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A stay in intensive care unit (ICU) exposes patients to a risk of carnitine deficiency. Moreover, acylated derivates of carnitine (acylcarnitines, AC) are biomarkers for metabolic mitochondrial dysfunction that have been linked to post-ICU disorders. This study aimed to describe the AC profile of survivors of a prolonged ICU stay (≥7 days). Survivors enrolled in our post-ICU clinic between September 2020 and July 2021 were included. Blood analysis was routinely performed during the days after ICU discharge, focusing on metabolic markers and including AC profile. Serum AC concentrations were determined by LC-MS/MS and were compared to the reference ranges (RR) established from serum samples of 50 non-hospitalized Belgian adults aged from 18 to 81 years. A total 162 patients (65.4% males, age 67 (58.7–73) years) survived an ICU stay of 9.7 (7.1–19.3) days and were evaluated 5 (3–8) days after discharge. Their AC profile was significantly different compared to RR, mostly in terms of short chain AC: the sum of C3, C4 and C5 derivates reached 1.36 (0.98–1.99) and 0.86 (0.66–0.99) µmol/L respectively (p < 0.001). Free carnitine (C0) concentration of survivors (46.06 (35.04–56.35) µmol/L) was similar to RR (43.64 (36.43–52.96) µmol/L) (p = 0.55). C0 below percentile 2.5 of RR was observed in 6/162 (3.7%) survivors. Their total AC/C0 ratio was 0.33 (0.22–0.42). A ratio above 0.4 was observed in 45/162 (27.8%) patients. In ICU survivors, carnitine deficiency was rare, but AC profile was altered and AC/C0 ratio was abnormal in more than 25%. The value of AC profile as a marker of post-ICU dysmetabolism needs further investigations.

L-Carnitine (levocarnitine) is a naturally occurring compound found in all mammalian species. The most important biological function of L-carnitine is in the transport of fatty acids into the mitochondria for subsequent β-oxidation, a process which results in the esterification of L-carnitine to form acylcarnitine derivatives. As such, the endogenous carnitine pool is comprised of L-carnitine and various short-, medium- and long-chain acylcarnitines. The physiological importance of L-carnitine and its obligatory role in the mitochondrial metabolism of fatty acids has been clearly established; however, more recently, additional functions of the carnitine system have been described, including the removal of excess acyl groups from the body and the modulation of intracellular coenzyme A (CoA) homeostasis. In light of this, acylcarnitines cannot simply be considered by-products of the enzymatic carnitine transfer system, but provide indirect evidence of altered mitochondrial metabolism. Consequently, examination of the contribution of L-carnitine and acylcarnitines to the endogenous carnitine pool (i.e. carnitine pool composition) is critical in order to adequately characterize metabolic status. The concentrations of L-carnitine and its esters are maintained within relatively narrow limits for normal biological functioning in their pivotal roles in fatty acid oxidation and maintenance of free CoA availability. The homeostasis of carnitine is multifaceted with concentrations achieved and maintained by a combination of oral absorption, de novo biosynthesis, carrier-mediated distribution into tissues and extensive, but saturable, renal tubular reabsorption. Various disorders of carnitine insufficiency have been described but ultimately all result in impaired entry of fatty acids into the mitochondria and consequently disturbed lipid oxidation. Given the sensitivity of acylcarnitine concentrations and the relative carnitine pool composition in reflecting the intramitochondrial acyl-CoA to free CoA ratio (and, hence, any disturbances in mitochondrial metabolism), the relative contribution of L-carnitine and acylcarnitines within the total carnitine pool is therefore considered critical in the identification of mitochondria dysfunction. Although there is considerable research in the literature focused on disorders of carnitine insufficiency, relatively few have examined relative carnitine pool composition in these conditions; consequently, the complexity of these disorders may not be fully understood. Similarly, although important studies have been conducted establishing the pharmacokinetics of exogenous carnitine and short-chain carnitine esters in healthy volunteers, few studies have examined carnitine pharmacokinetics in patient groups. Furthermore, the impact of L-carnitine administration on the kinetics of acylcarnitines has not been established. Given the importance of L-carnitine as well as acylcarnitines in maintaining normal mitochondrial function, this review seeks to examine previous research associated with the homeostasis and pharmacokinetics of L-carnitine and its esters, and highlight potential areas of future research.

ObjectiveMetabolic reprogramming of tumour cells that allows for adaptation to their local environment is a hallmark of cancer. Interestingly, obesity-driven and non-alcoholic steatohepatitis (NASH)-driven hepatocellular carcinoma (HCC) mouse models commonly exhibit strong steatosis in tumour cells as seen in human steatohepatitic HCC (SH-HCC), which may reflect a characteristic metabolic alteration.DesignNon-tumour and HCC tissues obtained from diethylnitrosamine-injected mice fed either a normal or a high-fat diet (HFD) were subjected to comprehensive metabolome analysis, and the significance of obesity-mediated metabolic alteration in hepatocarcinogenesis was evaluated.ResultsThe extensive accumulation of acylcarnitine species was seen in HCC tissues and in the serum of HFD-fed mice. A similar increase was found in the serum of patients with NASH-HCC. The accumulation of acylcarnitine could be attributed to the downregulation of carnitine palmitoyltransferase 2 (CPT2), which was also seen in human SH-HCC. CPT2 downregulation induced the suppression of fatty acid β-oxidation, which would account for the steatotic changes in HCC. CPT2 knockdown in HCC cells resulted in their resistance to lipotoxicity by inhibiting the Src-mediated JNK activation. Additionally, oleoylcarnitine enhanced sphere formation by HCC cells via STAT3 activation, suggesting that acylcarnitine accumulation was a surrogate marker of CPT2 downregulation and directly contributed to hepatocarcinogenesis. HFD feeding and carnitine supplementation synergistically enhanced HCC development accompanied by acylcarnitine accumulation in vivo.ConclusionIn obesity-driven and NASH-driven HCC, metabolic reprogramming mediated by the downregulation of CPT2 enables HCC cells to escape lipotoxicity and promotes hepatocarcinogenesis.

Tumor cells exhibit unique metabolic adaptations that are increasingly viewed as potential targets for novel and specific cancer therapies. Among these targets, the carnitine palmitoyltransferase system is responsible for delivering the long-chain fatty acid (FA) from cytoplasm into mitochondria for oxidation, where carnitine palmitoyltransferase I (CPTI) catalyzes the rate-limiting step of fatty acid oxidation (FAO). With increasing understanding of the crucial role had by fatty acid oxidation in cancer, CPTI has received renewed attention as a pivotal mediator in cancer metabolic mechanism. CPTI activates FAO and fuels cancer growth via ATP and NADPH production, constituting an essential part of cancer metabolism adaptation. Moreover, CPTI also functionally intertwines with other key pathways and factors to regulate gene expression and apoptosis of cancer cell. Here, we summarize recent findings and update the current understanding of FAO and CPTI in cancer and provide theoretical basis for this enzyme as an emerging potential molecular target in cancer therapeutic intervention.

Early detection and accurate monitoring of chronic kidney disease (CKD) could improve care and retard progression to end-stage renal disease. Here, using untargeted metabolomics in 2155 participants including patients with stage 1–5 CKD and healthy controls, we identify five metabolites, including 5-methoxytryptophan (5-MTP), whose levels strongly correlate with clinical markers of kidney disease. 5-MTP levels decrease with progression of CKD, and in mouse kidneys after unilateral ureteral obstruction (UUO). Treatment with 5-MTP ameliorates renal interstitial fibrosis, inhibits IκB/NF-κB signaling, and enhances Keap1/Nrf2 signaling in mice with UUO or ischemia/reperfusion injury, as well as in cultured human kidney cells. Overexpression of tryptophan hydroxylase-1 (TPH-1), an enzyme involved in 5-MTP synthesis, reduces renal injury by attenuating renal inflammation and fibrosis, whereas TPH-1 deficiency exacerbates renal injury and fibrosis by activating NF-κB and inhibiting Nrf2 pathways. Together, our results suggest that TPH-1 may serve as a target in the treatment of CKD. Accurate monitoring of chronic kidney disease (CKD) progression is essential for efficient disease management. Here Chen et al. identify five serum metabolites in patients with stage 1–5 CKD whose levels associate with disease progression, and find that 5-methoxytryptophan and its regulatory enzyme TPH-1 exert anti-fibrotic effects in mouse models of kidney injury.

Key Points Long-chain acylcarnitines (LCACs) are lipid derivatives generated from carnitine by mitochondrial carnitine O-palmitoyltransferase 1 or through the reversible activity of carnitine O-palmitoyltransferase 2 on long-chain acyl-coenzyme A metabolites Long-chain acyl-coenzyme A metabolites are impermeable to mitochondrial membranes; therefore, LCACs act as the fatty acid transport moieties for oxidative catabolism Mutations in key enzymes increase mitochondrial and cytosolic pools of long-chain acyl-coenzyme A, promoting an accumulation of LCACs that is diagnostic of fatty acid oxidation disorders LCACs can modulate inflammation, insulin sensitivity, myocyte stress, protein kinase C signalling and ion balance, which suggests that they contribute to both physiological and pathophysiological processes beyond fuel trafficking A model is proposed to explain how LCACs affect disparate cell systems on the basis of their zwitterion biochemical structure and published evidence that they interact with plasma membranes In this model, accumulation of LCACs is predicted to alter the activities of key receptors, transporters, channels and enzymes that associate with (or involve) plasma, mitochondrial or other membranes Long-chain acylcarnitines (LCACs) are widely used as diagnostic markers in several metabolic disorders; however, research into the potential effects of excessive accumulation of LCACs or the roles of acylcarnitines as physiological modulators of cell metabolism is lacking. This Review, therefore, aims to provide a theoretical framework for the potential consequences of tissue build-up of LCACs among individuals with metabolic disorders. Perturbations in metabolic pathways can cause substantial increases in plasma and tissue concentrations of long-chain acylcarnitines (LCACs). For example, the levels of LCACs and other acylcarnitines rise in the blood and muscle during exercise, as changes in tissue pools of acyl-coenzyme A reflect accelerated fuel flux that is incompletely coupled to mitochondrial energy demand and capacity of the tricarboxylic acid cycle. This natural ebb and flow of acylcarnitine generation and accumulation contrasts with that of inherited fatty acid oxidation disorders (FAODs), cardiac ischaemia or type 2 diabetes mellitus. These conditions are characterized by very high (FAODs, ischaemia) or modestly increased (type 2 diabetes mellitus) tissue and blood levels of LCACs. Although specific plasma concentrations of LCACs and chain-lengths are widely used as diagnostic markers of FAODs, research into the potential effects of excessive LCAC accumulation or the roles of acylcarnitines as physiological modulators of cell metabolism is lacking. Nevertheless, a growing body of evidence has highlighted possible effects of LCACs on disparate aspects of pathophysiology, such as cardiac ischaemia outcomes, insulin sensitivity and inflammation. This Review, therefore, aims to provide a theoretical framework for the potential consequences of tissue build-up of LCACs among individuals with metabolic disorders.

Key Points The human metabolome reflects genetic variability, intrinsic biochemical processes, environmental challenges and complex interactions of all these factors Metabolomics is instrumental in discovering specific biomarkers in diseases with systemic effects such as chronic kidney disease (CKD) Metabolomics analysis can detect CKD-relevant biomarkers in tissues, plasma, serum and urine samples Most metabolite biomarkers of CKD are markers of glomerular filtration, markers of tubular function or metabolites that reflect a decline in mitochondrial function, alterations in the urea cycle or amino acid metabolism As CKD stage increases, the metabolic biomarker signatures of different renal diseases tends to become more similar and less dependent on the underlying renal disease Metabolic biomarkers seen in the later stages of CKD reflect a loss of glomerular filtration, tubular function and a decline in kidney metabolism and endocrine function Metabolomics has been instrumental for the identification of new biomarkers of chronic kidney disease (CKD). Here, the authors discuss metabolomics technologies and their application in renal disease, including the specificity and functional relevance of CKD-associated metabolic biomarkers. Chronic kidney disease (CKD) has a high prevalence in the general population and is associated with high mortality; a need therefore exists for better biomarkers for diagnosis, monitoring of disease progression and therapy stratification. Moreover, very sensitive biomarkers are needed in drug development and clinical research to increase understanding of the efficacy and safety of potential and existing therapies. Metabolomics analyses can identify and quantify all metabolites present in a given sample, covering hundreds to thousands of metabolites. Sample preparation for metabolomics requires a very fast arrest of biochemical processes. Present key technologies for metabolomics are mass spectrometry and proton nuclear magnetic resonance spectroscopy, which require sophisticated biostatistic and bioinformatic data analyses. The use of metabolomics has been instrumental in identifying new biomarkers of CKD such as acylcarnitines, glycerolipids, dimethylarginines and metabolites of tryptophan, the citric acid cycle and the urea cycle. Biomarkers such as c-mannosyl tryptophan and pseudouridine have better performance in CKD stratification than does creatinine. Future challenges in metabolomics analyses are prospective studies and deconvolution of CKD biomarkers from those of other diseases such as metabolic syndrome, diabetes mellitus, inflammatory conditions, stress and cancer.

It is inconclusive whether trimethylamine N-oxide (TMAO) and choline and related metabolites, namely trimethylamine (TMA), l-carnitine, betaine and dimethylglycine (DMG), are associated with non-alcoholic fatty liver disease (NAFLD). Our objective was to investigate these potential associations. Additionally, we sought to determine the mediating role of TMAO. In this 1:1 age- and sex-matched case–control study, a total of 150 pairs comprising NAFLD cases and healthy controls were identified. According to the fully adjusted model, after the highest tertile was compared with the lowest tertile, the plasma TMAO concentration (OR = 2·02 (95 % CI 1·04, 3·92); P trend = 0·003), l-carnitine concentration (OR = 1·79 (1·01, 3·17); P trend = 0·020) and DMG concentration (OR = 1·81 (1·00, 3·28); P trend = 0·014) were significantly positively associated with NAFLD incidence. However, a significantly negative association was found for plasma betaine (OR = 0. 50 (0·28, 0·88); P trend = 0·001). The restricted cubic splines model consistently indicated positive dose–response relationships between exposure to TMAO, l-carnitine, and DMG and NAFLD risk, with a negative association being observed for betaine. The corresponding AUC increased significantly from 0·685 (0·626, 0·745) in the traditional risk factor model to 0·769 (0·716, 0·822) when TMAO and its precursors were included (l-carnitine, betaine and choline) (P = 0·032). Mediation analyses revealed that 14·7 and 18·6 % of the excess NAFLD risk associated with l-carnitine and DMG, respectively, was mediated by TMAO (the P values for the mediating effects were 0·021 and 0·036, respectively). These results suggest that a higher concentration of TMAO is associated with increased NAFLD risk among Chinese adults and provide evidence of the possible mediating role of TMAO.

Pregnancy is characterized by a complexity of metabolic processes that may impact fetal development and ultimately, infant health outcomes. However, our understanding of whole body maternal and fetal metabolism during this critical life stage remains incomplete. The objective of this study is to utilize metabolomics to profile longitudinal patterns of fasting maternal metabolites among a cohort of non-diabetic, healthy pregnant women in order to advance our understanding of changes in protein and lipid concentrations across gestation, the biochemical pathways by which they are metabolized and to describe variation in maternal metabolites between ethnic groups. Among 160 pregnant women, amino acids, tricarboxylic acid (TCA) cycle intermediates, keto-bodies and non-esterified fatty acids were detected by liquid chromatography coupled with mass spectrometry, while polar lipids were detected through flow-injected mass spectrometry. The maternal plasma concentration of several essential and non-essential amino acids, long-chain polyunsaturated fatty acids, free carnitine, acetylcarnitine, phosphatidylcholines and sphingomyelins significantly decreased across pregnancy. Concentrations of several TCA intermediates increase as pregnancy progresses, as well as the keto-body β-hydroxybutyrate. Ratios of specific acylcarnitines used as indicators of metabolic pathways suggest a decreased beta-oxidation rate and increased carnitine palmitoyltransferase-1 enzyme activity with advancing gestation. Decreasing amino acid concentrations likely reflects placental uptake and tissue biosynthesis. The absence of any increase in plasma non-esterified fatty acids is unexpected in the catabolic phase of later pregnancy and may reflect enhanced placental fatty acid uptake and utilization for fetal tissue growth. While it appears that energy production through the TCA cycle increases as pregnancy progresses, decreasing patterns of free carnitine and acetylcarnitine as well as increased carnitine palmitoyltransferase-1 rate and β-hydroxybutyrate levels suggest a concomitant upregulation of ketogenesis to ensure sufficient energy supply in the fasting state. Several differences in metabolomic profiles between Hispanic and non-Hispanic women demonstrate phenotypic variations in prenatal metabolism which should be considered in future studies.