Effect of Flavin-Containing Monooxygenase Genotype, Mouse Strain, and Gender on Trimethylamine <i>N</i>-oxide Production, Plasma Cholesterol Concentration, and an Index of Atherosclerosis

Veeravalli, Sunil; Karu, Kersti; Scott, Fiona; Fennema, Diede; Phillips, Ian; Shephard, Elizabeth A.

doi:10.1124/dmd.117.077636

Cited by 31 publications

(36 citation statements)

References 42 publications

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“…Despite that fact, no atherosclerotic lesions in the colon and aorta [32] or drastic changes in the overall plasma metabolome [36] have been noted. Moreover, under normal dietary conditions, TMAO does not increase plasma cholesterol or act as a proatherogenic molecule in mice [35]. Furthermore, human studies could not confirm that elevated fasting blood TMAO levels predict increased risk of cardiovascular disease [33,34].…”

Section: Discussion/conclusionmentioning

confidence: 82%

L-Carnitine Supplementation Increases Trimethylamine-N-Oxide but not Markers of Atherosclerosis in Healthy Aged Women

et al. 2018

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Background: L-carnitine can be metabolized to trimethylamine N-oxide (TMAO), a molecule that promotes atherogenesis through its interaction with macrophages and lipid metabolism. Objective: The aim of the present study was to assess whether L-carnitine supplementation may promote changes in selected serum biomarkers of atherosclerosis. Methods: Before the start, in the mid-point and after completing the 24-weeks supplementation protocol, fasting blood samples were taken from the antecubital vein. Plasma free L-carnitine and TMAO were determined by the UPLC/MS/MS method. Serum proteins were determined by the enzyme immunoassay method using commercially available kits. Total cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, and triglycerides have been determined using standard automatic analyzer. Results: L-carnitine supplementation elevated fasting plasma carnitine in the mid-point of our study and it remained increased until the end of supplementation period. Moreover, it induced tenfold increase in plasma TMAO concentration but did not affect serum C-reactive protein, interleukin-6, tumour necrosis factor-α, L-selectin, P-selectin, vascular cell adhesion molecule-1, intercellular adhesion molecule-1 or lipid profile markers. Conclusion: We demonstrated that although oral L-carnitine supplementation significantly increased plasma TMAO concentration, no lipid profile changes or other markers of adverse cardiovascular events were detected in healthy aged women over the period of 24 weeks.

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Section: Discussion/conclusionmentioning

confidence: 82%

L-Carnitine Supplementation Increases Trimethylamine-N-Oxide but not Markers of Atherosclerosis in Healthy Aged Women

et al. 2018

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“…Previous phenotypic analysis (10)(11)(12)(13) has identified metabolic differences between mice in which the Fmo1, Fmo2 and Fmo4 genes had been deleted (Fmo1 -/-, 2 -/-, 4 -/mice) (10) and wild-type animals. As an extension of this work we have used one-dimensional (1D) 1 H NMR spectroscopy to compare the urinary metabolic profiles of the knockout mouse line and wild-type animals.…”

Section: Resultsmentioning

confidence: 99%

“…Conversely, taurine supplementation has been reported to have positive effects on health, for instance, in lowering total plasma cholesterol (29) and in overcoming insulin resistance (2). Given our finding that FMO1 catalyzes the formation of taurine from hypotaurine it is of interest that Fmo1-null mice exhibit some characteristics in common with those of taurine deficiency: raised plasma concentrations of cholesterol (13) and glucose (12).…”

Section: Discussionmentioning

confidence: 99%

FMO1 catalyzes the production of taurine from hypotaurine

Shephard

Veeravalli

Phillips

et al. 2019

Preprint

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Taurine is one of the most abundant amino acids in mammalian tissues. It is obtained from the diet and by de novo synthesis, from cysteic acid or hypotaurine. Despite the discovery in 1954 that the oxygenation of hypotaurine produces taurine, the identification of an enzyme catalyzing this reaction has remained elusive. In large part this is due to the incorrect assignment, in 1962, of the enzyme as a NAD-dependent hypotaurine dehydrogenase. For more than 55 years the literature has continued to refer to this enzyme as such. Here we show, both in vivo and in vitro, that the enzyme that oxygenates hypotaurine to produce taurine is flavin-containing monooxygenase 1 (FMO1). Metabolite analysis of the urine of Fmo1-null mice by 1 H NMR spectroscopy revealed a build-up of hypotaurine and a deficit of taurine in comparison with the concentrations of these compounds in the urine of wild-type mice. In vitro assays confirmed that FMO1 of human catalyzes the conversion of hypotaurine to taurine utilizing either NADPH or NADH as co-factor. FMO1 has a wide substrate range and is best known as a xenobiotic-or drug-metabolizing enzyme. The identification that the endogenous molecule hypotaurine is a substrate for the FMO1catalyzed production of taurine resolves a long-standing mystery. This finding should help establish the role FMO1 plays in a range of biological processes in which taurine or its deficiency is implicated, including conjugation of bile acids, neurotransmitter, anti-oxidant and anti-inflammatory functions, the pathogenesis of obesity and skeletal muscle disorders.

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“…Many of the studies that implicate trimethylamine N-oxide as a causative factor of cardiovascular disease involve chronic administration to mice of precursors of trimethylamine in amounts far higher than those in normal diets. In contrast, a study of males and females of two mouse strains (C57BL/6J and CD-1) and two knockout-mouse lines (Fmo1 −/− , Fmo2 −/− , Fmo4 −/− , which lacks genes encoding FMO1, FMO2 and FMO4; and Fmo5 −/− , in which the gene encoding FMO5 is disrupted) fed a standard chow diet found that plasma cholesterol concentration was negatively correlated with production and urinary concentration of trimethylamine N-oxide and that there was no correlation between an index of atherosclerosis and either trimethylamine N-oxide production or its urinary concentration [73]. Thus, under normal dietary conditions trimethylamine N-oxide does not act as a proatherogenic molecule.…”

Section: Trimethylaminementioning

confidence: 99%

Endogenous Roles of Mammalian Flavin-Containing Monooxygenases

Phillips

Shephard

2019

Catalysts

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Flavin-containing monooxygenases (FMOs) catalyze the oxygenation of numerous foreign chemicals. This review considers the roles of FMOs in the metabolism of endogenous substrates and in physiological processes, and focuses on FMOs of human and mouse. Tyramine, phenethylamine, trimethylamine, cysteamine, methionine, lipoic acid and lipoamide have been identified as endogenous or dietary-derived substrates of FMOs in vitro. However, with the exception of trimethylamine, the role of FMOs in the metabolism of these compounds in vivo is unclear. The use, as experimental models, of knockout-mouse lines deficient in various Fmo genes has revealed previously unsuspected roles for FMOs in endogenous metabolic processes. FMO1 has been identified as a novel regulator of energy balance that acts to promote metabolic efficiency, and also as being involved in the biosynthesis of taurine, by catalyzing the S-oxygenation of hypotaurine. FMO5 has been identified as a regulator of metabolic ageing and glucose homeostasis that apparently acts by sensing or responding to gut bacteria. Thus, FMOs do not function only as xenobiotic-metabolizing enzymes and there is a risk that exposure to drugs and environmental chemicals that are substrates or inducers of FMOs would perturb the endogenous functions of these enzymes.

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Effect of Flavin-Containing Monooxygenase Genotype, Mouse Strain, and Gender on Trimethylamine N-oxide Production, Plasma Cholesterol Concentration, and an Index of Atherosclerosis

Cited by 31 publications

References 42 publications

L-Carnitine Supplementation Increases Trimethylamine-N-Oxide but not Markers of Atherosclerosis in Healthy Aged Women

L-Carnitine Supplementation Increases Trimethylamine-N-Oxide but not Markers of Atherosclerosis in Healthy Aged Women

FMO1 catalyzes the production of taurine from hypotaurine

Endogenous Roles of Mammalian Flavin-Containing Monooxygenases

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