Higher Carnitine Concentrations Research Articles

Lower plasma glutathione, choline, and betaine concentrations are associated with fatty liver in postmenopausal women

Postmenopausal women are at high risk of hepatic steatosis, which may be associated one-carbon metabolism (OCM) abnormalities. We hypothesized that lower folate, choline, betaine, and glutathione (GSH) concentrations but higher total homocysteine and trimethylamine N-oxide concentrations are associated with fatty liver (FL) in postmenopausal women. We aimed to identify relationships between OCM and nonalcoholic fatty liver disease biomarkers in postmenopausal women. A total of 131 postmenopausal women participated in this study and were stratified by the incidence of FL based on the hepatic steatosis index (HSI). Food intake was evaluated using dietary records. Aspartate aminotransferase and alanine aminotransferase concentrations in serum were measured using the colorimetric method. Total homocysteine and GSH concentrations in plasma were measured using high-performance liquid chromatography. Folate and phosphatidylcholine (PC) concentrations were determined in red blood cells using an enzyme-linked immunosorbent assay. Other OCM biomarkers concentrations were measured using the isotope dilution analysis. Women with FL (HSI > 36) had lower GSH, choline, and betaine concentrations than women without FL (HSI < 36). Higher HSI level was negatively correlated with betaine and PC and positively correlated with plasma choline/betaine ratio. Lower GSH and higher carnitine concentrations in the blood are associated with an increased risk of FL. MTHFR (rs180130) T-allele carriers had lower levels of GSH than the CC homozygotes. Postmenopausal women with FL have lower GSH, choline, and betaine concentrations, which may play a role in fat accumulation in the liver. It seems important to consider the dietary intakes of these nutrients in postmenopausal women.

Neonatal carnitine concentrations in relation to gestational age and weight.

BackgroundFree carnitine has been measured in the Dutch newborn screening (NBS) program since 2007 with a referral threshold of ≤5 μmol/L, regardless of gestational age or birthweight. However, several studies suggest that carnitine concentrations may depend on gestational age and birthweight. We evaluated differences in postnatal day‐to‐day carnitine concentrations in newborns based on gestational age (GA) and/or weight for GA (WfGA).MethodsA retrospective study was performed using data from the Dutch NBS. Dried blood spot (DBS) carnitine concentrations, collected between the 3rd and 10th day of life, of nearly 2 million newborns were included. Individuals were grouped based on GA and WfGA. Median carnitine concentrations were calculated for each group. Mann‐Whitney U tests, and chi‐square tests were applied to test for significant differences between groups.ResultsPreterm, postterm, and small for GA (SGA) newborns have higher carnitine concentrations at the third day of life compared to term newborns. The median carnitine concentration of preterm newborns declines from day 3 onwards, and approximates that of term newborns at the sixth day of life, while median concentrations of postterm and SGA newborns remain elevated at least throughout the first 10 days of life. Carnitine concentrations ≤5 μmol/L were found less frequently in SGA newborns and newborns born between 32 and 37 weeks of gestation, compared to term newborns.ConclusionsMedian carnitine concentrations in NBS DBS vary with day of sampling, GA, and WfGA. It is important to take these variables into account when interpreting NBS results..

Effects of fish oil and conjugated linoleic acids on carnitine homeostasis in laying hens

1. The effects of n−3 polyunsaturated fatty acids (PUFA) and conjugated linoleic acids (CLA) on genes involved in carnitine homeostasis were compared in laying hens. Three groups of laying hens were fed on a control diet or a diet with either 3% of fish oil or CLA for 4 weeks. 2. Feed intake and egg production rate did not differ between the three groups. Diets with fish oil or CLA had only a weak effect on mRNA levels of PPARα target genes (ACO, CPT-I) in the liver and did not influence mRNA concentrations of the most important carnitine transporter OCTN2, enzymes of involved in carnitine synthesis (TMLD, TMABA-DH, BBD) or concentrations of carnitine in plasma, liver and total egg contents. 3. Hens fed the CLA diet had lower concentrations of free and total carnitine in egg yolk but higher concentrations of carnitine in albumen than control hens (P < 0·05), whereas the amount of free and total carnitine in whole egg did not differ. 4. In conclusion, the study showed that feeding fish oil or CLA causes only a weak activation of PPARα in tissues of laying hens that probably explained the lack of effect on carnitine homeostasis. The results contrast with those in humans and mice that show a significant effect of synthetic PPARα agonists on carnitine homeostasis in humans and mice.

A Comparative Study of Erythrocytic Total, Free, Short-chain Acyl and Long-chain Acyl Carnitine Concentrations in Arabian Camel (Camelus dromedarius) with Different Species

Carnitine plays a critical role in lipid metabolism. Carnitine deficiency may adversely affect the oxidation of fatty acids and further aggravate abnormal lipid metabolism. Its presence is considerable in tissues that utilise fatty acids as an important source of energy, such as the heart and skeletal muscle. The presence of total (TC), free (FC), short-chain acyl (SC) and long-chain acyl (LC) carnitine was shown for the first time in one-humped Arabian camel (Camelus dromedarius) erythrocytes. The results showed that concentrations of FC, AC, SC and TC in camel erythrocytes were significantly higher when compared with bovine, rabbit, rat and humans; however, these carnitine fractions were not significantly different when compared with sheep. Moreover, the concentration of LC in camel erythrocytes was significantly higher when compared with rabbit, rat and humans, but there was no significant difference compared with either sheep or bovine. The results showed that there were significant variations in the ratio of acyl carnitine (AC) to FC among the species erythrocytes studied. The ratio in camel erythrocytes was significantly higher when compared with rat, but there was no significant difference in this ratio in camel erythrocytes when compared with bovine, rabbit, sheep and humans. The higher carnitine concentrations and a higher proportion of AC in erythrocytes of the Arabian camel suggest an adaptive mechanism that could be common to desert animal species.

Case Report: Efficacy of Oral Carnitine Therapy for Dilated Cardiomyopathy in Boxer Dogs

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 +/- SD concentration of 1493 +/- 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.

Taurine: An overview of its role in preventive medicine

Taurine (2-aminoethanesulfonic acid), well known for its role in bile salt synthesis, is also involved in a number of crucial physiological processes including modulation of calcium flux and neuronal excitability, osmoregulation, detoxification, and membrane stabilization. With the exception of cow's milk, taurine is widely distributed in foods from many animal, but not plant, sources. Although taurine is synthesized from sulfur-containing amino acids, concern has been expressed about the adequacy of endogenous sources, especially in neonates. Accordingly, proprietary milk formulas are now supplemented with taurine. Retinal dysfunction occurs in taurine-deficient animals. A milder form of this condition has been observed in children on long-term total parenteral nutrition. Preliminary evidence suggests a possible role for taurine administration in congestive heart disease, acute hepatitis, cystic fibrosis, and myotonia. Further studies are required before taurine can be routinely advocated for use in these and other disorders. Recent discoveries concerning taurine's role in cellular proliferation and membrane protection underscore its physiological significance. In this context, taurine's interaction with other nutrients, biochemicals, and xenobiotics warrants extensive exploration. As a conditionally essential nutrient, taurine has several important preventive medical applications.

Carnitine plasma concentrations in 353 metabolically healthy children.

Carnitine plasma concentrations were determined by an enzymatic radioisotopic method in 353 metabolically healthy children and in 41 adults. There was a positive correlation between total and free carnitine plasma concentrations and the age of the children. Both free and acylcarnitine concentrations were elevated on the 1st day of life, reflecting an increased rate of fatty acid oxidation. Carnitine plasma concentrations decreased after the 1st day and subsequently increased during the 1st year. From the 2nd year of life until adulthood, no further change was noted. Up to 17 years of age no differences were seen between male and female individuals. However, adult males had higher carnitine concentrations in plasma than adult females. Total carnitine concentrations were higher in 10- to 17-year-old females and lower in 10- to 17-year-old males compared with adults of the same sex, indicating a possible role for sex hormones in the regulation of carnitine plasma concentrations.

Effect of malonyl-CoA on the kinetics and substrate cooperativity of membrane-bound carnitine palmitoyltransferase of rat heart mitochdonria

The effect of malonyl-CoA on the kinetic parameters of carnitine palmitoyltransferase (outer) the outer form of carnitine palmitoyltransferase (palmitoyl-CoA: l-carnitine O-palmitoyltransferase, EC 2.3.1.21) from rat heart mitochondria was investigated using a kinetic analyzer in the absence of bovine serum albumin with non-swelling conditions and decanoyl-CoA as the cosubstrate. The K 0.5 for decanoyl-CoA is 3 μM for heart mitochondria from both fed and fasted rats. Membrane-bound carnitine palmitoyltransferase (outer) shows substrate cooperativity for both carnitine and acyl-CoA, similar to that exhibited by the enzyme purified from bovine heart mitochondria. The Hill coefficient for decanoyl-CoA varied from 1.5 to 2.0, depending on the method of assay and the preparation of mitochondria. Malonyl-CoA increased the K 0.5 for decanoyl-CoA with no apparent increase in sigmoidicity or V max. With 20 μM malonyl-CoA and a Hill coefficient of n = 2.1, the K 0.5 for decanoyl-CoA increased to 185 μM. Carnitine palmitoyltransferase (outer) from fed rats had an apparent K i for malonyl-CoA of 0.3 μM, while hat from 48-h-fasted rats was 2.5 μM. The kinetics with l-carnitine were variable: for different preparations of mitochondria, the K 0.5 ranged from 0.2 to 0.7 mM and the Hill coefficient varied from 1.2 to 1.8. When an isotope forward assay was used to determine the effect of malonyl-CoA on carnitine palmitoyltransferase (outer) activity of heart mitochondria from fed and fasted animals, the difference was much less than that obtained using a continuous rate assay. Carnitine palmitoyltransferase (outer) was less sensitive to malonyl-CoA at low compared to high carnitine concentrations, particularly with mitochondria from fasted animals. The data show that carnitine palmitoyltransferase (outer) exhibits substrate cooperativity for both acyl-CoA and l-carnitine in its native state. The data show that membrane-bound carnitine palmitoyltransferase (outer) like carnitine palmitoyltansferase purified from heart mitochondria exhibits substrate cooperativity indicative of allosteric enzymes and indicate that malonyl-CoA acts like a negative allosteric modifier by shifting the acyl-CoA saturation to the right. A slow form of membrane-bound carnitine palmitoyltransferase (outer) was not detected, and thus, like purified carnitine palmitoyltransferase, substrate-induced hysteretic behavior is not the cause of the positive substrate cooperativity.

Ketogenic effects of low and high levels of carnitine during total parenteral nutrition in the rat

Male Wistar rats received total parenteral alimentation for 3 d. The animals were divided into three groups: group 1, without L-carnitine; group 2, 10 mg (62.1 mumol) L-carnitine X kg-1 X d-1; and group 3, 100 mg (621.1 mumol) L-carnitine X kg-1 X d-1. Fat oxidation was followed by indirect calorimetry. Maximal oxidative metabolism of fatty acids was achieved with supplementation of L-carnitine in small amounts (10 mg X kg-1 X d-1). This was demonstrated by a decrease of the RQ and of the serum concentrations of fatty acids and by an increase of beta-OH-butyric acid. Decreased liver free and long-chain acylcarnitine and increased short-chain acylcarnitine concentrations in this group also demonstrate an increased ketogenicity. This ketogenic effect of carnitine decreases when higher concentrations of carnitine are used. This study demonstrates that the ketogenic effect of carnitine is dose dependent.

Carnitine: An overview of its role in preventive medicine

Carnitine (β-hydroxy- γ- N-trimethylaminobutyric acid) is required for transport of long-chain fatty acids into the inner mitochondrial compartment for β-oxidation. Widely distributed in foods from animal, but not plant, sources, carnitine is also synthesized endogenously from two essential amino acids, lysine and methionine. Human skeletal and cardiac muscles contain relatively high carnitine concentrations which they receive from the plasma, since they are incapable of carnitine biosynthesis themselves. Since the discovery of a primary genetic carnitine deficiency syndrome in 1973, carnitine has become the subject of extensive research. It is now recognized that carnitine deficiency may also occur secondary to genetic disorders of intermediary metabolism as well as to a variety of clinical disorders, including renal disease treated by hemodialysis, the renal Fanconi syndrome, cirrhosis, untreated diabetes mellitus, malnutrition, Reye's syndrome, and certain disorders of the endocrine, neuromuscular, and reproductive systems. Administration of the anticonvulsant valproic acid and total parenteral nutrition may also induce hypocarnitinemia. In many instances, the physiological implications of secondary carnitine deficiency have not been resolved. However, evidence for a specific carnitine requirement for the newborn, especially if preterm, is accumulating. Moreover, carnitine administration may have a favorable effect on some forms of hyperlipoproteinemia. Carnitine, now recognized as a conditionally essential nutrient, is a significant factor in preventive medicine.

Carnitine and Short-Chain Acylcarnitines in the Lumen of the Human Male Reproductive Tract

Bioautography of human semen demonstrated the presence of L-carnitine, acetylcarnitine, propionylcarnitine and C4-acylcanitines (butyrylcarnitines). In studies designed to ascertain the organs secreting these compounds into semen it was found that: 1. Quantitative analyses of semen obtained pre- and post-vasectomy showed markedly decreased L-carnitine concentrations, slightly decreased acetylcarnitine levels, and unchanged propionyl- and butyrylcarnitine concentrations as a result of vasectomy. 2. The earlier portion of human split ejaculate samples characteristically contained higher concentrations of carnitine and its propionyl- and butyryl esters and a lower concentration of acetylcarnitine than did the later portion. 3. Vas deferens luminal fluid contained carnitine and each of the short-chain acyl derivatives, as shown by bioautography. 4. Prostatic fluid contained only small amounts of carnitine and its derivatives. 5. Spermatozoa contained much more acetylcarnitine than free carnitine, and only trace amounts of the other acylcarnitines. It is concluded that carnitine in semen is secreted primarily by the epididymis, that a proportion of the acetylcarnitine derives from the seminal vesicles and epididymis, and that propionylcarnitine and butytylcarnitine enter semen, at least in part, together with the vas deferens contents.

Effect of carnitine on mitochondrial oxidation of palmitoylearnitine.

The effects of carnitine on the metabolism of palmitoylcarnitine were studied by using isolated rat liver mitochondria. Particular attention was given to carnitine acyltransferase-mediated interactions between carnitine and the mitochondrial CoA pool. Carnitine concentrations less than 1.25mm resulted in an increased production of acetylcarnitine during palmitoylcarnitine oxidation. Despite this shunting of C(2) units to acetylcarnitine formation, no change was observed in the rate of oxygen consumption or major product formation (citrate or acetoacetate). Further, no changes were observed in the mitochondrial content of acetyl-CoA, total acid-soluble CoA or acid-insoluble acyl-CoA. These observations support the concept, based on studies in vivo, that the carnitine/acylcarnitine pool is metabolically sluggish and the acyl-group flux low as compared with the CoA/acyl-CoA pool. Acid-insoluble acyl-CoA content was decreased and CoA content increased at carnitine concentrations greater than 1.25mm. When [(14)C]carnitine was used in the incubations, it was demonstrated that this resulted from acid-insoluble acylcarnitine formation from intramitochondrial acid-insoluble acyl-CoA mediated by carnitine palmitoyltransferase B. Again, the higher carnitine concentrations resulted in no changes in the rates of oxygen consumption or major product formation. The above effects of carnitine were observed whether citrate or acetoacetate was the major product of oxidation. In contrast, an increase in acetyl-CoA concentration was observed at high carnitine concentrations only when acetoacetate was the product. Since the rate of acetoacetate production was not changed, these higher acetyl-CoA concentrations suggest that a new steady state had been established to maintain acetoacetate-production rates. Since there was no change in acetyl-CoA concentration when citrate was the major product, a change in the activity of the pathway utilizing acetyl-CoA for ketone-body synthesis and the potential regulation of this pathway must be considered.

Palmitate oxidation by rat skeletal muscle mitochondria: Comparison of polarographic and radiochemical experiments

Oxidation of palmitate by rat skeletal muscle mitochondria was determined polarographically and radiochemically under state 3 conditions. Maximal oxidation rate is reached at 4 μ m palmitate, palmitoyl-CoA, or palmitoyl- l-carnitine. At palmitoyl-CoA concentrations higher than 30 μ m oxidation is inhibited. At limiting substrate concentrations as used in polarographic experiments palmitate is totally degraded to CO 2. At higher concentrations the palmitate molecule is only partially degraded, due to the accumulation of intermediates. Citric acid cycle intermediates, especially 2-oxoglutarate, accumulate during oxidation of palmitate in the presence of malate. It is suggested that this accumulation is stimulated by dicarboxylate exchange. The rate of formation of 14CO 2 and 14C-labeled perchloric acid-soluble products is higher from [1- 14C]palmitate than that from [ U- 14C]palmitate. This difference, which is enhanced by higher carnitine concentrations indicates incomplete oxidation during the β-oxidation in state 3. The simultaneous determination of 14CO 2 production and 14C-labeled perchloric acid-soluble products appears to be a more accurate and sensitive method for measuring 14C-fatty acid oxidation than that of 14CO 2 production alone.