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In our previous study, L-carnitine was shown to have cytoprotective effect against hydrogen peroxide ([H.sub.2][O.sub.2])induced injury in human normal HL7702 hepatocytes. The aim of this study was to investigate whether the protective effect of L-carnitine was associated with the nuclear factor erythroid 2 (NFE2)-related factor 2 ([Nrf.sub.2]) pathway. Our results showed that pretreatment with L-carnitine augmented [Nrf.sub.2] nuclear translocation, DNA binding activity and heme oxygenase-1 (HO-1) expression in [H.sub.2][O.sub.2]-treated HL7702 cells, although L-carnitine treatment alone had no effect on them. Analysis using [Nrf.sub.2] siRNA demonstrated that [Nrf.sub.2] activation was involved in L-carnitine-induced HO-1 expression. In addition, L-carnitine- mediated protection against [H.sub.2][O.sub.2] toxicity was abrogated by [Nrf.sub.2] siRNA, indicating the important role of [Nrf.sub.2] in L-carnitine-induced cytoprotection. Further experiments revealed that L-carnitine pretreatment enhanced the phosphorylation of Akt in [H.sub.2][O.sub.2]- treated cells. Blocking Akt pathway with inhibitor partly abrogated the protective effect of L-carnitine. Moreover, our finding demonstrated that the induction of [Nrf.sub.2] translocation and HO-1 expression by L-carnitine directly correlated with the Akt pathway because Akt inhibitor showed inhibitory effects on the [Nrf.sub.2] translocation and HO-1 expression. Altogether, these results demonstrate that L-carnitine protects HL7702 cells against [H.sub.2][O.sub.2]-induced cell damage through Akt-mediated activation of [Nrf.sub.2] signaling pathway. Key words: L-carnitine, hepatocyte, hydrogen peroxide, NFE2-related factor 2, Akt. Lors d'une etude precedente realisee par les auteurs, la L-carnitine avait montre un effet cytoprotecteur contre le dommage induit par le peroxyde d'hydrogene ([H.sub.2][O.sub.2]) chez les hepatocytes humains normaux de la lignee HL7702. Le but de l'etude presente etait d'examiner si l'effet protecteur de la L-carnitine etait associe a la voie du [Nrf.sub.2] (acronyme de ≪ nuclear factor erythroid 2 (NFE2)-related factor 2 ≫). Les resultats ont montre qu'un pretraitement a la L-carnitine accroissait la translocation nucleaire du [Nrf.sub.2], l'activite de liaison a l'ADN et l'expression de l'heme-oxygenase-1 (HO-1) chez les cellules HL7702 traitees au [H.sub.2][O.sub.2], alors que le traitement a la L-carnitine seule n'avait pas d'effet sur ces parametres. Une analyse realisee avec un petit ARNi de [Nrf.sub.2] a demontre que l'activation de [Nrf.sub.2] etait impliquee dans l'expression de HO-1 induite par la L- carnitine. De plus, la protection conferee par la L-carnitine envers la toxicite du [H.sub.2][O.sub.2] etait abolie par le petit ARNi de [Nrf.sub.2], temoignant du role important de [Nrf.sub.2] dans la cytoprotection induite par la L-carnitine. D'autres experiences ont revele qu'un pretraitement a la L-carnitine augmentait la phosphorylation de Akt chez les cellules traitees au [H.sub.2][O.sub.2]. Le blocage de la voie de Akt a l'aide d'un inhibiteur abolissait partiellement l'effet protecteur de la L-carnitine. Qui plus est, les donnees demontraient que l'induction de la translocation de [Nrf.sub.2] et de l'expression de HO-1 par la L-carnitine etait directement reliee avec la voie de Akt car l'inhibiteur de Akt exercait des effets inhibiteurs sur la translocation de [Nrf.sub.2] et l'expression de HO-1. En somme, ces resultats demontrent que la L-carnitine protege les cellules HL7702 du dommage cellulaire induit par le [H.sub.2][O.sub.2] par l'intermediaire de l'activation de la voie de signalisation de [Nrf.sub.2] par Akt. [Traduit par la Redaction] Mots-cles : L-carnitine, hepatocyte, peroxyde d'hydrogene, facteur [Nrf.sub.2], Akt., Introduction Oxidative stress is a disturbance in the balance between the production of free radicals and antioxidant defense systems. It has been implicated as one of the most commonly invoked [...]

Background/Objectives: It has been shown that plasma carnitine concentrations markedly decline during gestation in women. The reason for this, however, is unknown. One objective of this study was to investigate the effect of carnitine supplementation on plasma carnitine concentrations in pregnant women. The second objective was to investigate the hypothesis that reduced plasma carnitine concentrations during gestation are caused by a reduced carnitine synthesis because of a diminished iron status. Subjects/Methods: Healthy pregnant women (n=26) were randomly assigned in two groups receiving either a L-carnitine supplement (500 mg L-carnitine per day as L-carnitine L-tartrate) (n=13) or placebo (n=13) from the 13th week of gestation to term. Results: In the control group, there was a marked reduction of plasma carnitine concentration from the 12th week of gestation to term. This reduction was prevented by the supplementation of carnitine. In the control group, there was a positive relationship between the parameters of iron status (mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and ferritin) and plasma concentration of carnitine (P Conclusions: This study confirms that plasma carnitine concentrations decline in the course of pregnancy, an effect that can be prevented by the supplementation of carnitine. Data of this study, moreover, suggest that the decline of plasma carnitine concentration during pregnancy could be caused by a reduced rate of carnitine biosynthesis, possibly because of an inadequate iron status. doi:10.1038/ejcn.2009.36; published online 3 June 2009 Keywords: pregnancy; carnitine status; carnitine supplement; iron status; ferritin, Introduction Carnitine (L-3-hydroxy-4-N-N-N-trimethylaminobutyrate) is an essential metabolite, which has a number of indispensable functions in intermediary metabolism. The most important function lies in its role in the transport of activated [...]

Objective: Electrospray ionization-tandem mass spectrometry (ESI-MS/MS) is increasingly used in newborn screening programs. Acylcarnifine profiles from dried blood spots (DBS) are used to detect fatty acid oxidation disorders, carnitine cycle disorders, and organic acidurias. Stored dried blood is also a valuable source for postmortem investigations to unravel the cause of unexplained death in early childhood. However, diagnostic uncertainties arising from the unknown stability of acylcarnitines and free carnitine during prolonged storage have not yet been studied in a systematic manner. Methods: Whole blood spiked with acylcarnitines was stored either at -18[degrees]C or at room temperature up to 1000 days. At regular time intervals 3.2 mm spots of these samples were extracted with 150 [micro]L of methanol. Free carnitine and acylcarnifines were converted to their corresponding butyl esters and analyzed by ESI-MS/MS. Results: At-18[degrees]C acylcarnitines are stable for at least 330 days. If stored for prolonged periods at room temperature (> 14 days), acylcarnitines are hydrolyzed to free carnitine and the corresponding fatty acids. The velocity of decay is logarithmic and depends on the chain length of the acylcarnitines. Short-chain acylcarnitines hydrolyze quicker than long-chain acylcarnitines. Conclusion: The data indicate that stored filter cards should only be used for retrospective quantitation of acylcarnitines if appropriate correction for sample decay during storage is applied. Free carnitine increases upon storage but can reliably be quantitated under standardized derivatization conditions. Furthermore, carnitine transporter (OCTN2) deficiency can reliably be diagnosed by examining acylcarnitine profiles, which can supplement free carnitine levels as a discriminatory marker.

Byline: Lokesh. Saini, Biswaroop. Chakrabarty, Atin. Kumar, Sheffali. Gulati A premorbidly normal, 10-month old boy, born to a third-degree consanguineous couple, presented with subacute onset regression of milestones, preceded by [...]

The effects of high-fat (HF) feeding on gene expression in the small intestine were examined using obesity-resistant A/J mice and obesity-prone C57BL/6J (B6) mice. Both strains of mice were maintained on low-fat (LF; 5% fat) or HF (30% fat) diets for 2 wk. Quantitative reverse transcription-PCR analysis revealed that lipid metabolism-related genes, including carnitine palmitoyltransferase (CPT) I, liver fatty acid binding protein, pyruvate dehydrogenase kinase-4, and [NADP.sup.+]-dependent cytosolic malic enzyme, were upregulated by HF feeding in both strains of mice. The upregulated gene expression levels were higher in A/J mice than in B6 mice, suggesting more active lipid metabolism in the small intestine of A/J mice. The prominent upregulation of the lipid metabolism-related genes were specific to the small intestine; the expression levels were little or unchanged in the liver, muscle, and white adipose tissue. The increase by HF feeding and predominant expression of the intestinal lipid metabolism-related genes in A/J mice were reflected in the enzyme activities; malic enzyme, CPT, and [beta]-oxidation activities were increased by HF feeding, and the upregulated malic enzyme and CPT activities were significantly higher in obesity-resistant A/J mice compared with those in obesity-prone B6 mice. These findings suggest that intestinal lipid metabolism is associated with susceptibility to obesity. high fat; intestine; [beta]-oxidation; carnitine palmitoyltransferase; nicotinamide adenine dinucleotide [phosphate.sup.+]-dependent cytosolic malic enzyme

Byline: Pauline A. Filipek (1,2,5), Jenifer Juranek (1), Minh T. Nguyen (1), Christa Cummings (1), J. Jay Gargus (1,3,4) Keywords: Lactic acidosis; mitochondrial disease; autism; hyperammonemia Abstract: A random retrospective chart review was conducted to document serum carnitine levels on 100 children with autism. Concurrently drawn serum pyruvate, lactate, ammonia, and alanine levels were also available in many of these children. Values of free and total carnitine (p &lt 0.001), and pyruvate (p=0.006) were significantly reduced while ammonia and alanine levels were considerably elevated (p &lt 0.001) in our autistic subjects. The relative carnitine deficiency in these patients, accompanied by slight elevations in lactate and significant elevations in alanine and ammonia levels, is suggestive of mild mitochondrial dysfunction. It is hypothesized that a mitochondrial defect may be the origin of the carnitine deficiency in these autistic children. Author Affiliation: (1) Department of Pediatrics, College of Medicine, University of California, Irvine, CA, USA (2) Division of Child Neurology, College of Medicine, University of California, Irvine, CA, USA (3) Division of Human Genetics, College of Medicine, University of California, Irvine, CA, USA (4) Department of Physiology and Biophysics, College of Medicine, University of California, Irvine, CA, USA (5) UCI Medical Center, Route 81-4482, 101 City Drive South, Orange, CA, 92868-3201, USA Article History: Registration Date: 20/08/2004

Objective. Carnitine is thought to be a conditionally essential biological cofactor for premature infants. A preliminary study suggested that carnitine could significantly reduce apnea of prematurity. The objective of this study was to evaluate critically the role of carnitine in idiopathic apnea of prematurity and to determine whether the use of carnitine would facilitate discontinuation of mechanical ventilatory support, shorten the duration of ventilatory support, and reduce the amount of time that such infants are exposed to both mechanical ventilation and oxygen. We also wanted to determine the effects of supplemental carnitine on weight gain, time to regain birth weight, time to achieve full enteral feedings, and length of hospital stay. Methods. A prospective, randomized, blinded trial was conducted on 44 preterm infants who were from the same neonatal intensive care unit and who were [less than or equal to] 32 weeks' gestational age with a postnatal age Results. There were no significant differences between the 2 groups in the occurrence of apnea as detected by cardiorespiratorygram or nursing observation. There were no significant differences between the groups in regard to total days on ventilator, days of nasal continuous positive airway pressure, time to regain birth weight, time to reach enteral feedings of 120 mL/kg/d, discharge weight, adjusted age at discharge, need for oxygen at 28 days' and 36 weeks' adjusted age, or length of stay. The plasma carnitine level was a median of 15.5 [micro]mol/L (range: 7.6-30.5) for the placebo infants compared with a median of 195.3/[micro]mol/L (range: 71.7-343.6) for the carnitine infants. Conclusions. In this blinded, randomized, placebo-controlled study, we found that infants who received supplemental carnitine did not demonstrate any reduction in apnea of prematurity, ventilator or nasal continuous positive airway pressure days, or the need for supplemental oxygen therapy. Although carnitine may be of significant nutritional benefit for very low birth weight infants, our study does not support its use to reduce apnea of prematurity or decrease dependence on mechanical ventilation. Pediatrics 2002;109:622-626; prematurity, apnea, carnitine. ABBREVIATIONS. TPN, total parenteral nutrition; CPAP, continuous positive airway pressure; CRG, cardiorespirogram., With increasing survival of extremely low birth weight infants, apnea of prematurity has become the most common recurring problem within the neonatal intensive care unit. L-Carnitine is synthesized from the [...]

A trial was conducted to biochemically explain the decreased lipid deposition and increased protein accretion observed in pigs fed carnitine. Our hypothesis was that an increase in the ratio of acetyl CoA:CoA-SH produced by stimulation of fatty acid oxidation by supplemental L-carnitine may decrease branched-chain [alpha]-keto acid dehydrogenase activity and increase pyruvate carboxylase activity. Such changes could reduce oxidative loss of branched-chain amino acids and provide more carbons for amino acid biosynthesis. Yorkshire gilts (n = 36; 12 per treatment) were fed a control diet or diets containing either 50 or 125 ppm of added L-carnitine during growth from 56 to 120 kg. After slaughter, the semitendinosus muscle and liver were collected for isolation of mitochondria and hepatocytes. Increasing dietary L-carnitine did not infiuence growth performance (P > 0.10) but linearly decreased (P < 0.05) 10th rib backfat thickness and increased (linear, P < 0.05) percentages of lean and muscle. The rates of [1-[sup.14.C]]palmitate oxidation in isolated hepatocytes and isolated mitochondria, and incorporation of [[sup.35.S]] methionine into the acid insoluble fraction of isolated hepatocytes were increased (linear, P < 0.01) in pigs fed L-carnitine. Flux through branched-chain [alpha]-keto acid dehydrogenase linearly decreased (P < 0.01) in isolated liver and muscle mitochondria with increasing dietary carnitine. Flux through pyruvate carboxylase was increased (linear, P < 0.01) in isolated mitochondria from liver of pigs fed carnitine, and assays with particle-free extracts indicated that the amount of mitochondrial pyruvate carboxylase was tripled by feeding carnitine (linear, P < 0.01). The association of increased protein accretion and reduced backfat thickness with greater rates of palmitate oxidation, more rapid flux through pyruvate carboxylase, and reduced flux through branched-chain [alpha]-keto acid dehydrogenase suggests pigs fed carnitine are more able to use fat for energy, divert carbon toward synthesis of amino acids, and spare branched-chain amino acids for protein synthesis. Key Words: Carnitine, Growth, Pigs, Protein Synthesis

Byline: Karen Choong (1), J.T.R. Clarke (2), E. Cutz (3), R.J. Pollit (4), S.E. Olpin (4) Keywords: Key words: cardiac arrhythmia, fatty acid oxidation, carnitine Abstract: Carnitine-acylcarnitine translocase (CACT) deficiency is an inherited defect of the co-transport of free and esterified carnitine across the inner mitochondrial membrane. We report a case of CACT deficiency in a newborn who died at 72 h of age from severe, intractable cardiac tachyarrhythmia, despite an improvement in his neurological and biochemical status. Postmortem examination showed marked steatosis of myocardium, liver, and kidney. In addition, electron microscopic studies showed virtually complete elimination of mitochondria from cardiomyocytes. It appears that the correction of the acute metabolic derangements in this condition may not prevent rapid progression to death, suggesting that the rhythm disturbances in CACT deficiency result from prior and ongoing accumulation of toxic metabolites, rather than from an acute metabolic derangement. Furthermore, we speculate that the choice of anti-arrhythmic agent in this patient may paradoxically have contributed to his death. Author Affiliation: (1) Department of Pediatrics, Division of Neonatology, Hospital for Sick Children and University of Toronto, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada, CA (2) Department of Pediatrics, Division of Clinical Genetics, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada, CA (3) Department of Pathology, Hospital for Sick Children and University of Toronto, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada, CA (4) Regional Neonatal Screening Laboratory, The Children's Hospital, Sheffield S10 2TH, UK, GB Article note: Received March 14, 2001 accepted June 22, 2001.

Metabolic evidence was sought to explain the reduced body fat and increased body protein observed in Atlantic salmon fed diets supplemented with L-carnitine. By stimulating fatty acid oxidation, dietary carnitine might increase flux through pyruvate carboxylase and decrease flux through the branched-chain [Alpha]-keto acid dehydrogenase complex, by increasing regulatory ratios of acetyl CoA:free enzyme A (CoA-SH) and ATP:ADP. Such changes could conserve nitrogen by providing more carbon for amino acid biosynthesis and by blocking oxidative loss of the branched-chain amino acids. Consistent with this hypothesis, salmon fed carnitine (23 mmol/kg diet) for 9 wk exhibited greater metabolic rates than cohorts fed a carnitine-free diet (P [less than] 0.05) for the following: 1) 1-[14C] palmitate oxidation by liver cubes (48%) and by isolated hepatocytes (151%), 2) pyruvate-dependent [14C[O.sub.2]]-fixation by isolated mitochondria (81%), 3) incorporation of 1-[14C] lactate into glucose by liver cubes (120%) and by isolated hepatocytes (210%), and 4) incorporation of [35S]-methionine into the acid-insoluble fraction of liver cubes (59%) and isolated hepatocytes (89%). Hepatic concentrations of seven amino acids, including the branched-chain amino acids, were greater (7-112%), as were the plasma concentrations of three of these (45-130%). However, 230% more enzyme in the mitochondria of carnitine-fed fish, and not a difference in the ratios of acetyl CoA:CoA-SH or ATP:ADP, appeared to account for accelerated flux through pyruvate carboxylase; flux through the dehydrogenase complex was unchanged. These results implicate induction of pyruvate carboxylase (or a reduction in turnover) and enhanced protein synthesis in the mechanism for carnitine-induced changes in gluconeogenesis and nitrogen metabolism. J. Nutr. 126: 1937-1950, 1996. INDEXING KEY WORDS: carnitine; growth; body composition; pyruvate carboxylase; Atlantic salmon

This paper investigates the role of carnitine in the etiology and treatment of dilated cardiomyopathy in boxers. Two boxers were diagnosed as having dilated cardiomyopathy on the basis of clinical presentation, chest radiographs, electrocardiography and echocardiography. In one dog, carnitine was administered at 6.0 g (or [approximately]250 mg/kg live weight (LW) daily per os, and this dog remained asymptomatic for 4 mo until it presented for anorexia, coughing and weakness. Necropsy and histologic findings were consistent with boxer cardiomyopathy in both dogs. Cardiac carnitine concentration was 567 nmol/g wet weight in the unsupplemented dog, which is below the normal mean [+ or -] SD concentration of 1493 [+ or -] 141 nmol/g wet weight. Low cardiac carnitine concentrations appear to be a consistent finding for dilated cardiomyopathy in boxers. However, in the dog that received carnitine therapy, cardiac carnitine was 2802 nmol/g wet weight, and all tissues assayed in the supplemented dog had higher carnitine concentrations than normal dogs. Elevation of tissue carnitine failed to ameliorate dilated cardiomyopathy in this dog. Oral carnitine supplementation in these therapeutic doses appears not to resolve dilated cardiomyopathy in all boxers. INDEXING KEY WORDS: * dogs * carnitine * cardiomyopathy

There is a heterogeneous class of myopathies (muscle diseases) which result from deficiencies in the electron transport chain within the mitochondria (components of cells), also called the respiratory chain. This intricate chain of enzymes is responsible for the conversion of chemical energy within the cell. Some such myopathies are fatal, while others resolve as the patient matures. Patients may be diagnosed with defects in the respiratory chain anytime from infancy to adulthood, and there is no correlation between the symptoms and the defect at the biochemical level. The authors describe the case of a six-year-old boy who had progressive muscle weakness. Prior to the onset of symptoms, he had been completely healthy and his medical history was unremarkable. Biochemical studies of biopsied muscle tissue revealed a deficiency of complex I activity, or NADH dehydrogenase. Patients found at a young age to have pure myopathy and a deficiency in complex I are extremely uncommon, and only nine seem to have been described in the medical literature. The boy was treated with a combination of riboflavin (vitamin B2) and carnitine; riboflavin is the metabolic precursor of the prosthetic group necessary for several enzymes, including NADH dehydrogenase, and carnitine helps carry fatty acids into the mitochondria where they combine with coenzyme A. The patient began to improve, and when reexamined after seven months he was again able to run and ride a bicycle, although a mild footdrop was seen on running. The patient continues to be well 18 months after diagnosis and treatment. It is impossible to say with certainty that the patient had a genetic defect in complex I. Extensive investigation failed to uncover any toxic, nutritional, or infectious event in his history which might have accounted for his symptoms, however. In addition, the mechanism by which the treatment helped is also unknown; the riboflavin might have stimulated the synthesis of more enzyme, or may have stabilized the enzyme which was already present. It is clear, however, that some patients with a defect in complex I of the respiratory chain may be helped greatly by the administration of riboflavin and carnitine. (Consumer Summary produced by Reliance Medical Information, Inc.)

Administration of carnitine to children with seizures being treated with valproic acid may have no beneficial effect on the nonspecific symptoms associated with valproic acid therapy. Lack of carnitine in the body has been linked with inborn errors of metabolism and muscle disease. Low levels of carnitine caused by chronic valproic acid therapy may produce symptoms such as fatigue, lack of appetite, poor school performance, and irritability. Thirty-seven children receiving either valproic acid or carbamazepine were evaluated by their parents while taking either carnitine or a placebo. Parents rated indicators such as energy, appetite and alertness. The placebo was reported to have the same effect as carnitine. A definite case for carnitine administration to children on anticonvulsant drugs needs to be made before doctors can continue to administer such an expensive drug as carnitine for nonspecific symptoms., Objective. This study was designed to assess the reported improvement in "well-being" perceived by parents when children who are taking anticonvulsant medications are administered carnitine. Methodology. Forty-seven children with seizures who were taking either valproic acid or carbamazepine were enrolled in a placebo-controlled, double-blinded, crossover study of the effects of oral carnitine administration (100 mg/kilo) on their well-being as perceived by their parents. The well-being scores were assessed weekly by phone and in person at the start and end of each 4-week phase. Results. The children&apos;s well-being scores improved weekly when either placebo or carnitine were administered. None of the analyses of improved well-being achieved statistical significance. Conclusion. We believe this study documents the necessity for controlled trials when assessing the subjective, beneficial effects of medications. Carnitine is expensive, costing approximately $.30/kilogram of body weight per day ($6 per day for a 20 kilo child). It would not appear warranted to administer carnitine prophylactically to children on anticonvulsant medications for alleviating common, nonspecific symptoms. Because there are no reliable clinical or laboratory tests of symptomatic carnitine deficiency caused by anticonvulsant administration, how to identify children in need of carnitine, and when to administer carnitine therapeutically to children receiving valproate or other anticonvulsants is unclear. Pediatrics 1994;93:893-895; well-being, anticonvulsant medications, carnitine.

Carnitine acts in skill transfer of long-chain fatty acids into the mitochondrial matrix to generate energy. The heart does not perform the biosynthesis of carnitine, although the cardiomyocytes require high [...]

Propionyl-L-carnitine improves exercise performance and functional status in patients with claudication. Hiatt WR, Regensteiner JG, Creager MA, et al. Am J Med 2001;110:616-622. PURPOSE: We tested the hypothesis that propionyl-L-carnitine [...]