A Pilot Study on the Effects of l-Carnitine and Trimethylamine-N-Oxide on Platelet Mitochondrial DNA Methylation and CVD Biomarkers in Aged Women (original) (raw)
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Carnitine homeostasis, mitochondrial function and cardiovascular disease
Drug Discovery Today: Disease Mechanisms, 2009
Carnitines are involved in mitochondrial transport of fatty acids and are of critical importance for maintaining normal mitochondrial function. This review summarizes recent experimental and clinical studies showing that mitochondrial dysfunction secondary to a disruption of carnitine homeostasis may play a role in decreased NO signaling and the development of endothelial dysfunction. Future challenges include development of agents that can positively modulate Lcarnitine homeostasis which may have high therapeutic potential. 1. Introduction L-carnitine is a ubiquitously occurring trimethylated amino acid that plays an important role in the transport of long chain fatty acids across the inner mitochondrial membrane [1]. Carnitines exist either as free carnitines or as acylcarnitines (Figure 1 A). The acylcarnitines are products of the reaction in which acyl moieties are transferred to carnitine from acyl-CoA. These acyl groups vary in length from short chain (acetyl) to long chain (palmitoyl). This reaction is catalyzed by a family of enzymes known as acyltransferases. These enzymes differ on the basis of the structural specificity of the acyl group and their sub-cellular localization. Carnitine deficiency or abnormalities in the carnitine acyltransferase systems results in a reduced β-oxidation of fatty acids and therefore, reduced energy (ATP) production. Recent studies suggest that mitochondrial dysfunction, secondary to a disruption of carnitine homeostasis, may also play a role in the loss of nitric oxide (NO) signaling and the development of endothelial dysfunction associated with a variety of cardiovascular diseases [2]. 2. Carnitine Biosynthesis Carnitine in humans is derived from diet and de novo biosynthesis using lysine and methionine. The main dietary sources of carnitine are red meat, fish, and dairy products
Nutrients
L-carnitine supplementation elevates plasma trimethylamine-N-oxide (TMAO), which may participate in atherosclerosis development by affecting cholesterol metabolism. The aim of the current study was to determine the effect of increased plasma TMAO on biochemical markers in the blood following cessation of L-carnitine supplementation. The follow-up measurements were performed on subjects who completed 24 weeks of L-carnitine or placebo supplementation protocol. Blood samples were taken after finishing the supplementation and then 4 and 12 months following the supplementation withdrawal. Four months after cessation of L-carnitine supplementation, plasma TMAO concentration reached a normal level which was stable for the following eight months. During this period, no modifications in serum lipid profile and circulating leukocyte count were noted. TMAO implications in health and disease is widely discussed. The results of this study demonstrate no adverse effects of elevated plasma TMAO, ...
Croatica Chemica Acta, 2006
Because of its role in a transport of fatty acids from cytosol into mitochondrion, a consumption of L-carnitine became popular among athletes, and/or as a weight loss supplement. In an attempt to obtain more data on the effect of L-carnitine supplementation on some biochemical parameters in blood serum, a double-blind, placebo-controlled study was carried. Healthy volunteers with declared sedentary activities received 2 g/day of either L-carnitine or placebo for 2 weeks. L-carnitine administration induced no statistically significant changes in blood serum concentrations of glucose, triacylglycerols, total cholesterol, HDL-cholesterol and creatinine, neither affected the activity of analysed enzymes (AST, ALT, LDH, and CK). The only observed effect was a decline in the concentration of free fatty acids in serum from 0.439 mmol/L at the beginning to 0.279 mmol/L at the end of the experiment. Body mass reduction was not achieved. We conclude that L-carnitine supplementation cannot be ...
Asian Journal of Sports Medicine, 2016
Background: The effectiveness of L-carnitine supplementation has been met with conflicting findings when used by sedentary and athletic adults. Objectives: This study aimed to investigate the acute effects of L-carnitine supplementation on aerobic metabolic efficiency and lipid profiles in sedentary and athletic men. Methods: Fifteen sedentary (20.4 ± 1.5 years) and 15 athletic (21.5 ± 2.4 years) men were studied in durations of control, placebo intake and 2 g of L-carnitine supplementation. Lipid profiles, including triglyceride, cholesterol, high-density lipoprotein (HDL) and very-low density lipoprotein (VLDL), were determined before and 40 min after either the placebo or L-carnitine intake. Oxygen consumption (direct VO2), ventilatory threshold (VT), and running time (RT) were recorded after a submaximal treadmill exercise test. Results: Direct VO2 increased significantly at 80% of maximal heart rate after L-carnitine supplementation in both athletic and sedentary men, whereas, a statistical increase in VT and RT occurred only after L-carnitine use in athletes, when compared to the control and placebo subjects. The sedentary group showed no changes in lipid parameters, but triglyceride levels reduced significantly in the athletes after consuming L-carnitine. Conclusions: Acute L-carnitine supplementation possibly affects exercise performance and triglycerides in athletes rather than sedentary men.
Mechanisms of Ageing and Development, 2012
Aging entails adaptations in energy metabolism to maintain cardiac pump function (Kates et al., 2003; McMillin et al., 1993). For example, fatty acid oxidation, which is typically the primary oxidizable substrate for myocardial bioenergetics, declines with age in rodents (Abu-Erreish et al., 1977; Hyyti et al., 2010; McMillin et al., 1993) and also in humans (Kates et al., 2003). While glucose oxidation appears to compensate this loss (Kates et al., 2003; McMillin et al., 1993), there is increasing evidence that such a shift in metabolism comes at a price, primarily in lower bioenergetic reserve capacity that limits response to heightened energy demands (Davila-Roman et al., 2002; Koonen et al., 2007; van der Meer et al., 2008). Moreover, as myocytes have limited means for exporting fatty acids in the form of triacylglyceride (Lewin and Coleman, 2003), lower fatty acid oxidation may shunt lipids into non-oxidizing metabolic pathways and/or lipid storage in the myocardium (Koonen et al., 2007; Sharma et al., 2004; van der Meer et al., 2008). In its extreme, the age-associated decline in fatty aciddriven mitochondrial bioenergetics may thus initiate a form of myocardial lipotoxicity (Brindley et al., 2010; Slawik and Vidal-Puig, 2006; Wende and Abel, 2010). Therefore, it is important to understand the mechanism for lower fatty acid oxidation in the aging heart muscle. While age-associated alterations in cardiac energy metabolism are undoubtedly multifactorial, several reports implicate carnitine palmitoyltransferase 1 (CPT1) as a key enzyme in the shift away from fatty acid oxidation (Lee et al., 2002; McMillin et al., 1993; Odiet et al., 1995). CPT1, the rate-controlling enzyme for overall fatty acid b-oxidation, catalyzes the condensation of acyl-CoA with L-carnitine to form acyl-carnitine esters, which are subsequently transported into mitochondria for further catabolism (Bartlett and
European Journal of Applied Physiology and Occupational Physiology, 1992
Carnitine has a potential effect on exercise capacity due to its role in the transport of long-chain fatty acids into the mitochondria for p-oxidation, the export of acyl-coenzyme A compounds from mitochondria and the activation of branched-chain amino acid oxidation in the muscle. We studied the effect of carnitine supplementation on palmitate oxidation, maximal exercise capacity and nitrogen balance in rats. Daily carnitine supplementation (500 mg. kg-1 body mass for 6 weeks) was given to 30 rats, 15 of which were on an otherwise carnitine-free diet (group I) and 15 pair-fed with a conventional pellet diet (group II). A control group (group III, n = 6) was fed ad libitum the pellet diet. Palmitate oxidation was measured by collecting 14CO2 after an intraperitoneal injection of [1-14C]palmitate and exercise capacity by swimming to exhaustion. After carnitine supplementation carnitine concentrations in serum were supranormal [group I, total 150.8 (SD 48.5), free 78.9 (SD 18.4); group II, total 170.9 (SD 27.9), free 115.8 (SD 24.6) gmol. 1 -l] and liver carnitine concentrations were normal in both groups [group I, total 1.6 (SD 0.3), free 1.2 (SD 0.2); group II, total 1.3 (SD 0.3), free 0.9 (SD 0.2) gmol.g-1 dry mass]. In muscle carnitine concentrations were normal in group I [total 3.8 (SD 1.2), free 3.2 (SD 1.0) gmol.g -1 dry mass] and increased in group II [total 6.6 (SD 0.5), free 4.9 (SD 0.9) gmol.g-i dry mass]. Despite the difference in muscle carnitine concentrations there were no differences among the groups in cumulative palmitate oxidation after 3 h [group I, 39.7 (SD 11.6)%; group II, 29.6 (SD 14.0)%; group III, 36.5 (SD 10.8)% of injected activity] or swimming time to exhaustion [group I, 9.7 (SD 2.9); group II, 8.4 (SD 3.6); group III, 7.1 (SD 2.8) h]. A borderline increase in nitrogen balance was observed in group II. We concluded that increasing carnitine tissue concentrations by carnitine supplementation had no effect on palmitate oxidation and maximal exercise capacity in the rats studied.
International Journal of Applied Exercise Physiology, 2018
The aim of this study was to investigate the effect of aerobic training and consumption of L-carnitine supplements on HMG-CoA reductase and LDL receptor in the liver of male Wistar rats toxicated by Boldenone. 30 male Wistar rats aged 12 weeks (weight 195±7.94g) were randomly divided into five groups: control, sham, boldenone (5mg/kg), L-carnitine, aerobic training- L-carnitine.The endurance moderate intensity training program (55-50% of maximal oxygen consumption) performed for 6 weeks and 5 times a week. Injection once a week, on an appointed day, and in the quadriceps and hamstring was conducted in depth. After anesthesia, autopsy was performed and the testes Isolated. The HMG-CoA reductase and LDL receptor expression in the samples was measured by Real Time PCR and the quantification of gene expression levels using the formula 2-ΔΔct were analyzed by One-way ANOVA and post hoc Scheffe at the significant level P<0. 05. The results showed that aerobic training and supplementat...
Nutrition & Metabolism
Background L-carnitine (L-C), a ubiquitous nutritional supplement, has been investigated as a potential therapy for cardiovascular disease, but its effects on human atherosclerosis are unknown. Clinical studies suggest improvement of some cardiovascular risk factors, whereas others show increased plasma levels of pro-atherogenic trimethylamine N-oxide. The primary aim was to determine whether L-C therapy led to progression or regression of carotid total plaque volume (TPV) in participants with metabolic syndrome (MetS). Methods This was a phase 2, prospective, double blinded, randomized, placebo-controlled, two-center trial. MetS was defined as ≥ 3/5 cardiac risk factors: elevated waist circumference; elevated triglycerides; reduced HDL-cholesterol; elevated blood pressure; elevated glucose or HbA1c; or on treatment. Participants with a baseline TPV ≥ 50 mm3 were randomized to placebo or 2 g L-C daily for 6 months. Results The primary outcome was the percent change in TPV over 6 mon...
Journal of Biological Chemistry, 2009
In addition to its essential role in permitting mitochondrial import and oxidation of long chain fatty acids, carnitine also functions as an acyl group acceptor that facilitates mitochondrial export of excess carbons in the form of acylcarnitines. Recent evidence suggests carnitine requirements increase under conditions of sustained metabolic stress. Accordingly, we hypothesized that carnitine insufficiency might contribute to mitochondrial dysfunction and obesity-related impairments in glucose tolerance. Consistent with this prediction whole body carnitine dimunition was identified as a common feature of insulin-resistant states such as advanced age, genetic diabetes, and diet-induced obesity. In rodents fed a lifelong (12 month) high fat diet, compromised carnitine status corresponded with increased skeletal muscle accumulation of acylcarnitine esters and diminished hepatic expression of carnitine biosynthetic genes. Diminished carnitine reserves in muscle of obese rats was accompanied by marked perturbations in mitochondrial fuel metabolism, including low rates of complete fatty acid oxidation, elevated incomplete -oxidation, and impaired substrate switching from fatty acid to pyruvate. These mitochondrial abnormalities were reversed by 8 weeks of oral carnitine supplementation, in concert with increased tissue efflux and urinary excretion of acetylcarnitine and improvement of whole body glucose tolerance. Acetylcarnitine is produced by the mitochondrial matrix enzyme, carnitine acetyltransferase (CrAT). A role for this enzyme in combating glucose intolerance was further supported by the finding that CrAT overexpression in primary human skeletal myocytes increased glucose uptake and attenuated lipid-induced suppression of glucose oxidation. These results implicate carnitine insufficiency and reduced CrAT activity as reversible components of the metabolic syndrome. Disturbances in mitochondrial genesis, morphology, and function are increasingly recognized as components of insulin resistance and the metabolic syndrome (1-3). Still unclear is whether poor mitochondrial performance is a predisposing factor or a consequence of the disease process. The latter view is supported by recent animal studies linking diet-induced insulin resistance to a dysregulated mitochondrial phenotype in skeletal muscle, marked by excessive -oxidation, impaired substrate switching during the fasted to fed transition, and coincident reduction of organic acid intermediates of the tricarboxylic acid cycle (4, 5). In these studies, both diet-induced and genetic forms of insulin resistance were specifically linked to high rates of incomplete fat oxidation and intramuscular accumulation of fatty acylcarnitines, byproducts of lipid catabolism that are produced under conditions of metabolic stress (5, 6). Most compelling, we showed that genetically engineered inhibition of fat oxidation lowered intramuscular acylcarnitine levels and preserved glucose tolerance in mice fed a high fat diet (5, 7). In aggregate, the findings established a strong connection between mitochondrial bioenergetics and insulin action while raising new questions regarding the roles of incomplete -oxidation and acylcarnitines as potential biomarkers and/or mediators of metabolic disease. In another recent investigation we found that oral carnitine supplementation improved insulin sensitivity in diabetic mice, in parallel with a marked rise in plasma acylcarnitines (8). This occurred in three distinct models of glucose intolerance; aging, genetic diabetes, and high fat feeding (8). The antidiabetic actions of carnitine were accompanied by an increase in whole body glucose oxidation, a surprising result given that carnitine is best known for its essential role in permitting mitochondrial translocation and oxidation of long chain acyl-CoAs. Carnitine palmitoyltransferase 1 (CPT1) 2 executes the initial step in this process by catalyzing the reversible transesterification of long chain acyl-CoA with carnitine. The long chain acylcarnitine * This work was supported, in whole or in part, by National Institutes of Health Grants P30-AG028716 and R01-AG028930 (to D. M. M.) and F32-DK080609 (to R. N.). This work was also supported by the American Diabetes Association (to D. M. M.
Pediatric Research, 1994
Carnitine plays a central role in lipid metabolism by transporting long-chain fatty acids into the mitochondria for @-oxidation. Reduction of carnitinc concentration docs not automatically imply that functional carnitine deficiency exists with direct consequences on energy metabolism. In our experimental model, we reduced tissue concentrations of carnitine to levels that arc comparable to those in patients with various metabolic disorders with secondary carnitine deficiency and did a study on the in vivo effects of moderate carnitine depletion on palmitate oxidation, excrcise capacity, and nitrogen balance. Thirty rats were divided into a carnitine-depleted group (group I) and pair-fed controls (group 11). Carnitine depletion resulting in a 48% reduction of tissue carnitine concentrations was induced by feeding ad libitum a carnitine-free oral diet consisting of parenteral nutrition solutions. Palmitate oxidation was measurcd by collecting cxpircd "CO, after an intrapcritoncal injection of [l-'JC]palmitatc, and exercise capacity was dctcrmined by having thc rats swim to exhaustion. Despite thc 48% dcplction of carnitinc in serum, muscle, and liver, there wcrc no diffcrcnccs in cumulative palmitate oxidation in 3 h (group I, 40 5 7%; group 11, 37 5 9% of injected activity), swimming time to exhaustion (group I, 8.1 5 2.8 h; group 11, 7.7 + 3.6 h), or nitrogen balance (group I, 1.1 r 0.5 g of nitrogenlkgld; group 11, 1.2 +-0.5 g of nitrogcnkgld). We concludc that carnitinc depiction of 48% has no effect on palmitatc oxidation, exercise capacity, or nitrogen balance in the rats studied. (Pedintr Res 36: [288][289][290][291][292] 1994)