L-Carnitine intake and high trimethylamine N-oxide plasma levels correlate with low aortic lesions in ApoE−/− transgenic mice expressing CETP

Collins, Heidi L.; Drazul-Schrader, Denise; Sulpizio, Anthony C.; Koster, Paul D.; Williamson, Yuping; Adelman, Steven J.; Owen, K.Q.; Sanli, Toran; Bellamine, Aouatef

doi:10.1016/j.atherosclerosis.2015.10.108

Cited by 159 publications

(123 citation statements)

References 56 publications

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“…A follow-up study found that none of three examined FMO3 polymorphisms predispose to hypertension in a sample of several hundred Caucasian patients, but also noted that severe, highly penetrant loss-of-function mutations could "unmask pressor effects of variation in other drug metabolizing enzymes previously buffered by FMO3" (51). At least two more recent studies are consistent with TMAO production having a reactive, protective function in response to CVD pathology (52,53), with one of these studies asserting that TMAO is, in fact, protective against CVD risk (53). What is clear from these publications is that TMAO is a molecule of great interest due to its diverse functions including osmolyte, chemical chaperone, reactive oxygen species scavenger, and now, potential risk factor (54).…”

Section: Atherosclerosis and Cardiovascular Disease (Cvd)mentioning

confidence: 57%

Flavin-containing monooxygenases in aging and disease: Emerging roles for ancient enzymes

Rossner

Kaeberlein

Leiser

2017

Journal of Biological Chemistry

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Edited by F. Peter GuengerichFlavin-containing monooxygenases (FMOs) are primarily studied as xenobiotic metabolizing enzymes with a prominent role in drug metabolism. In contrast, endogenous functions and substrates of FMOs are less well understood. A growing body of recent evidence, however, implicates FMOs in aging, several diseases, and metabolic pathways. The evidence suggests an important role for these well-conserved proteins in multiple processes and raises questions about the endogenous substrate(s) and regulation of FMOs. Here, we present an overview of evidence for FMOs' involvement in aging and disease, discussing the biological context and arguing for increased investigation into the function of these enzymes.

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Section: Atherosclerosis and Cardiovascular Disease (Cvd)mentioning

confidence: 57%

Flavin-containing monooxygenases in aging and disease: Emerging roles for ancient enzymes

Rossner

Kaeberlein

Leiser

2017

Journal of Biological Chemistry

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“…In addition, they also showed that higher TMAO level predicted increase risks for prevalent cardiovascular disease and incident adverse cardiac events. On the other hand, other reports demonstrated that oral L‐carnitine supplementation increases TMAO but reduces markers of vascular injury in hemodialysis patients34 or L‐carnitine intake and high TMAO plasma levels correlate with low aortic lesions 35. Therefore, the link between gut microbiota metabolism of L‐carnitine and cardiovascular disease risk has generated much debate over the utility of supplemental intake of L‐carnitine.…”

Section: Discussionmentioning

confidence: 99%

Potential therapeutic interventions for chronic kidney disease‐associated sarcopenia via indoxyl sulfate‐induced mitochondrial dysfunction

Enoki

Watanabe

Arake

et al. 2017

J cachexia sarcopenia muscle

131

132

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BackgroundChronic kidney disease (CKD) patients experience skeletal muscle wasting and decreased exercise endurance. Our previous study demonstrated that indoxyl sulfate (IS), a uremic toxin, accelerates skeletal muscle atrophy. The purpose of this study was to examine the issue of whether IS causes mitochondria dysfunction and IS‐targeted intervention using AST‐120, which inhibits IS accumulation, or mitochondria‐targeted intervention using L‐carnitine or teneligliptin, a dipeptidyl peptidase‐4 inhibitor which retains mitochondria function and alleviates skeletal muscle atrophy and muscle endurance in chronic kidney disease mice.MethodsThe in vitro effect of IS on mitochondrial status was evaluated using mouse myofibroblast cells (C2C12 cell). The mice were divided into sham or 5/6‐nephrectomized (CKD) mice group. Chronic kidney disease mice were also randomly assigned to non‐treatment group and AST‐120, L‐carnitine, or teneligliptin treatment groups.ResultsIn C2C12 cells, IS induced mitochondrial dysfunction by decreasing the expression of PGC‐1α and inducing autophagy in addition to decreasing mitochondrial membrane potential. Co‐incubation with an anti‐oxidant, ascorbic acid, L‐carnitine, or teneligliptine restored the values to their original state. In CKD mice, the body and skeletal muscle weights were decreased compared with sham mice. Compared with sham mice, the expression of interleukin‐6 and atrophy‐related factors such as myostatin and atrogin‐1 was increased in the skeletal muscle of CKD mice, whereas muscular Akt phosphorylation was decreased. In addition, a reduced exercise capacity was observed for the CKD mice, which was accompanied by a decreased expression of muscular PCG‐1α and increased muscular autophagy, as reflected by decreased mitochondria‐rich type I fibres. An AST‐120 treatment significantly restored these changes including skeletal muscle weight observed in CKD mice to the sham levels accompanied by a reduction in IS levels. An L‐carnitine or teneligliptin treatment also restored them to the sham levels without changing IS level.ConclusionsOur results indicate that IS induces mitochondrial dysfunction in skeletal muscle cells and provides a potential therapeutic strategy such as IS‐targeted and mitochondria‐targeted interventions for treating CKD‐induced muscle atrophy and decreased exercise endurance.

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“…It is worthy to note that ApoE-/-animal model, used in these studies is characterized by diverse risk factors on the development of atherosclerosis also because of the absence of cholesterylester transfer protein (CETP) in mouse plasma compared with the human one [28]. Conversely, in ApoE-/-mouse expressing hCETP (containing human CETP gene) TMAO plays a protective role in aortic lesion formation [29].…”

Section: Discussion/conclusionmentioning

confidence: 99%

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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L-Carnitine intake and high trimethylamine N-oxide plasma levels correlate with low aortic lesions in ApoE−/− transgenic mice expressing CETP

Abstract: These findings suggest that TMAO slows aortic lesion formation in this mouse model and may have a protective effect against atherosclerosis development in humans.

Cited by 159 publications

References 56 publications

Flavin-containing monooxygenases in aging and disease: Emerging roles for ancient enzymes

Flavin-containing monooxygenases in aging and disease: Emerging roles for ancient enzymes

Potential therapeutic interventions for chronic kidney disease‐associated sarcopenia via indoxyl sulfate‐induced mitochondrial dysfunction

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

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