Carnitine is a quaternary ammonium compound involved in metabolism in most mammals, plants, and some bacteria.[1][2][3][4] In support of energy metabolism, carnitine transports long-chain fatty acids into mitochondria to be oxidized for energy production, and also participates in removing products of metabolism from cells.[3] Given its key metabolic roles, carnitine is concentrated in tissues like skeletal and cardiac muscle that metabolize fatty acids as an energy source.[3]

Some individuals with genetic or medical disorders (such as preterm infants) cannot make enough carnitine, requiring dietary supplementation.[1][3][4][8] Preliminary clinical research indicates it may improve heart function in people with cardiovascular disease or neuropathy in people receiving chemotherapy.[9][1]

Biosynthesis and metabolism

Many eukaryotes have the ability to synthesize carnitine, including humans.[1]

Carnitine is involved in transporting fatty acids across the mitochondrial membrane, by forming a long chain acetylcarnitine ester and being transported by carnitine palmitoyltransferase I and carnitine palmitoyltransferase II.[12] Carnitine also plays a role in stabilizing Acetyl-CoA and coenzyme A levels through the ability to receive or give an acetyl group.[1]

Carnitine shuttle system

The free-floating fatty acids, released from adipose tissues to the blood, bind to carrier protein molecule known as serum albumin that carry the fatty acids to the cytoplasm of target cells such as the heart, skeletal muscle, and other tissue cells, where they are used for fuel. But before the target cells can use the fatty acids for ATP production and β oxidation, the fatty acids with chain lengths of 14 or more carbons must be activated and subsequently transported into mitochondrial matrix of the cells in three enzymatic reactions of the carnitine shuttle.[14]

The first reaction of the carnitine shuttle is a two-step process catalyzed by a family of isozymes of acyl-CoA synthetase that are found in the outer mitochondrial membrane, where they promote the activation of fatty acids by forming a thioester bond between the fatty acid carboxyl group and the thiol group of coenzyme A to yield a fatty acyl–CoA.[14]

In the first step of the reaction, acyl-CoA synthetase catalyzes the transfer of adenosine monophosphate group (AMP) from an ATP molecule onto the fatty acid generating a fatty acyl–adenylate intermediate and a pyrophosphate group (PPi). The pyrophosphate, formed from the hydrolysis of the two high-energy bonds in ATP, is immediately hydrolyzed to two molecule of Pi by inorganic pyrophosphatase. This reaction is highly exergonic which drives the activation reaction forward and makes it more favorable. In the second step, the thiol group of a cytosolic coenzyme A attacks the acyl-adenylate, displacing AMP to form thioester fatty acyl-CoA.[14]

In the second reaction, acyl-CoA is transiently attached to the hydroxyl group of carnitine to form fatty acyl–carnitine. This transesterification is catalyzed by an enzyme found in the outer membrane of the mitochondria known as carnitine acyltransferase 1 (also called carnitine palmitoyltransferase 1, CPT1).[14]

The fatty acyl–carnitine ester formed then diffuses across the intermembrane space and enters the matrix by facilitated diffusion through carnitine-acylcarnitine translocase (CACT) located on inner mitochondrial membrane. This antiporter return one molecule of carnitine from the matrix to the intermembrane space for every one molecule of fatty acyl–carnitine that moves into the matrix.[14]

In the third and final reaction of the carnitine shuttle, the fatty acyl group is transferred from fatty acyl-carnitine to coenzyme A, regenerating fatty acyl–CoA and a free carnitine molecule. This reaction takes place in the mitochondrial matrix and is catalyzed by carnitine acyltransferase 2 (also called carnitine palmitoyltransferase 2, CPT2), which is located on the inner face of the inner mitochondrial membrane. The carnitine molecule formed is then shuttled back into the intermembrane space by the same cotransporter (CACT) while the fatty acyl-CoA enters β-oxidation.[14]

Regulation of fatty acid β oxidation

The carnitine-mediated entry process is a rate-limiting factor for fatty acid oxidation and is an important point of regulation.[14]

Inhibition

The liver starts actively making triglycerides from excess glucose when it is supplied with glucose that cannot be oxidized or stored as glycogen. This increases the concentration of malonyl-CoA, the first intermediate in fatty acid synthesis, leading to the inhibition of carnitine acyltransferase 1, thereby preventing fatty acid entry into the mitochondrial matrix for β oxidation. This inhibition prevents fatty acid breakdown while synthesis occurs.[14]

Activation

Carnitine shuttle activation occurs due to a need for fatty acid oxidation which is required for energy production. During vigorous muscle contraction or during fasting, ATP concentration decreases and AMP concentration increases leading to the activation of AMP-activated protein kinase (AMPK). AMPK phosphorylates acetyl-CoA carboxylase, which normally catalyzes malonyl-CoA synthesis. This phosphorylation inhibits acetyl-CoA carboxylase, which in turn lowers the concentration of malonyl-CoA. Lower levels of malonyl-CoA disinhibits carnitine acyltransferase 1, allowing fatty acid import to the mitochondria, ultimately replenishing the supply of ATP.[14]

Metabolic defects of fatty acids oxidation

More than 20 human genetic defects in fatty acid transport or oxidation have been identified. In case of Fatty acid oxidation defects, acyl-carnitines accumulate in mitochondria and are transferred into the cytosol, and then into the blood. Plasma levels of acylcarnitine in newborn infants can be detected in a small blood sample by tandem mass spectrometry.[14]

When β oxidation is defective because of either mutation or deficiency in carnitine, the ω oxidation of fatty acids becomes more important in mammals. Actually, the ω Oxidation of Fatty Acids is another pathway for F-A degradation in some species of vertebrates and mammals that occurs in the endoplasmic reticulum of liver and kidney, it is the oxidation of the ω (omega) carbon—the carbon most far from the carboxyl group (in contrast to oxidation which occurs at the carboxyl end of fatty acid, in the mitochondria).[1][14]

Physiological effects

As an example of normal synthesis, a 70 kilograms (150 lb) person would produce 11–34 mg of carnitine per day.[1] Adults eating mixed diets of red meat and other animal products ingest some 60–180 mg of carnitine per day, while vegans consume about 10–12 mg per day.[3] Most (54–86%) carnitine obtained from the diet is absorbed in the small intestine before entering the blood.[3] The total body content of carnitine is about 20 grams (0.71 oz) in a person weighing 70 kilograms (150 lb), with nearly all of it contained within skeletal muscle cells.[3] Carnitine metabolizes at rates of about 400 μmol per day, an amount less than 1% of total body stores.[15]

Deficiency

Further information: Systemic primary carnitine deficiency

Carnitine deficiency is rare in healthy people without metabolic disorders, indicating that most people have normal, adequate levels of carnitine normally produced through fatty acid metabolism.[1] Infants, especially premature infants, have low stores of carnitine, necessitating use of carnitine-fortified infant formulas as a replacement for breast milk, if necessary.[1]

Two types of carnitine deficiency states exist. Primary carnitine deficiency is a genetic disorder of the cellular carnitine-transporter system that typically appears by the age of five with symptoms of cardiomyopathy, skeletal-muscle weakness, and hypoglycemia.[1][3] Secondary carnitine deficiencies may happen as the result of certain disorders, such as chronic kidney failure, or under conditions that reduce carnitine absorption or increase its excretion, such as use of antibiotics, malnutrition, and poor absorption following digestion.[1][3][16]

Supplementation

Carnitine has been studied in various cardiometabolic conditions, indicating its use as an adjunct in heart disease and diabetes, among numerous other disorders.[1] Carnitine has no effect on preventing mortality associated with cardiovascular diseases,[17] and has no significant effect on blood lipids.[18] Carnitine has no effect on most parameters in end-stage kidney disease, although it may lower c-reactive protein.[19]

Male infertility

The carnitine content of seminal fluid is directly related to sperm count and motility, suggesting that the compound might be of value in treating male infertility. One study concluded that carnitine supplementation may improve sperm quality, and the reported benefits may relate to increased mitochondrial fatty-acid oxidation (providing more energy for sperm) and reduced cell death in the testes of mice subjected to physical stress to the testes.[21]

Cardiovascular and peripheral arterial diseases

Several studies have approved the effectiveness of supplemental carnitine in the management of cardiac ischemia (restriction of blood flow to the heart) and peripheral arterial disease. If levels of carnitine are low in the failing heart muscle, supplemental amounts might counteract the toxic effects of free fatty acids and improve carbohydrate metabolism.[22] Carnitine has had anti-ischemic properties when given orally and by injection.[23][24]

Atherosclerosis

Koeth et al., from the Cleveland Clinic reported that carnitine[25] from animal flesh (four times as much in red meat as in fish or chicken), as well as phosphatidylcholine from egg yolk, are converted by intestinal bacteria to trimethylamine (the compound that causes uremic breath to smell fishy). Trimethylamine is oxidized in the liver to trimethylamine N-oxide (TMAO), which causes atherosclerosis in animal models. Patients in the top quartile of TMAO had a 2.5-fold increase in the 3-year risk of stroke, death, or myocardial infarction.

A key issue is that vegans who consumed L-carnitine did not produce TMAO because they did not have the intestinal bacteria that produce TMA from carnitine.[26]

Diabetes mellitus type 2

Type 2 diabetes, which is marked by insulin resistance, may be associated with a defect in fatty acid oxidation in muscle. Several studies suggest that carnitine supplementation may have a beneficial effect on glucose utilization and reduce diabetic neuropathy.[27]

AIDS and HIV

Generally HIV infected patients accumulate fat in some areas of the body and lose fat in other areas, besides having high blood levels of fats (hyperlipidemia) and insulin resistance which is known as the lipdystrophy syndrome. This syndrome causes a deficiency in L-carnitine which causes defects in fat metabolism in mitochondria.[28] Supplementation with carnitine in HIV-infected individuals may slow the death of lymphocytes, reduce neuropathy and favorably affect blood lipid levels.[28]

End stage renal disease and hemodialysis

The kidneys contribute to overall homeostasis in the body, including carnitine levels. In the case of renal impairment, urinary elimination of carnitine increasing, endogenous synthesis decreasing, and poor nutrition as a result of disease-induced anorexia can result in carnitine deficiency. Carnitine blood levels and muscle stores can become very low, which may contribute to anemia, muscle weakness, fatigue, altered levels of blood fats, and heart disorders. Some studies have shown that supplementation of high doses of L-carnitine (often injected) may aid in anemia management.[30][31]

Sources

The form present in the body is L-carnitine, which is also the form present in food. Food sources rich in L-carnitine are animal products, particularly beef and pork.[1] Redder meats tend to have higher levels of L-carnitine.[16][18][32] Adults eating diverse diets that contain animal products attain about 60–180 mg of carnitine per day.[33] Vegans get noticeably less (about 10–12 mg) since their diets lack these carnitine-rich animal-derived foods. Approximately 54% to 86% of dietary carnitine is absorbed in the small intestine, then enters the blood.[16][33]

Selected food sources of carnitine[1]
Food	Milligrams (mg)
Beef steak, cooked, 4 ounces (110 g)	56–162
Ground beef, cooked, 4 ounces (110 g)	87–99
Milk, whole, 1 cup (237 g)	8
Codfish, cooked, 4 ounces (110 g)	4–7
Chicken breast, cooked, 4 ounces (110 g)	3–5
Ice cream, ½ cup (125 mL)	3
Cheese, cheddar, 2 ounces (57 g)	2
Whole–wheat bread, 2 slices	0.2
Asparagus, cooked, ½ cup (62 g)	0.1

Drug interactions and adverse effects

Carnitine interacts with pivalate-conjugated antibiotics such as pivampicillin. Chronic administration of these antibiotics increases the excretion of pivaloyl-carnitine, which can lead to carnitine depletion.[16][33] Treatment with the anticonvulsants valproic acid, phenobarbital, phenytoin, or carbamazepine significantly reduces blood levels of carnitine.[4][39]

When taken in the amount of roughly 3 grams (0.11 oz) per day, carnitine may cause nausea, vomiting, abdominal cramps, diarrhea, and body odor smelling like fish.[4] Other possible adverse effects include skin rash, muscle weakness, or seizures in people with epilepsy.[4]

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