Quasi-vitamins: Carnitine Domina Petric, MD

Chemical nature Only the L-isomer is biologically active. Carnitine is the generic term for a number of compounds including L-carnitine and its acetyl and propionyl esters. Only the L-isomer is biologically active. November 13, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Nature.com November 13, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Biosynthesis Lysine and methionine provide the methyl groups. Carnitine is synthesized from two indispensable amino acids: lysine and methionine. Lysine and methionine provide the methyl groups. November 13, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Dietary sources November 13, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Plant origin food Food Carnitine μg/100 g Avocado 1,25 Cauliflower 0,13 Peanut 0,76 Bread 0,24 Wheat 0,35-1,22 Torula yeast 1,60-3,29 November 13, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Animal origin food Food Carnitine μg/100 g Beef 59,8-67,4 Beef kidney 1,8 Chicken 4,6-9,1 Cow´s milk 0,53-3,91 Beef liver 2,6 Beef heart 19,3 Lamb, muscle 78,0 November 13, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Absorption Carnitine appears to be absorbed across the gut by an active process dependent on Na+ co-transport, as well as by a passive, diffusional process that may be important for the absorption of large doses of carnitine. The efficiency of absorption appears to be high: 54-87%. November 13, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Absorption High doses are absorbed at lower efficiencies (1-18%), with <1% appearing in the urine and very little appearing in the feces. The uptake of carnitine from the intestinal lumen into the mucosa is rapid and about half of that taken up is acetylated in that tissue. November 13, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Transport Carnitine is released slowly from tissues (erythrocytes) into the plasma in both the free and acetylated forms, which are found there in simple solution. Plasma total carnitine concentrations in healthy adults are 30-89 µM, with men typically showing slightly greater (by 15%) concentrations. November 13, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Transport Carnitine is taken up, against concentration gradients, by peripheral tissues, most of which can also synthesize it. Tissue uptake is effected by high-affinity, Na+-dependent transporters related to the organic cation transporters. November 13, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Men and women show comparable concentrations. Transport Carnitine is located principally in the skeletal muscle, which contains 95% of the body’s carnitine. The carnitine concentrations of skeletal muscles are typically 70-fold that of plasma. Skeletal muscle carnitine concentrations in healthy adults are 11-52 nmol/mg non-collagen protein. Men and women show comparable concentrations. November 13, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

The turnover of carnitine in muscle is relatively slow. Excretion The turnover of carnitine in muscle is relatively slow. Turnover is increased substantially by exercise, which reduces muscle carnitine concentrations. The turnover times for carnitine in human tissues have been estimated to be 8 days in skeletal muscle and heart, 11.6 hours in liver and kidney, and 68 min in extracellular fluid. November 13, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Excretion Whole-body turnover time has been estimated to be 66 days, indicating significant reutilization of carnitine among the various tissues of the body. Exercise appears to produce a preferential mobilization of free carnitine, thus resulting in an apparent shift toward fatty acid esters of carnitine in the muscle. November 13, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Excretion Carnitine is highly conserved by the human kidney, which reabsorbs more than 90% of filtered carnitine. Kidney plays a dominant role in the regulation of plasma carnitine concentration. Renal excretion of carnitine adapts to the level of carnitine intake. November 13, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Excretion A small amount of carnitine is normally found in the urine, even in subjects with low plasma carnitine concentrations. Some of this may come from the renal secretion of carnitine either in free form or as short-chain acylcarnitine esters. November 13, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Excretion Short-chain acyl-CoAs are normally utilized as rapidly as they are generated. Little acylcarnitine accumulates. Conditions that lead to the accumulation and excretion of acylcarnitine are: propionic aciduria (propionyl-CoA carboxylase deficiency) methylmalonic aciduria (methylmalonyl-CoA mutase deficiency) supplemental dietary choline November 13, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Metabolic function Carnitine functions in the transport of long-chain fatty acids (fatty acyl-CoA) from the cytosol into the mitochondrial matrix for oxidation as sources of energy. The mitochondrial inner membrane is impermeable to long-chain fatty acids and their CoA derivatives, which are therefore dependent on activation as carnitine esters for entry into mitochondria. November 13, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Metabolic function carnitine acyltransferases I and II This transport process (carnitine transport shuttle) is effected by two trans-esterifications involving fatty acyl esters of CoA and carnitine and the action of three mitochondrial enzymes: carnitine acyltransferases I and II carnitine translocase November 13, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Metabolic function Carnitine acyltransferase I resides on the outer side of the inner mitochondrial membrane. Carnitine acyltransferase II is located on the matrix side. Acylcarnitine translocase spans the inner membrane. The acyltransferases catalyze the formation and hydrolysis of fatty acylcarnitine esters. November 13, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Metabolic function The translocase catalyzes the exchange of carnitine and acylcarnitines (produced by carnitine acyltransferase I) across the membrane. Long-chain fatty acids are brought into the mitochondrion by being esterified to carnitine and transported as fatty acylcarnitine esters. Carnitine is then released and returned to the outer side of the membrane, thus rendering the free fatty acid available for β-oxidation within the mitochrondrion. November 13, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Metabolic function Under normal metabolic conditions, short-chain acyl-CoAs are generated at rates comparable to their use rates: acylcarnitine does not accumulate. Under conditions of propionic acidemia or methylmalonic acidemia and aciduria, which occur in vitamin B12 deficiency, the urinary excretion of acylcarnitine is enhanced owing to the increased formation of short-chain acylcarnitines. November 13, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Primary muscle carnitine deficiency Primary systemic carnitine deficiency November 13, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Primary muscle carnitine deficiency Involves defective transport of carnitine into skeletal muscle due to deficiency of carnitine palmitoyltransferase II or acylcarnitine translocase. The major clinical features include mild to severe muscular weakness and excessive lipid accumulation in skeletal muscle fibers. November 13, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Primary systemic carnitine deficiency Heterogeneous clinical picture: multiple episodes of metabolic encephalopathy, cardiomyopathy, hypoglycemia, hypoprothrombinemia, hyperammonemia and hepatic steatosis. The etiology of this syndrome is heterogeneous: carnitine biosynthesis is thought to be normal, but, in at least some cases, renal carnitine reabsorption is impaired. November 13, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Health effects Carnitine-deficient individuals, diagnosed by low muscle and/or plasma carnitine levels, typically show lipid accumulation in muscle with high risk of encephalopathy, progressive muscular weakness and cardiomyopathy. November 13, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Infants and children Abnormally low circulating carnitine levels have been found in patients with severe protein malnutrition. Low plasma carnitine concentrations, which responded to nutritional therapy, have been found in children with schistosomiasis and associated signs of anemia and protein malnutrition (low serum albumin) in the Middle East. November 13, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Infants and children mitochondrial ε-N-trimethyllysine hydroxylase Two steps in the biosynthesis of carnitine require Fe2+: mitochondrial ε-N-trimethyllysine hydroxylase cytosolic γ-butyrobetaine hydroxylase Both the iron deficiency (manifested as anemia) and the protein deficiency (manifested as a low serum albumin concentration) of these patients may have reduced their abilities to synthesize carnitine. November 13, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Infants and children Neonates appear to have compromised endogenous carnitine synthesis (very low hepatic γ-butyrobetaine hydroxylase activities). Their carnitine status is dependent on that of the mother, on the placental transfer of carnitine in utero and on the availability of exogenous sources after birth. November 13, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Infants and children Infants fed soy-based formulas (which contain little or no carnitine) have been found to be unable to maintain normal plasma carnitine levels. November 13, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Infants and children Carnitine is an important cofactor for neonatal energy metabolism. Infants fed soy-based formula diets for as long as 2 weeks after birth have shown reduced hepatic carnitine concentrations with associated reductions in hepatic fatty acid oxidation and ketogenesis. Hypertriglyceridemia has also been reported in infants fed soy-based diets not supplemented with carnitine. November 13, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Hepatic function Hypocarnitinemia (plasma concentrations <55 µM) and tissue carnitine depletion appear to be common in patients with advanced cirrhosis. These patients have marginal intakes of carnitine and its precursors, but also have loss of hepatic function, including the capacity to synthesize carnitine. Carnitine supplementation has been found to protect against ammonia-induced encephalopathy in cirrhotics. November 13, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Renal function Patients with renal disease managed with chronic hemodialysis can be depleted of carnitine owing to the loss of carnitine in the dialysate, which greatly exceeds the amount normally lost in the urine. Tissue depletion of carnitine has been related to the complications attendant to hemodialysis: hyperlipidemia, cardiomyopathy, skeletal muscle asthenia and cramps. November 13, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Diabetes Reduction in the carnitine-dependent transport of fatty acids into the mitochondria, resulting in cytosolic triglyceride accumulation, has been implicated in the pathogenesis of insulin resistance. Studies have also shown that carnitine can stimulate the insulin-mediated disposal of glucose. Carnitine status may affects the control of glycolysis and/or gluconeogenesis. A clinical trial found carnitine to reduce fasting plasma glucose levels and to increase fasting triglycerides in type II diabetics. November 13, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Cardiovascular function Some studies have shown that carnitine supplementation can benefit cardiac function. Randomized, controlled trials with cardiac patients have shown carnitine treatment to reduce left ventrical dilatation and prevent ventricular remodeling. Long-term studies with chronic heart failure patients showed that carnitine supplementation improved exercise capability. November 13, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Neurologic function Multicenter, randomized, clinical intervention trial with Alzheimer’s disease patients found attenuated progression for several parameters of behavior, disability and cognitive performance. One study found carnitine supplementation to reduce attention problems and aggressive behavior in boys with attention-deficit hyperactivity disorder. November 13, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Male reproductive function Epididymal tissue and spermatozoa typically contain high concentrations of carnitine. Some studies in humans indicate that carnitine levels are related to sperm count, motility and maturation. Carnitine supplementation can improve sperm quality. November 13, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Thyroid function Carnitine appears to be a peripheral agonist of thyroid hormone action. A randomized, controlled trial found administration of carnitine to be effective in reversing symptoms of hyperthyroidism. November 13, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Athletic performance It has been suggested that oral carnitine supplementation may attenuate the deleterious effects of hypoxic training and thus hasten recovery from strenuous exercise. Recent review of the published literature concluded that there is no evidence that carnitine supplements can improve athletic performance. November 13, 2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Literature Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008. November 13, 2018