Methyl-γ-butyrobetaine decreases levels of acylcarnitines and attenuates the development of atherosclerosis

Vilšķe̅rsts, Reinis; Kuka, Janis; Liepinsh, Edgars; Makrecka-Kūka, Marina; Volska, Kristine; Makarova, Elina; Sevostjanovs, Eduards; Cirule, Helena; Grı̄nberga, Solveiga; Dambrova, Maija

doi:10.1016/j.vph.2015.05.005

Cited by 13 publications

(14 citation statements)

References 34 publications

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“…Treatment with inhibitors of carnitine biosynthesis and its transport into tissues (eg with the clinically prescribed drug meldonium (3‐(2,2,2‐trimethylhydraziniumyl) propionate) or experimental candidate methyl‐GBB (4‐[ethyl(dimethyl)ammonio]butanoate), is protective against cardiometabolic disease . These two compounds decrease long‐chain acylcarnitine content in cardiac tissues and mitochondria and therefore prevent acylcarnitine‐induced mitochondrial damage as well as impaired insulin signalling.…”

Section: Lifestyle and Pharmacological Interventions To Target Mitochmentioning

confidence: 99%

“…Treatment with inhibitors of carnitine biosynthesis and its transport into tissues (eg with the clinically prescribed drug meldonium (3-(2,2,2-trimethylhydraziniumyl) propionate) or experimental candidate methyl-GBB (4-[ethyl(dimethyl) ammonio]butanoate), is protective against cardiometabolic disease. 70,[270][271][272][273][274][275][276] These two compounds decrease long-chain acylcarnitine content in cardiac tissues and mitochondria and therefore prevent acylcarnitine-induced mitochondrial damage as well as impaired insulin signalling. Both compounds protect cardiac mitochondria against ischaemia-reperfusion injury, 272,277,278 reduce infarct size in healthy and diabetic animals and improve insulin sensitivity in experimental models of insulin resistance.…”

Section: Compounds To Reduce Lipotoxicitymentioning

confidence: 99%

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Altered mitochondrial metabolism in the insulin‐resistant heart

et al. 2019

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Obesity‐induced insulin resistance and type 2 diabetes mellitus can ultimately result in various complications, including diabetic cardiomyopathy. In this case, cardiac dysfunction is characterized by metabolic disturbances such as impaired glucose oxidation and an increased reliance on fatty acid (FA) oxidation. Mitochondrial dysfunction has often been associated with the altered metabolic function in the diabetic heart, and may result from FA‐induced lipotoxicity and uncoupling of oxidative phosphorylation. In this review, we address the metabolic changes in the diabetic heart, focusing on the loss of metabolic flexibility and cardiac mitochondrial function. We consider the alterations observed in mitochondrial substrate utilization, bioenergetics and dynamics, and highlight new areas of research which may improve our understanding of the cause and effect of cardiac mitochondrial dysfunction in diabetes. Finally, we explore how lifestyle (nutrition and exercise) and pharmacological interventions can prevent and treat metabolic and mitochondrial dysfunction in diabetes.

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Section: Lifestyle and Pharmacological Interventions To Target Mitochmentioning

confidence: 99%

Section: Compounds To Reduce Lipotoxicitymentioning

confidence: 99%

Altered mitochondrial metabolism in the insulin‐resistant heart

et al. 2019

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“…This may model the vicious cycle in vivo , at least in part, in that in a setting with abundant lipid carrier carnitine, the macrophages from one cycle of reaction to effete phospholipid debris die attempting to clear the material, making the problem worse, particularly if the lipid being transported is resistant to degradation. Recent experimental work supports this hypothesis, suggesting that limiting carnitine used as a fatty acid carrier attenuates atherosclerosis progression in an atherogenic mouse model [5]. If confirmed, properly controlled regulation of macrophage lipid metabolism may be an important new method of preventing progressive atherosclerosis.…”

Section: A Vicious Cycle Of Cell Death-induced Cell Death Contributesmentioning

confidence: 92%

“…This complex topic, where important progress has been made both in management of serum lipid profiles, and in improved control of related co-morbidities including blood pressure and adult onset diabetes, is very well reviewed elsewhere and is not addressed here [4]. On the other hand, there are new approaches that might, by different mechanisms, interrupt or reverse plaque development; these include limiting availability of the lipid carrier carnitine to prevent overload of macrophages with fat, and thus interrupting the vicious cycle of cell death and atherosclerosis, as reported in this issue in an atherogenic mouse model [5, in press].…”

Section: Introductionmentioning

confidence: 99%

Nature and nurture in atherosclerosis: The roles of acylcarnitine and cell membrane-fatty acid intermediates

Blair

Sepulveda

Papachristou

2016

Vascular Pharmacology

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Macrophages recycle components of dead cells, including cell membranes. When quantities of lipids from cell membranes of dead cells exceed processing capacity, phospholipid and cholesterol debris accumulate as atheromas. Plasma lipid profiles, particularly HDL and LDL cholesterol, are important tools to monitor atherosclerosis risk. Membrane lipids are exported, as triglycerides or phospholipids, or as cholesterol or cholesterol esters, via lipoproteins for disposal, for re-use in cell membranes, or for fat storage. Alternative assays evaluate other aspects of lipid pathology. A key process underlying atherosclerosis is backup of macrophage fatty acid catabolism. This can be quantified by accumulation of acylcarnitine intermediates in extracellular fluid, a direct assay of adequacy of β-oxidation to deal with membrane fatty acid recycling. Further, membranes of somatic cells, such as red blood cells (RBC), incorporate fatty acids that reflect dietary intake. Changes in RBC lipid composition occur within days of ingesting modified fats. Since diets with high saturated fat content or artificial trans-fatty acids promote atherosclerosis, RBC lipid content shifts occur with atherosclerosis, and can show cellular adaptation to pathologically stiff membranes by increased long-chain doubly unsaturated fatty acid production. Additional metabolic changes with atherosclerosis of potential utility include inflammatory cytokine production, modified macrophage signaling pathways, and altered lipid-handling enzymes. Even after atherosclerotic lesions appear, approaches to minimize macrophage overload by reducing rate of fat metabolism are promising. These include preventative measures, and drugs including statins and the newer PCSK9 inhibitors. New cell-based biochemical and cytokine assays provide data to prevent or monitor atherosclerosis progression.

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“…Thus, the mechanism of meldonium action is the inhibition of OCTN2, which leads to carnitine elimination by urine and decreased tissue carnitine content. Recent studies have shown that limited tissue content of carnitine prevents acylcarnitine accumulation during ischaemia–reperfusion and atherosclerosis and protects cardiac and vascular tissue against acylcarnitine‐induced damage . In addition, decreased acylcarnitine content improves muscle and heart insulin sensitivity and glucose tolerance .…”

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confidence: 99%

Carnitine and γ‐Butyrobetaine Stimulate Elimination of Meldonium due to Competition for OCTN2‐mediated Transport

Liepinsh

Makarova

Sevostjanovs

et al. 2017

Basic Clin Pharma Tox

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Meldonium (3-(2,2,2-trimethylhydrazinium)propionate) is the most potent clinically used inhibitor of organic cation transporter 2 (OCTN2). Inhibition of OCTN2 leads to a decrease in carnitine and acylcarnitine contents in tissues and energy metabolism optimization-related cardioprotective effects. The recent inclusion of meldonium in the World Anti-Doping Agency List of Prohibited Substances and Methods has raised questions about the pharmacokinetics of meldonium and its unusually long elimination time. Therefore, in this study, the rate of meldonium washout after the end of the treatment was tested with and without administration of carnitine, γ-butyrobetaine (GBB) and furosemide to evaluate the importance of competition for OCTN2 transport in mice. Here, we show that carnitine and GBB administration during the washout period effectively stimulated the elimination of meldonium. GBB induced a more pronounced effect on meldonium elimination than carnitine due to the higher affinity of GBB for OCTN2. The diuretic effect of furosemide did not significantly affect the elimination of meldonium, carnitine and GBB. In conclusion, the competition of meldonium, carnitine and GBB for OCTN2-mediated transport determines the pharmacokinetic properties of meldonium. Thus, due to their affinity for OCTN2, GBB and carnitine but not furosemide stimulated meldonium elimination. During long-term treatment, OCTN2-mediated transport ensures a high muscle content of meldonium, while tissue clearance depends on relatively slow diffusion, thus resulting in the unusually long complete elimination period of meldonium.

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Methyl-γ-butyrobetaine decreases levels of acylcarnitines and attenuates the development of atherosclerosis

Cited by 13 publications

References 34 publications

Altered mitochondrial metabolism in the insulin‐resistant heart

Altered mitochondrial metabolism in the insulin‐resistant heart

Nature and nurture in atherosclerosis: The roles of acylcarnitine and cell membrane-fatty acid intermediates

Carnitine and γ‐Butyrobetaine Stimulate Elimination of Meldonium due to Competition for OCTN2‐mediated Transport

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