Total parenteral nutrition and carnitine supplementation practices in preterm neonates - results of a national survey

Thesis (M.A.)--Boston UniversityBackground: The goal of postnatal total parenteral nutrition (TPN) in premature neonates (PT) is to mimic the intrauterine environment of the fetus. Micronutrients are essential for optimal development. Although carnitine is present in human breast milk and is supplemented in infant formula, very preterm infants primarily receive parenteral nutrition, often devoid of carnitine, shortly after birth. Carnitine plays a critical role in cellular and mitochondrial metabolism. Preterm infants are deficient in carnitine as it is transferred from the placenta to the fetus during late pregnancy. Previously, our group surveyed US neonatologists in 2001 regarding carnitine supplementation practices and found that the majority were not fully familiar with the implications of carnitine deficiency and only 28% of preterm neonates on TPN were receiving carnitine. Since this study, recent research has emphasized the impact of carnitine on early weight gain and its neuroprotective effects. Objective: To determine current TPN carnitine supplementation practices in fasting preterm neonates (< 32 wks and < 1,500g) by conducting a national survey of board- certified neonatologists. [TRUNCATED

Regulation of genes involved in carnitine homeostasis by PPARa across different species (rat, mouse, pig, cattle, chicken, and human)

Recent studies in rodents convincingly demonstrated that PPAR-alpha is a key regulator of genes involved in carnitine homeostasis, which serves as a reasonable explanation for the phenomenon that energy deprivation and fibrate treatment, both of which cause activation of hepatic PPAR-alpha, causes a strong increase of hepatic carnitine concentration in rats. The present paper aimed to comprehensively analyse available data from genetic and animal studies with mice, rats, pigs, cows, and laying hens and from human studies in order to compare the regulation of genes involved in carnitine homeostasis by PPAR-alpha across different species. Overall, our comparative analysis indicates that the role of PPAR-alpha as a regulator of carnitine homeostasis is well conserved across different species. However, despite demonstrating a well-conserved role of PPAR-alpha as a key regulator of carnitine homeostasis in general, our comprehensive analysis shows that this assumption particularly applies to the regulation by PPAR-alpha of carnitine uptake which is obviously highly conserved across species, whereas regulation by PPAR-alpha of carnitine biosynthesis appears less well conserved across species

Effects of exercise on l-carnitine and lipid metabolism in African catfish (Clarias gariepinus) fed different dietary l-carnitine and lipid levels

African catfish (Clarias gariepinus) were fed four isonitrogenous diets (34 % crude protein), each containing one of two lipid (100 or 180 g/kg) and two l-carnitine (15 or 1000 mg/kg) levels. After 81 d of feeding, thirty-two fish (body weight 32 g) from each dietary group were randomly selected, sixteen fish were induced to a 3-h swim (speed of 1.5 body length (BL)/s), while the other sixteen fish were kept under resting condition. Fish fed 1000 mg l-carnitine accumulated 3.5 and 5 times more l-carnitine in plasma and muscle, respectively, than fish fed the 15 mg l-carnitine. Muscle l-carnitine content was significantly lower in exercised fish than in rested fish. High dietary lipid level (fish oil) led to an increase in muscle n-3 PUFA content and a decrease in SFA and MUFA content. In liver, the increase in dietary lipid level resulted in an increased levels of both n-6 and n-3 PUFA. l-carnitine supplementation significantly decreased n-3 PUFA content. Exercise decreased n-3 PUFA in both muscle and liver. Plasma lactate and lactate dehydrogenase, normally associated with increased glycolytic processes, were positively correlated with exercise and inversely correlated with dietary l-carnitine level. l-carnitine supplementation reduced significantly the RQ from 0.72 to 0.63, and an interaction between dietary l-carnitine and lipid was observed (P <0.03). Our results indicate that an increase in fatty acids (FA) intake may promote FA oxidation, and both carnitine and exercise might influence the regulation of FA oxidation selectivity

Effect of Combined Oral Ferrotherapy with L-carnitine on Exercise Tolerance of Patients with Chronic Heart Failure with Reduced Ejection Fraction of Left Ventricle with Concomitant Iron Deficiency Anemia

According to numerous studies, a high prevalence of iron deficiency (ID) with anaemic syndrome and its association with mortality during chronic heart failure (CHF) have been revealed. Ferrocorrection of anaemia during CHF is important both to improve the clinical condition and to optimize the long-term prognosis of patients. However, the pathogenetic justification is the use of agents that have antihypoxic, antioxidant and membrane-stabilizing effects, except iron preparations, and at the same time exert a regulatory effect on the metabolism of physiologically active compounds and improve the functional condition of patients.The aim. The aim of this study was to identify and compare the effect of oral ferrotherapy and combined use of ferrotherapy with L-carnitine on exercise tolerance (ET) of patients with CHF with reduced ejection fraction of left ventricle (LVEF) with concomitant iron deficiency anemia (IDA) was determined and compared.Materials and methods. The study includes 62 patients with CHF with reduced LVEF FC II-III according to NYHA with IDА. Patients with hypertensive and ischemic etiology of HF took part in the study. Among them, 45 (72.6 %) were men and 17 (27.4 %) were women aged 70.0±0.9 years. Two study groups were formed: in addition to the standard therapy, the patients in the 1st group (n=32) were prescribed oral ferrous sulfate in a dose of 320 mg, equivalent to 100 mg of bivalent iron and 60 mg of ascorbic acid 2 tablets per day for 6 months; the patients in the 2nd group (n=30) received the standard therapy of CHF and not only iron, but also L-carnitine.Results and discussion. The use of two variants of ferrocorrection as an application to the standard treatment of CHF among the total number of studied patients with IDA indicates the sufficient effect both to eliminate the signs of anemia and to eliminate ID. The analysis of the dynamics of the passed test distance with a 6-minute walk in 32 patients with IDA on the background of standard treatment and additional ferrotherapy after 6 months showed an increase of the actual distance by 8.9 % (from 249.4 to 272.3 m, p&lt;0.0001). The analysis of changes in the value of travelled distance among patients with IDA who received combined 6-month ferrotherapy with L-carnitine also revealed a significant positive trend. In addition, the value obtained was significantly higher compared to the results of patients with only additional ferrotherapy, an increase of 19.4 % (from 259.5 to 304.5 m, p&lt;0.0001).Conclusions. The use of metabolic therapy with oral ferrotherapy is accompanied by a greater increase in ET, which is reflected in a significantly longer test distance with a 6-minute walk and greater frequency of decrease of FC of HF among patients, compared with using only iron sulfate ferrocorrection

Carnitine metabolism to trimethylamine by an unusual Rieske-type oxygenase from human microbiota

Dietary intake of L-carnitine can promote cardiovascular diseases in humans through microbial production of trimethylamine (TMA) and its subsequent oxidation to trimethylamine N-oxide (TMAO) by hepatic flavin-containing monooxygenases. Although our microbiota are responsible for TMA formation from carnitine, the underpinning molecular and biochemical mechanisms remain unclear. In this study, using bioinformatics approaches, we first identified a two-component Rieske-type oxygenase/reductase (CntAB) and associated gene cluster proposed to be involved in carnitine metabolism in representative genomes of the human microbiota. CntA belongs to a group of previously uncharacterized Rieske-type proteins and has an unusual "bridging" glutamate but not the aspartate residue, which is believed to facilitate inter-subunit electron transfer between the Rieske centre and the catalytic mononuclear iron centre. Using Acinetobacter baumannii as the model, we then demonstrate that cntAB is essential in carnitine degradation to TMA. Heterologous overexpression of cntAB enables Escherichia coli to produce TMA, confirming that these genes are sufficient in TMA formation. Site-directed mutagenesis experiments have confirmed that this unusual "bridging glutamate" residue in CntA is essential in catalysis and neither mutant (E205D, E205A) is able to produce TMA. Together, our study reveals the molecular and biochemical mechanisms underpinning carnitine metabolism to TMA in human microbiota and assigns the role of this novel group of Rieske-type proteins in microbial carnitine metabolism

Hyperinsulinism in short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency reveals the importance of beta-oxidation in insulin secretion

A female infant of nonconsanguineous Indian parents presented at 4 months with a hypoglycemic convulsion. Further episodes of hypoketotic hypoglycemia were associated with inappropriately elevated plasma insulin concentrations. However, unlike other children with hyperinsulinism, this patient had a persistently elevated blood spot hydroxybutyrylcarnitine concentration when fed, as well as when fasted. Measurement of the activity of L-3-hydroxyacyl-CoA dehydrogenase in cultured skin fibroblasts with acetoacetyl-CoA substrate showed reduced activity. In fibroblast mitochondria, the activity was less than 5% that of controls. Sequencing of the short-chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD) genomic DNA from the fibroblasts showed a homozygous mutation (C773T) changing proline to leucine at amino acid 258. Analysis of blood from the parents showed they were heterozygous for this mutation. Western blot studies showed undetectable levels of immunoreactive SCHAD protein in the child's fibroblasts. Expression studies showed that the P258L enzyme had no catalytic activity. We conclude that C773T is a disease-causing SCHAD mutation. This is the first defect in fatty acid beta -oxidation that has been associated with hyperinsulinism and raises interesting questions about the ways in which changes in fatty acid and ketone body metabolism modulate insulin secretion by the beta cell. The patient's hyperinsulinism was easily controlled with diazoxide and chlorothiazide

Na+-dependent and Na+-independent betaine transport across the apical membrane of rat renal epithelium

The low renal excretion of betaine indicates that the kidney efficiently reabsorbs the betaine filtered by the glomeruli but the mechanisms involved in such a process have been scarcely investigated. We have detected concentrative and non-concentrative betaine transport activity in brush-border membrane vesicles (BBMV) from rat renal cortex and medulla. The concentrative system is the Sodium/Imino-acid Transporter 1 (SIT1) because it is Na+- and Cl--dependent, electrogenic and is inhibited by an anti-SIT1 antibody. Its apparent affinity constant for betaine, Kt, is 1.1 ± 0.5 mM and its maximal transport velocity, Vmax, 0.5 ± 0.1 nmol betaine/mg protein/s. Inhibitors of the Na+/Cl-/betaine uptake are l-proline (75%) and cold betaine, l-carnitine and choline (40-60%). Neither creatine, TEA, taurine, β-alanine, GABA nor glycine significantly inhibited Na+/Cl-/betaine uptake. The non-concentrative betaine transport system is Na+- and H+-independent, electroneutral, with a Kt for betaine of 47 ± 7 μM and a Vmax of 7.8 ± 1 pmol betaine/mg protein/s. Its transport activity is nearly abolished by betaine, followed by L-carnitine (70-80%) and proline (40-50%), but a difference from the Na+/Cl-/betaine transport is that it is inhibited by TEA (approx. 50%) and unaffected by choline. The underlying carrier functions as an antiporter linking betaine entry into the BBMV with the efflux of either l-carnitine or betaine, an exchange unaffected by the anti-SIT1 antibody. As far as we know this is the first work reporting that betaine crosses the apical membrane of rat renal epithelium by SIT1 and by a Na+- and H+-independent transport system.Ministerio de Ciencia y Tecnología BFI2003-00222Junta de Andalucía 2010/BIO-14