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L-Carnitine, Acetyl-L-Carnitine, and Propionyl-L-Carnitine


L-Carnitine [known chemically as R(−)--hydroxy--

(N,N,N-trimethylammonio)butyrate; molecular weight:

161.2 g/mol] is a water-soluble quaternary amine that facilitates

lipid metabolism.


Only the L isomer is biologically

active. Humans acquire varying amounts of L-carnitine

from dietary sources, but a dietary requirement has not

been established. The goal of this chapter is to survey the

literature on the clinical findings on L-carnitine and its esters

acetyl-L-carnitine and propionyl-L-carnitine. Due to

space constraints, this is not an exhaustive review. Readers

are directed to the references for more information.



The human body synthesizes L-carnitine from the essential

amino acids lysine and methionine in amounts that are

limited but adequate for the maintenance of normal health

(1). L-Carnitine participates in reversible transesterification

reactions, in which an acyl group is transferred from

coenzyme A to the hydroxyl group of L-carnitine (Fig. 1).

Acetyl-L-carnitine, propionyl-L-carnitine, and other esters

are biosynthesized in this manner. Carnitine and acetyl-Lcarnitine

(and lesser amounts of other esters of carnitine)

are also obtained from the diet (1).

Transfer of Long-Chain Fatty Acids from Cytoplasm

into Mitochondria

Long-chain fatty acids, as free acids or coenzyme A esters,

cannot cross the mitochondrial inner membrane.

In contrast, long-chain acylcarnitine esters rapidly cross

this membrane, facilitated by a carrier protein, carnitine acylcarnitine

translocase (CACT) (2). In the cytoplasm,

transesterification of long-chain fatty acids from coenzyme

A to L-carnitine is catalyzed by carnitine palmitoyltransferase

I (CPT I), an integral protein of the mitochondrial

outer membrane. This enzyme serves as the primary

regulator in partitioning fatty acids toward oxidation in

mitochondria or triglyceride synthesis, and its activity is

regulated principally through inhibition by malonyl-CoA

(3). On the matrix side of the mitochondrial inner membrane,

the acyl group of the carnitine ester is transferred to

intramitochondrial coenzyme A and carnitine is released

(2). This reaction is catalyzed by carnitine palmitoyltransferase

II (CPT II), an enzyme bound to the surface of the

membrane (2). L-Carnitine, either nonesterified or as a

short-chain acyl ester, may then exit the mitochondrion

via CACT

Acyl-coenzyme A ester



Reduced coenzyme A

Acyl-L-carnitine ester


Transesterification reaction between L-carnitine and coenzyme A.

Transfer of Chain-Shortened Fatty Acids from

Peroxisomes to Mitochondria

Very long-chain fatty acids are not metabolized in the mitochondria.

Instead, they enter peroxisomes and undergo

one or more -oxidation cycles, leading to the generation

of medium-chain acyl-CoA. These acyl groups are

then transesterified by carnitine octanoyltransferase for

export from the mitochondria (2). Medium-chain acylcarnitine

esters exported from peroxisomes are transported

into mitochondria by CACT, and the acyl moieties are

transesterified to coenzyme A and oxidized (Fig. 2) (2).

Modulation of the Acyl-CoA/CoA Ratio

in Cellular Compartments

Coenzyme A participates in many metabolic processes in

the cellular cytoplasm and organelles. However, neither

coenzyme A nor its thioesters can cross the membranes

separating these compartments. Thus, in each compartment,

sufficient nonesterified coenzyme A must be made

available to maintain metabolic activities in that part of

the cell. Because of its ability to be transported across

organelle membranes and undergo rapid transesterification

with coenzyme A, L-carnitine facilitates availability

of adequate amounts of the deacylated coenzyme. In mitochondria,

the amount of acetyl-CoA generated from

rapid -oxidation of fatty acids or carbohydrate utilization


L-Carnitine and acetyl-L-carnitine transport and function. Abbreviations: Carn, L-carnitine; AcCarn, acetyl-L-carnitine; OCTN2, organic cation transporter

2; UnTr, unidentified transporter(s); LCA-CoA, long-chain acyl-coenzyme A; MCA-CoA, medium-chain acyl-coenzyme A; VLCA-CoA, very long-chain acyl-coenzyme

A; LCA-Carn, long-chain acylcarnitine esters; MCA-Carn, medium-chain acylcarnitine esters; Ac-CoA, acetyl-coenzyme A; CPT I, carnitine palmitoyltransferase

I; CPT II, carnitine palmitoyltransferase II; CAT, carnitine acetyltransferase; COT, carnitine octanoyltransferase; CACT, carnitine-acylcarnitine translocase; PDH,

pyruvate dehydrogenase complex.

may exceed the capacity of the citric acid cycle to release

the coenzyme. Transesterification of acetyl units to

L-carnitine, catalyzed by carnitine acetyltransferase

(CAT), frees intramitochondrial coenzyme A for participation

in subsequent cycles of substrate utilization (3,4).

Lowering of the acetyl-CoA/CoA ratio stimulates pyruvate

oxidation, secondary to an increase in pyruvate dehydrogenase

complex activity (4). Acetyl-L-carnitine can

be removed from the mitochondrion via CACT for use in

the cytoplasm, for export and use in other cells or tissues,

or for excretion (3,4). This function has long been viewed

primarily as a means to dispose of acetyl units from mitochondria.

However, export of acetyl-L-carnitine fromsome

cells and tissues (e.g., liver and kidney) may be important

for supply of this metabolite to other tissues (e.g., brain),

where it may have specific functions in addition to its

use as a substrate for energy production. Moreover, by

modulating the intramitochondrial acetyl-CoA/CoA ratio,

L-carnitine plays a significant role in regulating glucose

metabolism in skeletal muscle and heart (4).

Membrane Phospholipid Remodeling

L-Carnitine and extramitochondrial CPT are important

modulators of long-chain fatty acid utilization for

membrane phospholipid biosynthesis and remodeling.

L-Carnitine acts as a reservoir of long-chain fatty acids

for incorporation into erythrocyte membrane phospholipids

during repair after oxidative insult (2) and for

use in the synthesis of dipalmitoylphosphatidylcholine,

the major component of surfactant, in lung alveolar

cells (2).

Other Reported Actions of L-Carnitine and/or Its Acetyl

and Proponyl Esters

L-Carnitine may mimic some of the actions of glucocorticoids

in vivo. In HeLa cells, L-carnitine reduces

glucocorticoid receptor- affinity for its steroid ligand and

triggers nuclear translocation of the receptor (5). It suppresses

glucocorticoid receptor–mediated tumor necrosis

factor- and interleukin-12 release by human primary

L-Carnitine, Acetyl-L-Carnitine, and Propionyl-L-Carnitine 109

monocytes stimulated with lipopolysaccharide ex vivo

(5). All of these effects of L-carnitine are concentration

dependent. In rats and mice, L-carnitine is found to

markedly suppress liposaccharide-induced cytokine production,

improving their survival during cachexia and

septic shock (5). In humans, L-carnitine supplementation

of surgical and AIDS patients decreased serum tumor

necrosis factor- concentration (5). Glucocorticoids also

increase the expression and activity of urea cycle enzymes.

Hyperammonemia associated with chronic valproic acid

therapy and with several inborn errors of metabolism,

including CACT deficiency and medium-chain acyl-CoA

dehydrogenase deficiency, is attenuated by L-carnitine

administration. It has been experimentally found that

L-carnitine supplementation protects against lethal ammonia

intoxication in mice (6). One suggested mechanism

for these effects of L-carnitine is increased synthesis and

activity of urea cycle enzymes, a process also responsive to


L-Carnitine is a peripheral antagonist of thyroid hormone

action in some tissues (7). It inhibits thyroid hormone

entry into cell nuclei. In a controlled clinical trial,

L-carnitine was shown to reverse or prevent some symptoms

of hyperthyroidism (7).

Acetyl-L-carnitine may directly or indirectly reverse

age-associated mitochondrial decay (8). It acts as a chaperone

to protect macromolecules, including CAT, from

structural alteration and/or loss of function. Acetyl-Lcarnitine

partially reverses age-associated loss of mitochondrial

membrane potential and decline in membrane

cardiolipin concentration, and protects against oxidative

damage to mitochondrial DNA (8).

L-Carnitine inhibits arachidonic acid incorporation

into platelet phospholipids, agonist-induced arachidonic

acid release, and arachidonic acid–inducedNADPH

(nicotinamide adenine dinucleotide phosphate)-oxidase

activation (9). It has been proposed and some evidence

has been obtained to support this notion that acetyl-

L-carnitine stimulates or upregulates expression of heat

shock proteins, redox-sensitive transcription factors, and

sirtuins that protect against oxidative cellular damage (10).

These actions may be particularly important in modulating

the aging process and in slowing the progression of

neurodegenerative diseases.



Dietary Intake and Biosynthesis

Meat, fish, chicken, and dairy products are rich sources of

dietary L-carnitine (1). Plant-derived foods contain very

small amounts of the substance. Most commercially available

infant formulas contain L-carnitine, either provided

from the milk component or supplemented, as in the

case of soy-protein-based formulas. There is no recommended

dietary allowance or dietary reference intake for


In mammals, L-carnitine is synthesized from

ε-N-trimethyllysine, which is derived from posttranslationally

methylated lysine residues in proteins, and

protein turnover (1). In normal humans, the rate of synthesis

is estimated to be approximately 1.2 mol/kg body

weight/day (1). The rate of L-carnitine biosynthesis is regulated

by the availability of ε-N-trimethyllysine. Thus,

conditions that increase protein methylation and/or protein

turnover may increase the rate of L-carnitine biosynthesis



Dietary L-carnitine may be absorbed through active or

passive mechanisms. Evidence from several in vivo and

in vitro studies indicates that L-carnitine is actively transported

from the small intestinal lumen into enterocytes

(11). However, the preponderance of data suggests that

intracellular L-carnitine in the intestinal mucosa does not

cross serosal membranes by an active transport mechanism.

Absorption of dietary L-carnitine and L-carnitine

supplements appears to occur primarily by passive diffusion

(11). In humans, approximately 54% to 87% of dietary

L-carnitine is absorbed, depending on the amount

in the diet. The bioavailability of dietary supplements

(0.6–4 g/day) is 15% to 20% (11,12). Unabsorbed

L-carnitine is degraded by microorganisms in the large intestine.

Major metabolites identified are trimethylamine

oxide in urine and -butyrobetaine in feces (11,12).

Bioavailability of oral acetyl-L-carnitine has not been studied

in normal healthy humans.

Distribution in Tissues, Fluids, and Cells

L-Carnitine and acylcarnitine esters are present in all tissues.

In most tissues and cells, they are present in higher

concentration than in the circulation. For example, in human

skeletal muscle and liver, respectively, nonesterified

L-carnitine is concentrated 76-fold and 50-fold from that

in serum (estimated from data in Ref. 13).


Tissue Accumulation

L-Carnitine and acetyl-L-carnitine are concentrated in

most tissues via high-affinity, Na+-dependent organic

cation transporter OCTN2 (14). Kt for L-carnitine binding

is 3 to 5 M; OCTN2 binds acetyl-L-carnitine and

propionyl-L-carnitine with comparable affinity. This protein

is highly expressed in heart, placenta, skeletal muscle,

kidney, pancreas, testis, and epididymis and weakly

expressed in brain, lung, and liver. L-Carnitine entry

into the liver occurs via a low-affinity (Kt = 5 mM)

transporter, probably distinct from OCTN2. Several other

L-carnitine transporters have been identified, including

OCTN1, OCTN3, and ATB0,+, and Oat9S (2,15). Specific

roles for these transporters in carnitine metabolism in humans

have not been determined.

Homeostasis, Renal Reabsorption, and Excretion

Circulating L-carnitine concentrations are maintained

at a fairly constant level of around 50 M, predominantly

through efficient reabsorption by the kidney

(11). At a filtered load of 50 mol/L, the efficiency of

L-carnitine and acylcarnitine ester reabsorption is 90% to

98%. However, as the filtered load of L-carnitine increases,

for example, after consumption of a dietary supplement

or after intravenous infusion, the efficiency of reabsorption

declines rapidly. Physiologically, the efficiency of

L-carnitine reabsorption is sensitive to the amount in the

diet as well as the differences in the macronutrient content

of the diet. Clearance of acylcarnitine esters is often

higher than that of nonesterified L-carnitine. Experimental

110 Rebouche

studies have shown that in rats and humans, kidneys

are able to synthesize acetyl-L-carnitine from L-carnitine

and either acetoacetate or -hydroxybutyrate, and that

L-carnitine, acetyl-L-carnitine, and -butyrobetaine (also

synthesized in human kidneys) are secreted from mucosal

cells into the tubular lumen (11). Because the kinetics of

transport of these metabolites by the sodium-dependent

L-carnitine transporter are not different, the relative proportions

appearing in urine reflect not only those in the

glomerular filtrate but also those in the renal tubular epithelium

that are secreted into the lumen. Thus, under

conditions of rapid intracellular synthesis of acylcarnitine

esters or direct accumulation from the circulation, secretion

of these species will lead to a higher proportion of

acylcarnitine esters in urine compared to that in the circulation.

By inference, kidneys may be substantially involved

in the regulation of circulating acylcarnitine ester

concentrations (11).



L-Carnitine deficiency is defined biochemically as abnormally

low concentration (<20 M) of nonesterified

L-carnitine in plasma (2). A concentration ratio of acylcarnitine

esters/nonesterified L-carnitine of 0.4 or greater

in plasma is also considered abnormal. Nutritional

L-carnitine deficiency has not been shown to occur in the

absence of other mitigating factors (2).

Primary L-carnitine deficiency occurs as a result of

defects in the gene coding for the plasma membrane

L-carnitine transporter OCTN2 (16). Characteristic features

of this disease are cardiomyopathy, hypoketotic hypoglycemia,

and muscle weakness. Secondary carnitine

deficiency occurs in association with genetic diseases of

organic acid metabolism and in genetic diseases involving

defects in fatty acid oxidation. Secondary carnitine deficiency

has been described in patients with end-stage renal

disease requiring maintenance hemodialysis. Secondary

carnitine deficiency has been observed during chronic use

of drugs, including valproic acid, cisplatin, ifosfamide, zidovudine,

and pivalic acid-containing prodrugs (17–20).



L-Carnitine, acetyl-L-carnitine, and/or propionyl-Lcarnitine

may be used for replacement therapy to

restore normal carnitine concentrations and/or abnormal

nonesterified-to-esterified carnitine ratio. They may be

used as supplements to increase the carnitine load of

the body and/or increase the flux of carnitine among

compartments. In some conditions, both replacement

therapy and supplementation are appropriate. For primary

and some secondary carnitine deficiencies (see

earlier), L-carnitine is used for replacement therapy.

L-Carnitine Supplementation in Neonatal Nutrition

L-Carnitine has been described as a conditionally essential

nutrient for infants. For the last 25 years, commercial

enteral infant formula products have included L-carnitine,

where necessary, to achieve an L-carnitine concentration

similar to that in human milk (∼60 mol/L). Bovine milkbased

formulas typically contain a higher concentration

of L-carnitine than does human milk. On the other hand,

premature infant formulas, both enteral and parenteral,

typically do not include L-carnitine at the time of manufacture,

but are sometimes supplemented at the time of

use. The rationale for supplementation is twofold: Infants

utilize lipids as a primary source for energy and growth after

birth, requiring a high rate of mitochondrial oxidation,

and the concentration of L-carnitine in infant circulation

and tissues typically is lower without supplementation

than in infants fed human milk or formulas containing

carnitine. Studies in premature infants typically have focused

on the effect of L-carnitine supplements on growth

rate and morbidity, with mixed results. In one doubleblind,

placebo-controlled, randomized trial of L-carnitine

supplementation in premature infants 28 to 34 gestational

weeks of age at birth, no differences in two-week

weight gain over 8 weeks were observed between supplemented

and nonsupplemented infants (21). More recently,

in another prospective, randomized, placebo-controlled,

double-blinded study, 29 premature neonates received

carnitine supplementation (20 mg/kg body weight/day)

or placebo for up to eight weeks. Supplemented neonates

regained their birth weight more rapidly than placebo

group neonates, indicating that L-carnitine supplementation

may promote more rapid catch-up growth (22). An

extensive review of these and many more relevant studies

has been published (23). For infants expected to be on

parenteral nutrition for seven days or longer, supplementation

with L-carnitine 10 to 20 mg/kg body weight/day,

given intravenously or orally, is recommended (23).

L-Carnitine Replacement Therapy and Supplementation

in End-Stage Renal Disease

Regular L-carnitine supplementation in hemodialysis patients

can improve lipid metabolism, antioxidant status,

and anemia requiring erythropoietin and may reduce incidence

of intradialytic muscle cramps, hypotension, asthenia,

muscle weakness, and cardiomyopathy (24,25). The

recommended dosage is 50 mg/kg body weight/day, to a

maximum of 3 g/day.

L-Carnitine and Propionyl-L-Carnitine Supplementation

for Cardiac Ischemia, Congestive Heart Failure,

Cardiomyopathy, and Peripheral Arterial Disease

Experimental studies have shown L-carnitine to be an

effective antianginal agent that reduces ST-segment depression

and left ventricular end-diastolic pressure during

stress in patients with coronary artery disease (25). Cardioprotective

effects of L-carnitine have been observed following

aortocoronary bypass grafting and following acute

myocardial infarction. Carnitine administration initiated

early after acute myocardial infarction attenuated left ventricular

dilation and resulted in smaller left ventricular

volumes (25).

L-Carnitine deficiency syndromes sometimes

present with dilated cardiomyopathy and are often

effectively treated with L-carnitine (26). Thus, it was suggested

that cardiomyopathy progressing to congestive

heart failure but not associated with inherited L-carnitine

deficiency might respond to L-carnitine supplementation.

A large-scale clinical trial of L-carnitine supplementation

L-Carnitine, Acetyl-L-Carnitine, and Propionyl-L-Carnitine 111

versus placebo in 574 patients with heart failure produced

promising results with regard to improvement in maximum

duration of exercise, but other endpoints, including

death and hospital admissions during the follow-up

period, were not different between treatment groups

(26). Utility of L-carnitine supplements for congestive

heart failure not associated with inherited L-carnitine

deficiency remains debatable (26,27).

Peripheral arterial disease is a common manifestation

of atherosclerosis and is associated with reduced arterial

circulation in the lower extremities. In five large, randomized,

double-blind, placebo-controlled studies, with

long duration of therapy, and three short-duration studies,

propionyl-L-carnitine supplementation (1–3 g/day,

orally) for up to one year improved initial claudication

distance (distance walked before muscular symptoms appeared)

and absolute claudication distance (distance at

which patient stopped walking due to muscular cramps)

(28). Quality of life outcomes were also improved with

propionyl-L-carnitine treatment relative to placebo. Experimental

and clinical studies suggest that the improvements

observed in clinical trials are due to protection

by propionyl-L-carnitine from the effects of oxidative

stress and inflammation in ischemic tissue endothelium

(28), as well as due to increased blood flow resulting

from endothelium-dependent vasodilation elicited by

propionyl-L-carnitine (29).

L-Carnitine Supplementation for Exercise Performance

and Weight Reduction

L-Carnitine supplementation has been suggested to improve

exercise performance in healthy humans. Proposed

mechanisms include enhanced muscle fatty acid oxidation,

altered glucose homeostasis, enhanced acylcarnitine

production, modification of training responses, and altered

muscle fatigue resistance (30).Areview of published

studies has led to the conclusion that L-carnitine supplements

do not improve exercise performance in healthy humans

(30–33). On the other hand, in conditions where the

nonesterified L-carnitine concentration of skeletal muscle

may be significantly reduced, such as in peripheral arterial

disease and end-stage renal disease, L-carnitine supplementation

has afforded some benefit to muscle function

and exercise performance (33).

In a double-blind, placebo-controlled, crossover design

clinical trial, oral administration of 4.5 g of propionyl-

L-carnitine (as glycine propionyl-L-carnitine) to trained

athletes significantly enhanced peak power production

in resistance-trained males with significantly lower lactate

accumulation (34). The incremental differences in

power production were modest and were observed only

after repeated short-durationWingate cycle sprints. However,

it is noted that, particularly for elite athletes, modest

enhancement in performance can be highly significant

in outcomes in competitive sports. Propionyl-L-carnitine

may be more effective in enhancement of exercise performance

than L-carnitine, because of its ability to increase

nitric oxide production and vasodilation.Moreover,

propionyl-L-carnitine may enhance citric acid cycle activity

by providing propionyl units that can be converted to


Because of its role in facilitating fatty acid oxidation,

L-carnitine has been suggested to aid in weight loss

regimes. Two facts argue against this. First, there is no

evidence that it facilitates, directly or indirectly, mobilization

of fatty acids from adipose tissue. Second, in normal

humans, the intracellular concentration of L-carnitine is

not rate-limiting for transesterification of fatty acids by

CPT I. Adding an increment of L-carnitine will not increase

the rate at which this reaction occurs. There is no

scientific evidence that L-carnitine supplements facilitate

weight loss in humans.

L-Carnitine and Acetyl-L-Carnitine Replacement Therapy

and Supplementation for Chronic Fatigue

L-Carnitine may improve symptoms of fatigue in humans.

Use of the cancer chemotherapeutic agents cisplatin and

ifosfamide is associated with fatigue. In a prospective,

open-label study, improvement of symptoms of fatigue

was observed in 50 nonanemic patients following

L-carnitine supplementation to the chemotherapeutic

regimen of cisplatin or ifosfamide (35). However, in a subsequent

randomized, double-blind, placebo-controlled

trial, no improvement in measures of fatigue was observed

as a result of L-carnitine supplementation (36).

The study included an open-label phase, in which fatigue

symptoms did show some improvement with L-carnitine


Chronic fatigue syndrome (CFS) in humans was

found to be associated with low circulating acetyl-Lcarnitine

concentration and decreased accumulation in

several brain regions (37). It has been suggested that

acetyl-L-carnitine helps maintain neuronal metabolic activity

by promoting glucose and lactate uptake and utilization

through its role as a precursor of glutamate in

neurons (38). In a randomized, open-label study of 30

patients with CFS, acetyl-L-carnitine and propionyl-Lcarnitine

showed beneficial effects on fatigue and attention

concentration (39).

Acetyl-L-Carnitine Supplementation for Depression and

Cognitive Function in the Elderly

Acetyl-L-carnitine appears to have specific and perhaps

unique roles in brain metabolism. Animal studies and

in vitro experiments suggest that this agent has promise

in slowing or reversing memory and cognition decline

as well as the decline in physical performance that normally

occurs in the process of aging. In studies of the

elderly, patients with depressive syndrome scored significantly

lower on the Hamilton Rating Scale for Depression

(modified for the elderly) following supplementation with

acetyl-L-carnitine (40). Older subjects with mild mental

impairment had improved scores on cognitive performance

tests following such supplementation (41).Ametaanalysis

of the efficacy of acetyl-L-carnitine in mild cognitive

impairment and mild Alzheimer disease included

all identified double-blind, placebo-controlled, prospective,

parallel-group studies using treatment doses of 1.5

to 3.0 g/day of acetyl-L-carnitine that were conducted between

1983 and 2000 (42). This analysis showed a significant

advantage for acetyl-L-carnitine compared to placebo,

with beneficial effects observed on both clinical scales and

psychometric tests. The benefit of supplement use was

112 Rebouche

observed for three months, and it was found to increase

over time. The typical usage recommended by vendors is

1 to 3 g/day.

L-Carnitine Supplementation in Liver Dysfunction with


Hyperammonemia occurs in some inborn errors of

metabolism and as a result of drug- or toxicant-induced

hepatotoxicity. Mortality and metabolic consequences

of acute ammonium intoxication in mice are reduced

by pharmacologic administration of L-carnitine (6). The

mechanism for this effect may have two components.

L-Carnitine administration normalizes the redox state

of the brain (perhaps by increasing the availability of

-hydroxybutyrate and/or acetyl-L-carnitine to the brain),

and it increases the rate of urea synthesis in the liver,

perhaps, in part, by activation of the glucocorticoid receptor.

At least part of the protective effect is associated

with flux through the carnitine acyltransferases, as

analogs of L-carnitine that are competitive inhibitors of

carnitine acyltransferases enhance the toxicity of acute

ammonium administration (6). Thus, it has been proposed

that L-carnitine increases urea synthesis in the liver by facilitating

fatty acid entry into mitochondria, leading to increased

flux through the -oxidation pathway, an increase

of intramitochondrial reducing equivalents, and enhancement

of ATP production (6). Carnitine supplementation

may benefit individuals with hepatic dysfunction due to

inborn errors of metabolism or chemical intoxication.

L-Carnitine and Acetyl-L-Carnitine Replacement Therapy

and Supplementation in Diabetes

L-Carnitine infusion improves insulin sensitivity in

insulin-resistant diabetic patients (43). Glucose oxidation

is increased during L-carnitine administration, concurrent

with lower plasma concentration of lactate. These

observations suggest that L-carnitine activates normally

depressed pyruvate dehydrogenase activity in insulinresistant

patients (43). Intravenous administration of

acetyl-L-carnitine increases glucose disposal in Type 2 diabetic

patients (44). Such administration appears to promote

storage of glucose as glycogen, rather than increase

in glucose oxidation (44).

L-Carnitine and Acetyl-L-Carnitine Replacement Therapy

and Supplementation in HIV Infection

L-Carnitine and acetyl-L-carnitine ester concentrations are

below normal in some human immunodeficiency virus

(HIV)-infected patients undergoing antiretroviral therapy

(45). L-Carnitine administration as part of antiretroviral

therapy with either zidovudine or didanosine reduced

lymphocyte apoptosis and oxidant stress compared to the

antiretroviral regimens without L-carnitine (46).

L-Carnitine and Acetyl-L-Carnitine Supplementation in


Male Reproductive Dysfunction

L-Carnitine and/or acetyl-L-carnitine supplementation

may be beneficial in men with oligoasthenospermia, a condition

in which low sperm count is associated with low

sperm motility. Epididymal fluid contains the highest concentration

of L-carnitine in the human body. L-Carnitine is

secreted from the epithelium into epididymal plasma via

a testis-specific carnitine transporter (47). The very high

concentration of L-carnitine in epididymal fluid provides

for passive diffusion of L-carnitine into spermatozoa during

transit and maturation through the epididymis. Mature

spermatozoa acetylate L-carnitine to generate a pool

of intracellular acetyl-L-carnitine (48). In semen obtained

from 101 men with normal or abnormal spermiograms,

concentrations of L-carnitine and acetyl-L-carnitine correlated

positively with the number of spermatozoa, the

percentage of motile spermatozoa, and the percentage of

normal cells (49). A meta-analysis comparing L-carnitine

and/or acetyl-L-carnitine to placebo treatment and including

nine randomized, controlled clinical trials revealed

significant improvements in pregnancy rate, total sperm

motility, forward sperm motility, and presence of atypical

sperm cells (50). The benefits of L-carnitine and acetyl-Lcarnitine

may be due to increased mitochondrial fatty acid

oxidation, resulting in improvement in motility epididymal

sperm, as well as due to the putative antiapoptotic

effect(s) of carnitine in the testes (51).


Transient diarrhea, nausea, vomiting, abdominal cramps,

and/or “fish-odor syndrome” have been noted in rare

cases after consumption of 2 to 6 g of L-carnitine (52).


L-Carnitine is approved as a pharmaceutical by the U.S.

Food and Drug Administration for treatment of primary

systemic carnitine deficiency, as well as for acute

and chronic treatment of patients with inborn errors

of metabolism that result in secondary carnitine deficiency

(e.g., medium-chain acyl-CoA dehydrogenase deficiency,

glutaric aciduria, Type 2 diabetes, methylmalonic

aciduria, and propionic acidemia) (52). L-Carnitine is also

approved, by the U.S. Food and Drug Administration, as

a pharmaceutical for the prevention and treatment of carnitine

deficiency in patients with end-stage renal disease

who are undergoing dialysis (52).



L-Carnitine and esters of L-carnitine have a proven, essential

role in cellular fatty acid metabolism. Beyond that,

numerous other functions have been suggested by physiological

and pharmacological studies in experimental animals

and in humans. These include, but are not limited

to, antioxidant and antiapoptotic properties, a role

in membrane lipid remodeling, and modulation of gene

expression. Identification of and evidence for these putative

functions have led to hypotheses concerning a role for

L-carnitine and its esters in promotion of physiological

function (e.g., exercise performance), in prevention,

slowing, or attenuation of progressive alteration or loss

of physiological function (e.g., cognitive function in aging,

cardiac or liver dysfunction, and male reproductive

dysfunction). In some cases, establishment of a positive

role for L-carnitine supplementation through blinded,

L-Carnitine, Acetyl-L-Carnitine, and Propionyl-L-Carnitine 113

randomized clinical trials has been hampered by lack

of accessibility of definitive, quantitative endpoint(s),

and/or by the requirement for large sample sizes to detect

small but meaningful physiological or pathological

differences in a heterogeneous population. Nevertheless,

it seems likely that new data will emerge from welldesigned

clinical trials to provide definitive answers regarding

the efficacy of L-carnitine and/or its esters supplementation

to promote better health and function in the

human population.



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