Acylcarnitines

Schooneman, Marieke G.; Vaz, Frédéric M.; Houten, Sander M.; Soeters, Maarten R.

doi:10.2337/db12-0466

Cited by 531 publications

(330 citation statements)

References 81 publications

(153 reference statements)

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“…BCAA catabolism and lipid processing produce acylcarnitine products in the mitochondria that have been shown to effect gluconeogenesis (Newgard et al 2009; Newgard 2012). Furthermore, high lipid loads such as those associated with NAFLD may lead to an increase in acylcarnitine production in tissues according to previous studies (Schooneman et al 2013). …”

Section: Introductionmentioning

confidence: 66%

“…Alterations in carnitine levels have been reported in the literature to be a result of high lipid loads, mitochondrial lipotoxicity, and altered lipid metabolism (Schooneman et al 2013). Increased levels of acylcarnitines in the plasma of NASH patients have been previously reported (Kalhan et al 2011) which are comparable to the hepatic elevations observed in the present study.…”

Section: Discussionmentioning

confidence: 99%

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Branched chain amino acid metabolism profiles in progressive human nonalcoholic fatty liver disease

et al. 2014

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Nonalcoholic fatty liver disease (NAFLD) is a globally widespread disease of increasing clinical significance. The pathological progression of the disease from simple steatosis to nonalcoholic steatohepatitis (NASH) has been well defined, however, the contribution of altered branched chain amino acid metabolomic profiles to the progression of NAFLD is not known. The three BCAAs: leucine, isoleucine and valine are known to mediate activation of several important hepatic metabolic signaling pathways ranging from insulin signaling to glucose regulation. The purpose of this study is to profile changes in hepatic BCAA metabolite levels with transcriptomic changes in the progression of human NAFLD to discover novel mechanisms of disease progression. Metabolomic and transcriptomic data sets representing the spectrum of human NAFLD (normal, steatosis, NASH fatty, and NASH not fatty livers) were utilized for this study. During the transition from steatosis to NASH, increases in the levels of leucine (127 % of normal), isoleucine (139 %), and valine (147 %) were observed. Carnitine metabolites also exhibited significantly elevated profiles in NASH fatty and NASH not fatty samples and included propionyl, hexanoyl, lauryl, acetyl and butyryl carnitine. Amino acid and BCAA metabolism gene sets were significantly enriched among downregulated genes during NASH. These cumulative alterations in BCAA metabolite and amino acid metabolism gene profiles represent adaptive physiological responses to disease-induced hepatic stress in NASH patients.

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Section: Introductionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Branched chain amino acid metabolism profiles in progressive human nonalcoholic fatty liver disease

et al. 2014

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“…Although typically short‐lived, LCAC accumulate in states of inefficient fatty acid oxidation (FAO), which may be attributed to (1) defects in mitochondrial FAO enzymes or (2) increased FAO relative to tricarboxylic acid (TCA) flux; this leads to a bottleneck of carbon substrates at the TCA cycle 53, 54. Such defects can be caused or exacerbated by IR, which has, in turn, been associated with elevations in plasma LCAC 54, 55, 56, 57. However, we found no correlation between plasma LCAC and IR in this study; this suggests that the observed LCAC elevations were not driven by IR 54, 55, 56, 57.…”

Section: Discussionmentioning

confidence: 99%

“…Such defects can be caused or exacerbated by IR, which has, in turn, been associated with elevations in plasma LCAC 54, 55, 56, 57. However, we found no correlation between plasma LCAC and IR in this study; this suggests that the observed LCAC elevations were not driven by IR 54, 55, 56, 57. Regardless of the precise cause, LCAC are transported out to the plasma, where they are subsequently metabolized in several tissues (especially skeletal muscle, liver, and heart) or excreted in urine or bile 52, 56, 57.…”

Section: Discussionmentioning

confidence: 99%

“…Regardless of the precise cause, LCAC are transported out to the plasma, where they are subsequently metabolized in several tissues (especially skeletal muscle, liver, and heart) or excreted in urine or bile 52, 56, 57. The relative contribution of individual organs to the plasma LCAC pool has not been well characterized in humans; however, animal and cell culture studies suggest that plasma LCAC levels predominantly reflect liver and skeletal muscle secretion as well as renal excretion 56, 57, 58…”

Section: Discussionmentioning

confidence: 99%

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Metabolomic Profiling Identifies Novel Circulating Biomarkers of Mitochondrial Dysfunction Differentially Elevated in Heart Failure With Preserved Versus Reduced Ejection Fraction: Evidence for Shared Metabolic Impairments in Clinical Heart Failure

Hunter

Kelly

McGarrah

et al. 2016

JAHA

201

137

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BackgroundMetabolic impairment is an important contributor to heart failure (HF) pathogenesis and progression. Dysregulated metabolic pathways remain poorly characterized in patients with HF and preserved ejection fraction (HFpEF). We sought to determine metabolic abnormalities in HFpEF and identify pathways differentially altered in HFpEF versus HF with reduced ejection fraction (HFrEF).Methods and ResultsWe identified HFpEF cases, HFrEF controls, and no‐HF controls from the CATHGEN study of sequential patients undergoing cardiac catheterization. HFpEF cases (N=282) were defined by left ventricular ejection fraction (LVEF) ≥45%, diastolic dysfunction grade ≥1, and history of HF; HFrEF controls (N=279) were defined similarly, except for having LVEF <45%. No‐HF controls (N=191) had LVEF ≥45%, normal diastolic function, and no HF diagnosis. Targeted mass spectrometry and enzymatic assays were used to quantify 63 metabolites in fasting plasma. Principal components analysis reduced the 63 metabolites to uncorrelated factors, which were compared across groups using ANCOVA. In basic and fully adjusted models, long‐chain acylcarnitine factor levels differed significantly across groups (P<0.0001) and were greater in HFrEF than HFpEF (P=0.0004), both of which were greater than no‐HF controls. We confirmed these findings in sensitivity analyses using stricter inclusion criteria, alternative LVEF thresholds, and adjustment for insulin resistance.ConclusionsWe identified novel circulating metabolites reflecting impaired or dysregulated fatty acid oxidation that are independently associated with HF and differentially elevated in HFpEF and HFrEF. These results elucidate a specific metabolic pathway in HF and suggest a shared metabolic mechanism in HF along the LVEF spectrum.

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Prenatal Exposure to Chemical Mixtures and Metabolic Syndrome Risk in Children

Güil-Oumrait,

Stratakis,

Maitre

et al. 2024

JAMA Netw Open

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ImportancePrenatal exposure to ubiquitous endocrine-disrupting chemicals (EDCs) may increase the risk of metabolic syndrome (MetS) in children, but few studies have studied chemical mixtures or explored underlying protein and metabolic signatures.ObjectiveTo investigate associations of prenatal exposure to EDC mixtures with MetS risk score in children and identify associated proteins and metabolites.Design, Setting, and ParticipantsThis population-based, birth cohort study used data collected between April 1, 2003, and February 26, 2016, from the Human Early Life Exposome cohort based in France, Greece, Lithuania, Norway, Spain, and the UK. Eligible participants included mother-child pairs with measured prenatal EDC exposures and complete data on childhood MetS risk factors, proteins, and metabolites. Data were analyzed between October 2022 and July 2023.ExposuresNine metals, 3 organochlorine pesticides, 5 polychlorinated biphenyls, 2 polybrominated diphenyl ethers (PBDEs), 5 perfluoroalkyl substances (PFAS), 10 phthalate metabolites, 3 phenols, 4 parabens, and 4 organophosphate pesticide metabolites measured in urine and blood samples collected during pregnancy.Main Outcomes and MeasuresAt 6 to 11 years of age, a composite MetS risk score was constructed using z scores of waist circumference, systolic and diastolic blood pressures, triglycerides, high-density lipoprotein cholesterol, and insulin levels. Childhood levels of 44 urinary metabolites, 177 serum metabolites, and 35 plasma proteins were quantified using targeted methods. Associations were assessed using bayesian weighted quantile sum regressions applied to mixtures for each chemical group.ResultsThe study included 1134 mothers (mean [SD] age at birth, 30.7 [4.9] years) and their children (mean [SD] age, 7.8 [1.5] years; 617 male children [54.4%] and 517 female children [45.6%]; mean [SD] MetS risk score, −0.1 [2.3]). MetS score increased per 1-quartile increase of the mixture for metals (β = 0.44; 95% credible interval [CrI], 0.30 to 0.59), organochlorine pesticides (β = 0.22; 95% CrI, 0.15 to 0.29), PBDEs (β = 0.17; 95% CrI, 0.06 to 0.27), and PFAS (β = 0.19; 95% CrI, 0.14 to 0.24). High-molecular weight phthalate mixtures (β = −0.07; 95% CrI, −0.10 to −0.04) and low-molecular weight phthalate mixtures (β = −0.13; 95% CrI, −0.18 to −0.08) were associated with a decreased MetS score. Most EDC mixtures were associated with elevated proinflammatory proteins, amino acids, and altered glycerophospholipids, which in turn were associated with increased MetS score.Conclusions and RelevanceThis cohort study suggests that prenatal exposure to EDC mixtures may be associated with adverse metabolic health in children. Given the pervasive nature of EDCs and the increase in MetS, these findings hold substantial public health implications.

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Acylcarnitines

Cited by 531 publications

References 81 publications

Branched chain amino acid metabolism profiles in progressive human nonalcoholic fatty liver disease

Branched chain amino acid metabolism profiles in progressive human nonalcoholic fatty liver disease

Metabolomic Profiling Identifies Novel Circulating Biomarkers of Mitochondrial Dysfunction Differentially Elevated in Heart Failure With Preserved Versus Reduced Ejection Fraction: Evidence for Shared Metabolic Impairments in Clinical Heart Failure

Prenatal Exposure to Chemical Mixtures and Metabolic Syndrome Risk in Children

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