nutrition 5, Supplement_2 (June 2021): 778. http://dx.doi.org/10.1093/cdn/nzab046_075.
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Abstract Objectives Plasma profile of acylcarnitines has been suggested to associate with adverse maternal outcomes such as gestational diabetes. However, data on their associations with neonatal outcomes are sparse. Therefore, this study aimed to examine the prospective profile of acylcarnitines across gestation and its association with neonatal anthropometry, including birthweight (BW), BW z-score, the sum of skinfolds (SSF), length, and circumferences. Methods Among 321 pregnant women from the NICHD Fetal Growth Studies-Singletons cohort, we quantified 28 acylcarnitines using electrospray ionization tandem mass spectrometry in the plasma at gestational weeks 10–14, 15–26, 23–31 and 33–39, accordingly. We firstly applied a latent-class trajectory approach to identify trajectories of acylcarnitines across gestation, and secondly examined associations of individual acylcarnitine and distinct trajectory groups with neonatal anthropometry using weighted linear models with robust standard errors, adjusting for maternal age, race/ethnicity, education, parity, gestational week of blood collection, and pre-pregnancy body mass index. Results We identified three distinct trajectory groups of C2, C3 and C4, and two trajectory groups of C5, C10, C5-DC, C8:1, C10:1 and C12, respectively. Newborns of women with nonlinear decline of C12 levels across gestation (5.7%) had significantly smaller BW (−475 g; 95% CI: −942, −6.79 g), BW z-score (−0.39; −0.71, −0.06), and length (−1.38 cm; −2.49, −0.27 cm) than those with persistently stable C12 levels (94.3%). Newborns of women with consistently higher levels of C10 (6.1%) had greater sum of skinfolds (4.91 mm; 0.85, 8.98 mm) than those with lower levels (93.9%) across pregnancy, whereas newborns of women with declining C10:1 levels (12.6%) had larger sum of skinfolds (3.23 mm; 0.19, 6.27 mm) than those with abruptly increasing levels (87.4%). Conclusions In conclusion, gestational trajectories of C10, C10:1, and C12 acylcarnitine levels were significantly associated with neonatal anthropometry. Further studies are needed to verify and further explore the potential clinical utility of these findings. Funding Sources Eunice Kennedy Shriver National Institute of Child Health and Human Development intramural funding; American Recovery and Reinvestment Act funding.
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Wang, Feijie, Liang Sun, Qi Sun, Liming Liang, Xianfu Gao, Rongxia Li, An Pan, et al. "Associations of Plasma Amino Acid and Acylcarnitine Profiles with Incident Reduced Glomerular Filtration Rate." Clinical Journal of the American Society of Nephrology 13, no. 4 (March 8, 2018): 560–68. http://dx.doi.org/10.2215/cjn.07650717.
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Background and objectivesMetabolomics is instrumental in identifying novel biomarkers of kidney function to aid in the prevention and management of CKD. However, data linking the metabolome to incident eGFR are sparse, particularly in Asian populations with different genetic backgrounds and environmental exposures. Therefore, we aimed to investigate the associations of amino acid and acylcarnitine profiles with change in eGFR in a Chinese cohort.Design, setting, participants, & measurementsThis study included 1765 community-living Chinese adults aged 50–70 years with baseline eGFR≥60 ml/min per 1.73 m2. At baseline, 22 amino acids and 34 acylcarnitines in plasma were quantified by gas or liquid chromatography coupled with mass spectrometry. Annual rate of change in eGFR was calculated, and incident eGFR decline was defined as eGFR<60 ml/min per 1.73 m2 by the end of 6 years of follow-up.ResultsThe mean (SD) unadjusted annual change in eGFR was 2.2±2.0 ml/min per 1.73 m2 and the incidence of reduced eGFR was 16%. After Bonferroni correction, 13 of 56 metabolites were significantly associated with annual eGFR change. After multivariable adjustment of baseline covariates, including baseline eGFR, seven of the 13 metabolites, including cysteine, long-chain acylcarnitines (C14:1OH, C18, C18:2, and C20:4), and other acylcarnitines (C3DC and C10), were significantly associated with incident reduced eGFR (relative risks ranged from 1.16 to 1.25 per SD increment of metabolites; P<3.8E-03 after Bonferroni correction of multiple testing of the 13 metabolites). Moreover, principal component analysis identified two factors, consisting of cysteine and long-chain acylcarnitines, respectively, that were associated with incident reduced eGFR.ConclusionsElevated plasma levels of cysteine and a panel of acylcarnitines were associated with a higher incidence of reduced eGFR in Chinese adults, independent of baseline eGFR and other conventional risk factors.
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Hiatt, W. R., D. Nawaz, and E. P. Brass. "Carnitine metabolism during exercise in patients with peripheral vascular disease." Journal of Applied Physiology 62, no. 6 (June 1, 1987): 2383–87. http://dx.doi.org/10.1152/jappl.1987.62.6.2383.
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The distribution between carnitine and the acyl derivatives of carnitine reflects changes in the metabolic state of a variety of tissues. Patients with peripheral vascular disease (PVD) develop skeletal muscle ischemia with exertion. This impairment in oxidative metabolism during exercise may result in the generation of acylcarnitines. To test this hypothesis, 11 patients with PVD and 7 age-matched control subjects were evaluated with graded treadmill exercise. Subjects with PVD walked to maximal claudication pain at a peak O2 consumption (VO2) of 19.9 +/- 1.3 ml X kg-1 X min-1 (mean +/- SE). Control subjects were taken to a near-maximal work load at a VO2 of 31.3 +/- 1.0 ml X kg-1 X min-1. In patients with PVD, the plasma concentration of total acid-soluble, long-chain acylcarnitine and total carnitine was increased at peak exercise compared with resting values. Four minutes postexercise, the plasma short-chain acylcarnitine concentration was also increased. In control subjects taken to the higher work load, only the long-chain acylcarnitine concentration was increased at peak exercise. In patients with PVD, plasma short-chain acylcarnitine concentration at rest was negatively correlated with subsequent maximal walking time (r = -0.51, P less than 0.05). In conclusion, acylcarnitines increased in patients with PVD who walked to maximal claudication pain, whereas control subjects did not show equivalent changes even when taken to a higher work load. The relationship between short-chain acylcarnitine concentration at rest and subsequent exercise performance suggests that repeated episodes of ischemia may cause chronic accumulation of short-chain acylcarnitine in plasma in proportion to the severity of disease.(ABSTRACT TRUNCATED AT 250 WORDS)
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Michel, Miriam, Karl-Otto Dubowy, Manuela Zlamy, Daniela Karall, Mark Gordian Adam, Andreas Entenmann, Markus Andreas Keller, et al. "Targeted metabolomic analysis of serum phospholipid and acylcarnitine in the adult Fontan patient with a dominant left ventricle." Therapeutic Advances in Chronic Disease 11 (January 2020): 204062232091603. http://dx.doi.org/10.1177/2040622320916031.
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Background: Patients with a Fontan circulation have altered cholesterol and lipoprotein values. We analysed small organic molecules in extended phopsholipid and acylcarnitine metabolic pathways (‘metabolomes’) in adult Fontan patients with a dominant left ventricle, seeking differences between profiles in baseline and Fontan circulations. Methods: In an observational matched cross-sectional study, we compared phosphatidylcholine (PC), sphingomyelin (SM), and acylcarnitine metabolomes (105 analytes; AbsoluteIDQ® p180 kit (Biocrates Life Sciences AG, Innsbruck, Austria) in 20 adult Fontan patients having a dominant left ventricle with those in 20 age- and sex-matched healthy controls. Results: Serum levels of total PC ( q-value 0.01), total SM ( q-value 0.0002) were significantly lower, and total acylcarnitines ( q-value 0.02) were significantly higher in patients than in controls. After normalisation of data, serum levels of 12 PC and 1 SM Fontan patients were significantly lower ( q-values <0.05), and concentrations of 3 acylcarnitines were significantly higher than those in controls ( q-values <0.05). Conclusion: Metabolomic profiling can use small specimens to identify biomarker patterns that track derangement in multiple metabolic pathways. The striking alterations in the phospholipid and acylcarnitine metabolome that we found in Fontan patients may reflect altered cell signalling and metabolism as found in heart failure in biventricular patients, chronic low-level inflammation, and alteration of functional or structural properties of lymphatic or blood vessels. Trial registration number: ClinicalTrials.gov Identifier NCT03886935
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Hiatt, W. R., E. E. Wolfel, J. G. Regensteiner, and E. P. Brass. "Skeletal muscle carnitine metabolism in patients with unilateral peripheral arterial disease." Journal of Applied Physiology 73, no. 1 (July 1, 1992): 346–53. http://dx.doi.org/10.1152/jappl.1992.73.1.346.
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Patients with peripheral arterial disease (PAD) have abnormalities of carnitine metabolism that may contribute to their functional impairment. To test the hypothesis that muscle acylcarnitine generation (intermediates in oxidative metabolism) in patients with PAD provides a marker of the muscle dysfunction, 10 patients with unilateral PAD and 6 age-matched control subjects were studied at rest, and the patients were studied during exercise. At rest, biopsies of the gastrocnemius muscle in the patients' nonsymptomatic leg revealed a normal carnitine pool and lactate content compared with control subjects. In contrast, the patients' diseased leg had higher contents of lactate and long-chain acylcarnitines than controls. The muscle short-chain acylcarnitine content in the patients' diseased leg at rest was inversely correlated with peak exercise performance (r = -0.75, P less than 0.05). With graded treadmill exercise, only patients who exceeded their individual lactate threshold had an increase in muscle short-chain acylcarnitine content in the nonsymptomatic leg, which was identical to the muscle carnitine response in normal subjects. In the patients' diseased leg, muscle short-chain acylcarnitine content increased with exercise from 440 +/- 130 to 900 +/- 200 (SE) nmol/g (P less than 0.05). In contrast to the nonsymptomatic leg, there was no increase in muscle lactate content in the diseased leg with exercise, and the change in muscle carnitine metabolism was correlated with exercise duration (r = 0.82, P less than 0.01) and not with the lactate threshold. We conclude that energy metabolism in ischemic muscle of patients with PAD is characterized by the accumulation of acylcarnitines.(ABSTRACT TRUNCATED AT 250 WORDS)
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Lin, Yiming, Weifeng Zhang, Zhixu Chen, Chunmei Lin, Weihua Lin, Qingliu Fu, Weilin Peng, and Dongmei Chen. "Newborn screening and molecular features of patients with multiple acyl-CoA dehydrogenase deficiency in Quanzhou, China." Journal of Pediatric Endocrinology and Metabolism 34, no. 5 (April 7, 2021): 649–52. http://dx.doi.org/10.1515/jpem-2020-0694.
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Abstract Objectives Multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder of fatty acid, amino acid and choline metabolism. Late-onset MADD is caused by ETFDH mutations and is the most common lipid storage myopathy in China. However, few patients with MADD have been identified through newborn screening (NBS). This study assessed the acylcarnitine profiles and molecular features of patients with MADD identified through NBS. Methods From January 2014 to June 2020, 479,786 newborns screened via tandem mass spectrometry were recruited for this study. Newborns with elevated levels of multiple acylcarnitines were recalled, those who tested positive in the reassessment were referred for genetic analysis. Results Of 479,786 newborns screened, six were diagnosed with MADD. The MADD incidence in the Chinese population was estimated to be 1:79,964. Initial NBS revealed five patients with typical elevations in the levels of multiple acylcarnitines; however, in one patient, acylcarnitine levels were in the normal reference range during recall. Notably, one patient only exhibited a mildly increased isovalerylcarnitine (C5) level at NBS. The patient with an atypical acylcarnitine profile was diagnosed with MADD by targeted gene sequencing. Six distinct ETFDH missense variants were identified, with the most common variant being c.250G>A (p.A84T), with an allelic frequency of 58.35 (7/12). Conclusions These findings revealed that it is easy for patients with MADD to go unidentified, as they may have atypical acylcarnitine profiles at NBS and the recall stage, indicating the value of genetic analysis for confirming suspected inherited metabolic disorders in the NBS program. Therefore, false-negative (FN) results may be reduced by combining tandem mass spectrometry (MS/MS) with genetic testing in NBS for MADD.
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Mitro, Susanna D., Jing Wu, Mohammad L. Rahman, Yaqi Cao, Yeyi Zhu, Zhen Chen, Liwei Chen, et al. "Longitudinal Plasma Metabolomics Profile in Pregnancy—A Study in an Ethnically Diverse U.S. Pregnancy Cohort." Nutrients 13, no. 9 (September 1, 2021): 3080. http://dx.doi.org/10.3390/nu13093080.
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Amino acids, fatty acids, and acylcarnitine metabolites play a pivotal role in maternal and fetal health, but profiles of these metabolites over pregnancy are not completely established. We described longitudinal trajectories of targeted amino acids, fatty acids, and acylcarnitines in pregnancy. We quantified 102 metabolites and combinations (37 fatty acids, 37 amino acids, and 28 acylcarnitines) in plasma samples from pregnant women in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Fetal Growth Studies—Singletons cohort (n = 214 women at 10–14 and 15–26 weeks, 107 at 26–31 weeks, and 103 at 33–39 weeks). We used linear mixed models to estimate metabolite trajectories and examined variation by body mass index (BMI), race/ethnicity, and fetal sex. After excluding largely undetected metabolites, we analyzed 77 metabolites and combinations. Levels of 13 of 15 acylcarnitines, 7 of 25 amino acids, and 18 of 37 fatty acids significantly declined over gestation, while 8 of 25 amino acids and 10 of 37 fatty acids significantly increased. Several trajectories appeared to differ by BMI, race/ethnicity, and fetal sex although no tests for interactions remained significant after multiple testing correction. Future studies merit longitudinal measurements to capture metabolite changes in pregnancy, and larger samples to examine modifying effects of maternal and fetal characteristics.
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Gunther, Samuel H., Chin Meng Khoo, E.-Shyong Tai, Xueling Sim, Jean-Paul Kovalik, Jianhong Ching, Jeannette J. Lee, and Rob M. van Dam. "Serum acylcarnitines and amino acids and risk of type 2 diabetes in a multiethnic Asian population." BMJ Open Diabetes Research & Care 8, no. 1 (October 2020): e001315. http://dx.doi.org/10.1136/bmjdrc-2020-001315.
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IntroductionWe evaluated whether concentrations of serum acylcarnitines and amino acids are associated with risk of type 2 diabetes and can improve predictive diabetes models in an Asian population.Research design and methodsWe used data from 3313 male and female participants from the Singapore Prospective Study Program cohort who were diabetes-free at baseline. The average age at baseline was 48.0 years (SD: 11.9 years), and participants were of Chinese, Malay, and Indian ethnicity. Diabetes cases were identified through self-reported physician diagnosis, fasting glucose and glycated hemoglobin concentrations, and linkage to national disease registries. We measured fasting serum concentrations of 45 acylcarnitines and 14 amino acids. The association between metabolites and incident diabetes was modeled using Cox proportional hazards regression with adjustment for age, sex, ethnicity, height, and parental history of diabetes, and correction for multiple testing. Metabolites were added to the Atherosclerosis Risk in Communities (ARIC) predictive diabetes risk model to assess whether they could increase the area under the receiver operating characteristic curve (AUC).ResultsParticipants were followed up for an average of 8.4 years (SD: 2.1 years), during which time 314 developed diabetes. Branched-chain amino acids (HR: 1.477 per SD; 95% CI 1.325 to 1.647) and the alanine to glycine ratio (HR: 1.572; 95% CI 1.426 to 1.733) were most strongly associated with diabetes risk. Additionally, the acylcarnitines C4 and C16-OH, and the amino acids alanine, combined glutamate/glutamine, ornithine, phenylalanine, proline, and tyrosine were significantly associated with higher diabetes risk, and the acylcarnitine C8-DC and amino acids glycine and serine with lower risk. Adding selected metabolites to the ARIC model resulted in a significant increase in AUC from 0.836 to 0.846.ConclusionsWe identified acylcarnitines and amino acids associated with risk of type 2 diabetes in an Asian population. A subset of these modestly improved the prediction of diabetes when added to an established diabetes risk model.
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Ferro, F., T. A. Tran, A. Ouille, D. Babuty, F. Labarthe, and J. Y. Le Guennec. "G012 Long-chain acylcarnitines regulate ihERG while medium-chain acylcarnitine do not." Archives of Cardiovascular Diseases 102 (March 2009): S66. http://dx.doi.org/10.1016/s1875-2136(09)72287-9.
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Brass, E. P., and C. L. Hoppel. "Quantification of acylcarnitines." Clinical Chemistry 31, no. 3 (March 1, 1985): 491–92. http://dx.doi.org/10.1093/clinchem/31.3.491.
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Reuter, Stephanie E., and Allan M. Evans. "Carnitine and Acylcarnitines." Clinical Pharmacokinetics 51, no. 9 (September 2012): 553–72. http://dx.doi.org/10.1007/bf03261931.
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De Sousa, C., N. W. Y. Leung, R. A. Chalmers, and T. J. Peters. "Free and total carnitine and acylcarnitine content of plasma, urine, liver and muscle of alcoholics." Clinical Science 75, no. 4 (October 1, 1988): 437–40. http://dx.doi.org/10.1042/cs0750437.
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1. Plasma and urine free and total carnitine and acylcarnitine levels were assayed in 12 control subjects and 20 chronic alcoholics with fatty liver. Although the alcoholics had a wider range of values than the controls, there was no significant difference between the two groups. 2. Hepatic free and total carnitine and long- and short-chain acylcarnitines were assayed by a radioenzymatic method in samples from seven control subjects and seven alcoholics. No significant differences in any of the indices were noted between the patient and control groups and it was concluded that carnitine deficiency did not contribute to alcoholic fatty liver in patients without cirrhosis. 3. Skeletal muscle free and total carnitine and long-and short-chain acylcarnitines were assayed in eight alcoholics and seven control subjects. The alcoholics had significantly higher total and free carnitine levels. It is suggested that this reflects a selective enrichment of the biopsy sample with type I carnitine-rich fibres due to the type II fibre atrophy found in approximately half the patients.
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Cavedon, Catia Testa, Pierre Bourdoux, Karl Mertens, Hong Vien Van Thi, Nadine Herremans, Corinne de Laet, and Philippe Goyens. "Age-Related Variations in Acylcarnitine and Free Carnitine Concentrations Measured by Tandem Mass Spectrometry." Clinical Chemistry 51, no. 4 (April 1, 2005): 745–52. http://dx.doi.org/10.1373/clinchem.2004.043646.
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Abstract Background: The acylcarnitine profiles obtained from dried blood spots on “Guthrie cards” have been widely used for the diagnosis and follow-up of children suspected of carrying an inherited error of metabolism, but little attention has been paid to potential age-related variations in the reference values. In this study, we evaluated the variations in free carnitine and acylcarnitine concentrations with age, as measured by tandem mass spectrometry. Methods: Filter-paper blood spots were collected from 433 healthy individuals over a period of 17 months. Eight age groups were defined: cord blood, 3–6 days (control group), 15–55 days, 2–18 months, 19–59 months, 5–10 years, 11–17 years, and 18–54 years. Free carnitine and acylcarnitines were measured for each individual. Mean values were calculated for each age group and compared with those for the control group. Results: Free carnitine was significantly higher in older children than in newborns (P <0.05), but the concentrations of several acylcarnitines tended to be significantly lower in cord blood and in groups of older children than in the control group. Only minor sex-related differences were observed. Conclusion: Although the risk of underdiagnosis of fatty acid oxidation disorders with the use of newborn values as reference can be considered as small, in some circumstances the use of age-related reference values may have a potential impact on the diagnosis and management of inherited errors of metabolism.
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Soeters, Maarten R., Hans P. Sauerwein, Marinus Duran, Ronald J. Wanders, Mariëtte T. Ackermans, Eric Fliers, Sander M. Houten, and Mireille J. Serlie. "Muscle acylcarnitines during short-term fasting in lean healthy men." Clinical Science 116, no. 7 (March 2, 2009): 585–92. http://dx.doi.org/10.1042/cs20080433.
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The transition from the fed to the fasted resting state is characterized by, among other things, changes in lipid metabolism and peripheral insulin resistance. Acylcarnitines have been suggested to play a role in insulin resistance, as well as other long-chain fatty acid metabolites. Plasma levels of long-chain acylcarnitines increase during fasting, but this is unknown for muscle long-chain acylcarnitines. In the present study we investigated whether muscle long-chain acylcarnitines increase during fasting and we investigated their relationship with glucose/fat oxidation and insulin sensitivity in lean healthy humans. After 14 h and 62 h of fasting, glucose fluxes, substrate oxidation, and plasma and muscle acylcarnitines were measured before and during a hyperinsulinaemic–euglycaemic clamp. Hyperinsulinaemia decreased long-chain muscle acylcarnitines after 14 h of fasting, but not after 62 h of fasting. In both the basal state and during the clamp, glucose oxidation was lower and fatty acid oxidation was higher after 62 h compared with 14 h of fasting. Absolute changes in glucose and fatty acid oxidation in the basal compared with hyperinsulinaemic state were not different. Muscle long-chain acylcarnitines did not correlate with glucose oxidation, fatty acid oxidation or insulin-mediated peripheral glucose uptake. After 62 h of fasting, the suppression of muscle long-chain acylcarnitines by insulin was attenuated compared with 14 h of fasting. Muscle long-chain acylcarnitines do not unconditionally reflect fatty acid oxidation. The higher fatty acid oxidation during hyperinsulinaemia after 62 h compared with 14 h of fasting, although the absolute decrease in fatty acid oxidation was not different, suggests a different set point.
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Bogusiewicz, Joanna, Katarzyna Burlikowska, Karol Jaroch, Paulina Zofia Gorynska, Krzysztof Gorynski, Marcin Birski, Jacek Furtak, Dariusz Paczkowski, Marek Harat, and Barbara Bojko. "Profiling of Carnitine Shuttle System Intermediates in Gliomas Using Solid-Phase Microextraction (SPME)." Molecules 26, no. 20 (October 10, 2021): 6112. http://dx.doi.org/10.3390/molecules26206112.
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Alterations in the carnitine shuttle system may be an indication of the presence of cancer. As such, in-depth analyses of this pathway in different malignant tumors could be important for the detection and treatment of this disease. The current study aims to assess the profiles of carnitine and acylcarnitines in gliomas with respect to their grade, the presence of isocitrate dehydrogenase (IDH) mutations, and 1p/19q co-deletion. Brain tumors obtained from 19 patients were sampled on-site using solid-phase microextraction (SPME) immediately following excision. Analytes were desorbed and then analyzed via liquid chromatography–high-resolution mass spectrometry. The results showed that SPME enabled the extraction of carnitine and 22 acylcarnitines. An analysis of the correlation factor revealed the presence of two separate clusters: short-chain and long-chain carnitine esters. Slightly higher carnitine and acylcarnitine concentrations were observed in the higher-malignancy tumor samples (high vs. low grade) and in those samples with worse projected clinical outcomes (without vs. with IDH mutation; without vs. with 1p/19q co-deletion). Thus, the proposed chemical biopsy approach offers a simple solution for on-site sampling that enables sample preservation, thus supporting comprehensive multi-method analyses.
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Rotter, Markus, Stefan Brandmaier, Marcela Covic, Katarzyna Burek, Johannes Hertel, Martina Troll, Erik Bader, et al. "Night Shift Work Affects Urine Metabolite Profiles of Nurses with Early Chronotype." Metabolites 8, no. 3 (August 21, 2018): 45. http://dx.doi.org/10.3390/metabo8030045.
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Night shift work can have a serious impact on health. Here, we assess whether and how night shift work influences the metabolite profiles, specifically with respect to different chronotype classes. We have recruited 100 women including 68 nurses working both, day shift and night shifts for up to 5 consecutive days and collected 3640 spontaneous urine samples. About 424 waking-up urine samples were measured using a targeted metabolomics approach. To account for urine dilution, we applied three methods to normalize the metabolite values: creatinine-, osmolality- and regression-based normalization. Based on linear mixed effect models, we found 31 metabolites significantly (false discovery rate <0.05) affected in nurses working in night shifts. One metabolite, acylcarnitine C10:2, was consistently identified with all three normalization methods. We further observed 11 and 4 metabolites significantly associated with night shift in early and late chronotype classes, respectively. Increased levels of medium- and long chain acylcarnitines indicate a strong impairment of the fatty acid oxidation. Our results show that night shift work influences acylcarnitines and BCAAs, particularly in nurses in the early chronotype class. Women with intermediate and late chronotypes appear to be less affected by night shift work.
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Elshenawy, Summer, Sara E. Pinney, Tami Stuart, Paschalis-Thomas Doulias, Gabriella Zura, Samuel Parry, Michal A. Elovitz, et al. "The Metabolomic Signature of the Placenta in Spontaneous Preterm Birth." International Journal of Molecular Sciences 21, no. 3 (February 4, 2020): 1043. http://dx.doi.org/10.3390/ijms21031043.
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The placenta is metabolically active and supports the growth of the fetus. We hypothesize that deficits in the capacity of the placenta to maintain bioenergetic and metabolic stability during pregnancy may result in spontaneous preterm birth (SPTB). To explore this hypothesis, we performed a nested cased control study of metabolomic signatures in placentas from women with SPTB (<36 weeks gestation) compared to normal pregnancies (≥38 weeks gestation). To control for the effects of gestational age on placenta metabolism, we also studied a subset of metabolites in non-laboring preterm and term Rhesus monkeys. Comprehensive quantification of metabolites demonstrated a significant elevation in the levels of amino acids, prostaglandins, sphingolipids, lysolipids, and acylcarnitines in SPTB placenta compared to term placenta. Additional quantification of placental acylcarnitines by tandem mass spectrometry confirmed the significant elevation in SPTB human, with no significant differences between midgestation and term placenta in Rhesus macaque. Fatty acid oxidation as measured by the flux of 3H-palmitate in SPTB placenta was lower than term. Collectively, significant and biologically relevant alterations in the placenta metabolome were identified in SPTB placenta. Altered acylcarnitine levels and fatty acid oxidation suggest that disruption in normal substrate metabolism is associated with SPTB.
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Jafri, Lena, Aysha Habib Khan, Muhammad Ilyas, Imran Nisar, Javairia Khalid, Hafsa Majid, Aneeta Hotwani, and Fyezah Jehan. "Metabolomics of a neonatal cohort from the Alliance for Maternal and Newborn Health Improvement biorepository: Effect of preanalytical variables on reference intervals." PLOS ONE 18, no. 1 (January 6, 2023): e0279931. http://dx.doi.org/10.1371/journal.pone.0279931.
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Background The study was conducted to determine reference interval (RI) and evaluate the effect of preanalytical variables on Dried blood spot (DBS)-amino acids, acylcarnitines and succinylacetone of neonates. Methodology DBS samples were collected within 48–72 hours of life. Samples were analyzed for biochemical markers on tandem mass spectrometer at the University of Iowa. Comparison of RI across various categorical variables were performed. Results A total of 610 reference samples were selected based on exclusion criteria; 53.2% being females. Mean gestational age (GA) of mothers at the time of delivery was 38.7±1.6 weeks; 24.5% neonates were of low birth weight and 14.3% were preterm. Out of the total 610 neonates, 23.1% were small for GA. Reference intervals were generated for eleven amino acids, thirty-two acylcarnitines and succinylacetone concentrations. Markers were evaluated with respect to the influence of gender, GA, weight and time of sampling and statistically significant minimal differences were observed for some biomarkers. Conclusion RI for amino acids, succinylacetone and acylcarnitine on DBS has been established for healthy neonates, which could be of use in the clinical practice. Clinically significant effect of GA, weight, gender and time of sampling on these markers were not identified.
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Yuasa, Miori, Ikue Hata, Keiichi Sugihara, Yuko Isozaki, Yusei Ohshima, Keiichi Hara, Go Tajima, and Yosuke Shigematsu. "Evaluation of Metabolic Defects in Fatty Acid Oxidation Using Peripheral Blood Mononuclear Cells Loaded with Deuterium-Labeled Fatty Acids." Disease Markers 2019 (February 7, 2019): 1–11. http://dx.doi.org/10.1155/2019/2984747.
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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 β-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.
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Afshinnia, Farsad, Thekkelnaycke M. Rajendiran, Tanu Soni, Jaeman Byun, Stefanie Wernisch, Kelli M. Sas, Jennifer Hawkins, et al. "Impaired β-Oxidation and Altered Complex Lipid Fatty Acid Partitioning with Advancing CKD." Journal of the American Society of Nephrology 29, no. 1 (October 11, 2017): 295–306. http://dx.doi.org/10.1681/asn.2017030350.
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Studies of lipids in CKD, including ESRD, have been limited to measures of conventional lipid profiles. We aimed to systematically identify 17 different lipid classes and associate the abundance thereof with alterations in acylcarnitines, a metric of β-oxidation, across stages of CKD. From the Clinical Phenotyping Resource and Biobank Core (CPROBE) cohort of 1235 adults, we selected a panel of 214 participants: 36 with stage 1 or 2 CKD, 99 with stage 3 CKD, 61 with stage 4 CKD, and 18 with stage 5 CKD. Among participants, 110 were men (51.4%), 64 were black (29.9%), and 150 were white (70.1%), and the mean (SD) age was 60 (16) years old. We measured plasma lipids and acylcarnitines using liquid chromatography-mass spectrometry. Overall, we identified 330 different lipids across 17 different classes. Compared with earlier stages, stage 5 CKD associated with a higher abundance of saturated C16–C20 free fatty acids (FFAs) and long polyunsaturated complex lipids. Long-chain–to–intermediate-chain acylcarnitine ratio, a marker of efficiency of β-oxidation, exhibited a graded decrease from stage 2 to 5 CKD (P<0.001). Additionally, multiple linear regression revealed that the long-chain–to–intermediate-chain acylcarnitine ratio inversely associated with polyunsaturated long complex lipid subclasses and the C16–C20 FFAs but directly associated with short complex lipids with fewer double bonds. We conclude that increased abundance of saturated C16–C20 FFAs coupled with impaired β-oxidation of FFAs and inverse partitioning into complex lipids may be mechanisms underpinning lipid metabolism changes that typify advancing CKD.
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Rashed, M. S., P. T. Ozand, M. J. Bennett, J. J. Barnard, D. R. Govindaraju, and P. Rinaldo. "Inborn errors of metabolism diagnosed in sudden death cases by acylcarnitine analysis of postmortem bile." Clinical Chemistry 41, no. 8 (August 1, 1995): 1109–14. http://dx.doi.org/10.1093/clinchem/41.8.1109.
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Abstract Fatty acid oxidation (FAO) disorders represent a frequently misdiagnosed group of inborn errors of metabolism. Some patients die at the first episode of fasting intolerance and, if appropriate investigations are not undertaken, often meet the criteria of sudden infant death syndrome (SIDS). To expand existing protocols for the postmortem diagnosis of FAO and other metabolic disorders, we tested the hypothesis that analysis for acylcarnitine in bile, a specimen readily available at autopsy, may be utilized for diagnostic purposes. Using electrospray/tandem mass spectrometry, we analyzed for acylcarnitine postmortem bile specimens from two infants with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency, one infant with glutaryl-CoA dehydrogenase deficiency, and 17 uninformative SIDS cases as controls. The affected cases, and none of the controls, showed marked accumulation of C10-C18 acylcarnitines or glutarylcarnitine (acyl/free carnitine ratio: 5.2, 2.7, and 1.9, respectively; controls 0.2 +/- 0.1). In one patient, all other diagnostic methods were uninformative, suggesting that bile acylcarnitine profiling could lead to identification of previously overlooked cases.
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Jones, Lauren L., David A. McDonald, and Peggy R. Borum. "Acylcarnitines: Role in brain." Progress in Lipid Research 49, no. 1 (January 2010): 61–75. http://dx.doi.org/10.1016/j.plipres.2009.08.004.
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Sewell, A. C., and H. J. Böhles. "Acylcarnitines in intermediary metabolism." European Journal of Pediatrics 154, no. 11 (November 1995): 871–77. http://dx.doi.org/10.1007/bf01957495.
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Johnson, David W. "Synthesis of dicarboxylic acylcarnitines." Chemistry and Physics of Lipids 129, no. 2 (May 2004): 161–71. http://dx.doi.org/10.1016/j.chemphyslip.2004.01.001.
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Park, Deung-Dae, Bernd M. Gahr, Julia Krause, Wolfgang Rottbauer, Tanja Zeller, and Steffen Just. "Long-Chain Acyl-Carnitines Interfere with Mitochondrial ATP Production Leading to Cardiac Dysfunction in Zebrafish." International Journal of Molecular Sciences 22, no. 16 (August 6, 2021): 8468. http://dx.doi.org/10.3390/ijms22168468.
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In the human heart, the energy supplied by the production of ATP is predominately accomplished by ß-oxidation in mitochondria, using fatty acids (FAs) as the primary fuel. Long-chain acylcarnitines (LCACs) are intermediate forms of FA transport that are essential for FA delivery from the cytosol into mitochondria. Here, we analyzed the impact of the LCACs C18 and C18:1 on mitochondrial function and, subsequently, on heart functionality in the in vivo vertebrate model system of zebrafish (Danio rerio). Since LCACs are formed and metabolized in mitochondria, we assessed mitochondrial morphology, structure and density in C18- and C18:1-treated zebrafish and found no mitochondrial alterations compared to control-treated (short-chain acylcarnitine, C3) zebrafish embryos. However, mitochondrial function and subsequently ATP production was severely impaired in C18- and C18:1-treated zebrafish embryos. Furthermore, we found that C18 and C18:1 treatment of zebrafish embryos led to significantly impaired cardiac contractile function, accompanied by reduced heart rate and diminished atrial and ventricular fractional shortening, without interfering with cardiomyocyte differentiation, specification and growth. In summary, our findings provide insights into the direct role of long-chain acylcarnitines on vertebrate heart function by interfering with regular mitochondrial function and thereby energy allocation in cardiomyocytes.