Acylcarnitines: Nomenclature, Biomarkers, Therapeutic Potential, Drug Targets, and Clinical Trials

Dambrova, Maija; Makrecka-Kūka, Marina; Kuka, Janis; Vilšķe̅rsts, Reinis; Nordberg, Didi; Attwood, Misty M.; Smesny, Stefan; Şen, Zümrüt Duygu; Guo, An Chi; Oler, Eponine; Tian, Siyang; Zheng, Jiamin; Wishart, David S.; Liepinsh, Edgars; Schiöth, Helgi B.

doi:10.1124/pharmrev.121.000408

Cited by 163 publications

(150 citation statements)

References 593 publications

(563 reference statements)

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“…O’Connor et al, reported decreased levels of acylcarnitines that correlated with inflammation and the amount of bacteria in patients with CF, as a major finding of their recent untargeted metabolomic study in BALF samples [ 58 ]. Acylcarnitines are important for cellular energy production, mainly for the β-oxidation of fatty acids, as they are used as intermediates to transport acyl groups into the mitochondria [ 61 ]. Lower concentrations of acylcarnitines in CF could therefore be potentially related to an abnormal β-oxidation of fatty acids [ 59 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of Exhaled Metabolites in Children with Cystic Fibrosis

et al. 2022

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The early detection of inflammation and infection is important to prevent irreversible lung damage in cystic fibrosis. Novel and non-invasive monitoring tools would be of high benefit for the quality of life of patients. Our group previously detected over 100 exhaled mass-to-charge (m/z) features, using on-line secondary electrospray ionization high-resolution mass spectrometry (SESI-HRMS), which distinguish children with cystic fibrosis from healthy controls. The aim of this study was to annotate as many m/z features as possible with putative chemical structures. Compound identification was performed by applying a rigorous workflow, which included the analysis of on-line MS2 spectra and a literature comparison. A total of 49 discriminatory exhaled compounds were putatively identified. A group of compounds including glycolic acid, glyceric acid and xanthine were elevated in the cystic fibrosis group. A large group of acylcarnitines and aldehydes were found to be decreased in cystic fibrosis. The proposed compound identification workflow was used to identify signatures of volatile organic compounds that discriminate children with cystic fibrosis from healthy controls, which is the first step for future non-invasive and personalized applications.

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Section: Discussionmentioning

confidence: 99%

Identification of Exhaled Metabolites in Children with Cystic Fibrosis

et al. 2022

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“…Under conditions of the continuous oversupply of food and heightened substrate, competition mitochondria lose their capacity to switch freely between alternative forms of carbon energy, and metabolic health deteriorates [ 77 ]. SCACs (including C3, C4-OH, C5, C5-OH) can be derived from branched-chain amino acids (BCAA), which have been related to obesity through several potential mechanisms [ 15 , 78 , 79 ]. The accumulation of LCASs reflects the impaired FA oxidation that has been linked with insulin resistance and oxidative stress caused by mitochondrial overload [ 80 ].…”

Section: Discussionmentioning

confidence: 99%

“…It has been demonstrated that the acylcarnitine (AC) profile, or the concentration of ACs (esters arising from the conjugation of FAs with L-carnitine) with specific chain lengths could characterize the intracellular energy metabolism pattern and could be used as a marker of metabolic dysfunction [ 14 , 15 ]. The body carnitine pool is comprised of L-carnitine (C0), acetylcarnitine (C2), short-chain (C3–C5), medium-chain (C6–C12), and long-chain (C14–C20) ACs [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

“…Carnitine translocase (CACT) moves AC across the inner mitochondrial membrane as carnitine is exported. Inside the mitochondria, LCAC is converted back into LC acyl-CoAs for β-oxidation by CPT2, which can then be further oxidized via the tricarboxylic acid (TCA) cycle and respiratory chain to provide energy [ 15 , 17 ]. CPT1 deficiency can be screened using the ratio of (C16 + C18:1)/C0 and CPT2 deficiency can be screened using the ratio of (C16 + C18:1)/C2.…”

Section: Introductionmentioning

confidence: 99%

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A Marked Low-Grade Inflammation and a Significant Deterioration in Metabolic Status in First-Episode Schizophrenia: A Five-Year Follow-Up Study

et al. 2022

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The objective of this study was to evaluate how schizophrenia spectrum disorders and applied long-term (5.1 years) antipsychotic (AP) treatment affect the serum level of acylcarnitines (ACs), cytokines and metabolic biomarkers and to characterize the dynamics of inflammatory and metabolic changes in the early course of the disorder. A total of 112 adults participated in the study (54 patients with first-episode psychosis (FEP) and 58 control subjects). Biomolecule profiles were measured at the onset of first-episode psychosis and 0.6 years and 5.1 years after the initiation of APs. The results of the present study confirmed that specific metabolic–inflammatory imbalance characterizes AP-naïve patients. Short-term (0.6-years) AP treatment has a favourable effect on psychotic symptoms, as well as the recovery of metabolic flexibility and resolution of low-level inflammation. However, 5.1 years of AP treatment resulted in weight gain and increased serum levels of interleukin (IL)-2, IL-4, IL-6, IL-10, interferon-γ, hexoses, acetylcarnitine, short-chain ACs (C3, C4) and long-chain ACs (C16:2, C18:1, C18:2). In conclusion, despite the improvement in psychotic symptoms, 5.1 years of AP treatment was accompanied by a pronounced metabolic–inflammatory imbalance, which was confirmed by the presence of enhanced pro-inflammatory activity and increased obesity with changes in the metabolism of carbohydrates, lipids, and their metabolites.

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“…The general role of acylcarnitines is to transport acyl groups (organic acids and fatty acids) from the cytoplasm into the mitochondria so they can be broken down to produce energy. This process is known as betaoxidation (Dambrova et al, 2022). Regarding their relation to CKD, serum acylcarnitines increase in CKD and DD-CKD patients due to their impaired renal excretion (Fouque et al, 2006) and have been Frontiers in Physiology frontiersin.org associated with IgA nephropathy and diabetic nephropathy as potential biomarkers (Xia et al, 2019;Mu et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

The metabolomic differential plasma profile between dialysates. Pursuing to understand the mechanisms of citrate dialysate clinical benefits

et al. 2022

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Background: Currently, bicarbonate-based dialysate needs a buffer to prevent precipitation of bicarbonate salts with the bivalent cations, and acetate at 3–4 mmol/L is the most used. However, citrate is being postulated as a preferred option because of its association with better clinical results by poorly understood mechanisms. In that sense, this hypothesis-generating study aims to identify potential metabolites that could biologically explain these improvements found in patients using citrate dialysate.Methods: A unicentric, cross-over, prospective untargeted metabolomics study was designed to analyze the differences between two dialysates only differing in their buffer, one containing 4 mmol/L of acetate (AD) and the other 1 mmol/L of citrate (CD). Blood samples were collected in four moments (i.e., pre-, mid-, post-, and 30-min-post-dialysis) and analyzed in an untargeted metabolomics approach based on UPLC-Q-ToF mass spectrometry.Results: The 31 most discriminant metabolomic variables from the plasma samples of the 21 participants screened by their potential clinical implications show that, after dialysis with CD, some uremic toxins appear to be better cleared, the lysine degradation pathway is affected, and branched-chain amino acids post-dialysis levels are 9–10 times higher than with AD; and, on its part, dialysis with AD affects acylcarnitine clearance.Conclusion: Although most metabolic changes seen in this study could be attributable to the dialysis treatment itself, this study successfully identifies some metabolic variables that differ between CD and AD, which raise new hypotheses that may unveil the mechanisms involved in the clinical improvements observed with citrate in future research.

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Acylcarnitines: Nomenclature, Biomarkers, Therapeutic Potential, Drug Targets, and Clinical Trials

Cited by 163 publications

References 593 publications

Identification of Exhaled Metabolites in Children with Cystic Fibrosis

Identification of Exhaled Metabolites in Children with Cystic Fibrosis

A Marked Low-Grade Inflammation and a Significant Deterioration in Metabolic Status in First-Episode Schizophrenia: A Five-Year Follow-Up Study

The metabolomic differential plasma profile between dialysates. Pursuing to understand the mechanisms of citrate dialysate clinical benefits

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