Identification of ethylsuccinylcarnitine present in some human urines

Libert, R.; Hoof, F. Van; Laus, Gerhard; Nayer, Philippe De; Jiwan, Jean-Louis Habib; Hoffmann, Edmond de; Schanck, André

doi:10.1016/j.cccn.2004.12.020

Cited by 9 publications

(9 citation statements)

References 6 publications

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“…Once more, the extended duration of alteration was observed in the UN group. Libert et al reported that cis-3,4-methyleneheptanoylcarnitine is present in human urine, except in urine from newborn patients (26). These researchers further found that the acylcarnitines with a cyclopropane ring in their fatty acid moieties disappeared in the urine of humans treated with antibiotic.…”

Section: Resultsmentioning

confidence: 95%

Fecal Microbiota Transplantation in Experimental Ulcerative Colitis Reveals Associated Gut Microbial and Host Metabolic Reprogramming

Yan

Gao

et al. 2018

Appl Environ Microbiol

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Fecal microbiota transplantation (FMT) is gaining attention for the treatment of ulcerative colitis (UC). Data from individual case studies have suggested that FMT may be beneficial for UC, but the detailed microbial and molecular basis remains unknown. Here, we employ 16S rRNA gene sequencing and metabolomics to investigate the influence of FMT on gut microbial community composition and host metabolism in the dextran sulfate sodium-induced UC rat model. The findings from this pilot study suggest that FMT from normal donors to UC recipients could alleviate UC symptoms without close resemblance of donor's gut microbial and metabolic pattern. Meanwhile, FMT from UC donors to normal recipient rats triggered UC symptoms, UC-prone microbial shift, and host metabolic adaption. Gut microbiota under normal conditions could maintain stable species richness and diversity upon FMT intervention, but the disturbed gut microbiota under UC conditions could not maintain such homeostasis. Significant correlations between altered bacterial composition and host metabolism could be assigned to the pathological effects of UC (accounting for 8.0 to 16.2% of total variance) and/or the FMT intervention effects (3.9 to 7.0% of total variance). Overall, our study reveals diverse gut microbial shifts in UC related FMT and their association with host metabolic reprogramming. This study combined clinical symptoms measurement, 16S rRNA gene microbial profiling and metabolomics to comprehensively investigate the gut bacterial and host metabolic association and reprogramming in FMT-treated experimental UC. These data can advance our understanding of the effect of FMT on UC and the involvement of gut microbial dysbiosis in the development of UC.

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Section: Resultsmentioning

confidence: 95%

Fecal Microbiota Transplantation in Experimental Ulcerative Colitis Reveals Associated Gut Microbial and Host Metabolic Reprogramming

Yan

Gao

et al. 2018

Appl Environ Microbiol

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“…Extending those results, in the present study plasma cis-3,4-methylene-heptanoylcarnitine was significantly reduced in the postintervention conditions; this metabolite is a medium-chain derivative of a long-chain fatty acid that is almost certainly a xenometabolite. Acylcarnitine fatty acid metabolites with a cyclopropane ring reportedly disappeared in the urine of humans treated with the antibiotic adriamycin and were not detectable in urine from newborns (Libert et al 2005), suggestive of a gut microbe origin for the parent long-chain acyl group. It is proposed that cis-3,4-methylene-heptanoylcarnitine emanates from incomplete β-oxidation of cis-13, 14-methylene-heptadecanoic acid, a product of bacterial metabolism (also see Yang et al 2007).…”

Section: Discussionmentioning

confidence: 98%

“…Acylcarnitine fatty acid metabolites with a cyclopropane ring reportedly disappeared in the urine of humans treated with the antibiotic adriamycin and were not detectable in urine from newborns (Libert et al . ), suggestive of a gut microbe origin for the parent long‐chain acyl group. It is proposed that cis ‐3,4‐methylene‐heptanoylcarnitine emanates from incomplete β‐oxidation of cis ‐13,14‐methylene‐heptadecanoic acid, a product of bacterial metabolism (also see Yang et al .…”

Section: Discussionmentioning

confidence: 99%

Acylcarnitines as markers of exercise‐associated fuel partitioning, xenometabolism, and potential signals to muscle afferent neurons

Zhang

Light

Hoppel

et al. 2016

Experimental Physiology

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With insulin-resistance or type 2 diabetes mellitus, mismatches between mitochondrial fatty acid fuel delivery and oxidative phosphorylation/tricarboxylic acid cycle activity may contribute to inordinate accumulation of short- or medium-chain acylcarnitine fatty acid derivatives (markers of incomplete long-chain fatty acid oxidation [FAO]). We reasoned that incomplete FAO in muscle would be ameliorated concurrent with improved insulin sensitivity and fitness following a ~14 wk training and weight loss intervention in obese, sedentary, insulin-resistant women. Contrary to this hypothesis, overnight-fasted and exercise-induced plasma C4-C14 acylcarnitines did not differ between pre-intervention and post-intervention phases. These metabolites all increased robustly with exercise (~45% of pre-intervention VO2peak) and decreased during a 20 min cool-down. This supports the idea that, regardless of insulin sensitivity and fitness, intramitochondrial muscle β-oxidation and attendant incomplete FAO are closely tethered to absolute ATP turnover rate. Acute exercise also led to branched-chain amino acid (BCAA) acylcarnitine derivative patterns suggestive of rapid diminution of BCAA flux through mitochondrial branched-chain ketoacid dehydrogenase complex. We confirmed our prior novel observation that weight loss/fitness intervention alters plasma xenometabolites (i.e., cis-3,4-methylene-heptanoylcarnitine and γ-butyrobetaine [a co-metabolite possibly derived in part from gut bacteria]), suggesting that host metabolic health regulated gut microbe metabolism. Finally, we considered if acylcarnitine metabolites signal to muscle-innervating afferents: palmitoylcarnitine at concentrations as low as 1–10 μM activated a sub-set (~2.5–5%) of these neurons ex vivo. This supports the hypothesis that in addition to tracking exercise-associated shifts in fuel metabolism, muscle acylcarnitines act as exertion signals to short-loop somatosensory-motor circuits or to the brain.

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“…Many SCDAs result from the catabolism of amino acids, ω-oxidation of fatty acids or perhaps represent products of microbial metabolism [ 19 ], but the reasons for their accumulation in plasma in at-risk subjects, and how they may be related to CVD pathogenesis remain uncertain. Based on the convergence of GWAS, transcriptomic, metabolomic and functional data presented herein, we hypothesize that genetic and epigenetic variation predisposes to increased susceptibility to ER stress through proteasome dysfunction (reflected by the observation of upregulation of expression of ER stress genes), with ER stress in turn contributing to increased production of SCDA metabolites.…”

Section: Discussionmentioning

confidence: 99%

Metabolomic Quantitative Trait Loci (mQTL) Mapping Implicates the Ubiquitin Proteasome System in Cardiovascular Disease Pathogenesis

et al. 2015

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Levels of certain circulating short-chain dicarboxylacylcarnitine (SCDA), long-chain dicarboxylacylcarnitine (LCDA) and medium chain acylcarnitine (MCA) metabolites are heritable and predict cardiovascular disease (CVD) events. Little is known about the biological pathways that influence levels of most of these metabolites. Here, we analyzed genetics, epigenetics, and transcriptomics with metabolomics in samples from a large CVD cohort to identify novel genetic markers for CVD and to better understand the role of metabolites in CVD pathogenesis. Using genomewide association in the CATHGEN cohort (N = 1490), we observed associations of several metabolites with genetic loci. Our strongest findings were for SCDA metabolite levels with variants in genes that regulate components of endoplasmic reticulum (ER) stress (USP3, HERC1, STIM1, SEL1L, FBXO25, SUGT1) These findings were validated in a second cohort of CATHGEN subjects (N = 2022, combined p = 8.4x10-6–2.3x10-10). Importantly, variants in these genes independently predicted CVD events. Association of genomewide methylation profiles with SCDA metabolites identified two ER stress genes as differentially methylated (BRSK2 and HOOK2). Expression quantitative trait loci (eQTL) pathway analyses driven by gene variants and SCDA metabolites corroborated perturbations in ER stress and highlighted the ubiquitin proteasome system (UPS) arm. Moreover, culture of human kidney cells in the presence of levels of fatty acids found in individuals with cardiometabolic disease, induced accumulation of SCDA metabolites in parallel with increases in the ER stress marker BiP. Thus, our integrative strategy implicates the UPS arm of the ER stress pathway in CVD pathogenesis, and identifies novel genetic loci associated with CVD event risk.

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Identification of ethylsuccinylcarnitine present in some human urines

Cited by 9 publications

References 6 publications

Fecal Microbiota Transplantation in Experimental Ulcerative Colitis Reveals Associated Gut Microbial and Host Metabolic Reprogramming

Fecal Microbiota Transplantation in Experimental Ulcerative Colitis Reveals Associated Gut Microbial and Host Metabolic Reprogramming

Acylcarnitines as markers of exercise‐associated fuel partitioning, xenometabolism, and potential signals to muscle afferent neurons

Metabolomic Quantitative Trait Loci (mQTL) Mapping Implicates the Ubiquitin Proteasome System in Cardiovascular Disease Pathogenesis

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