The Role of Carnitine in Normal and Altered Fatty Acid Metabolism

Charles Hoppel, MD

● Carnitine is a low-molecular-weight compound obtained from the diet that also is biosynthesized from the
essential amino acids lysine and methionine. Carnitine has been identified in a variety of mammalian tissues and
has an obligate role in the mitochondrial oxidation of long-chain fatty acids through the action of specialized
acyltransferases. Other roles for carnitine include buffering of the acyl coenzyme A (CoA)-CoA ratio, branched-
chain amino acid metabolism, removal of excess acyl groups, and peroxisomal fatty acid oxidation. The growing
body of evidence about carnitine function has led to increased understanding and identification of disorders
associated with altered carnitine metabolism. Disorders of fatty acid oxidation and metabolism typically are
associated with primary and secondary forms of carnitine deficiency. These disorders, which include increased
lipolysis, increased lipid peroxidation, accumulation of acylcarnitines, and altered membrane permeability, have
significant consequences for patients with myocardial diseases and kidney failure. Therapeutic administration of
carnitine shows promise in treating selected groups of patients who have altered carnitine homeostasis, resulting
in improved cardiac function, increased exercise capacity, reduced muscle cramps, and reduced intradialytic
complications. Am J Kidney Dis 41:S4-S12.
© 2003 by the National Kidney Foundation, Inc.

INDEX WORDS: Levocarnitine (L-carnitine); fatty acid metabolism; dialysis; lipid peroxidation; end-stage renal
disease (ESRD); congestive cardiomyopathy; uremia; chronic renal failure (CRF); kidney failure.

C ARNITINE, a low-molecular-weight com-

pound, was first characterized in muscle
extracts in 1905 and named from the Latin carnis
include animal products, particularly red meat
and dairy. Because carnitine can be synthesized
in vivo, it is not considered an essential nutrient
(flesh).1 The chemical structure later was shown in the adult diet. It is believed that the amounts of
to be 3-hydroxy-4-(N-trimethylammonio)butano- carnitine normally found in the human diet result
ate,2 and in 1962, the physiological form of in almost complete absorption, with a small
carnitine was identified as the L(⫺) isomer, or amount degraded in the intestine.9 Carnitine is
levocarnitine3 (Fig 1). In the years after the biosynthesized from the essential amino acids
discovery of carnitine, extensive research has lysine and methionine. In mammals, trimethyl-
been conducted on its biosynthesis, biological lysine (mostly protein bound) acts as a precursor
function, and metabolism; much of this research for carnitine, and this conversion seems to be a
has been summarized elsewhere.4-8 relatively rapid process, evidenced by studies in
In mammals, carnitine is present as free carni- rat liver.10
tine and acylated carnitine; the latter are products However, the majority of body trimethyllysine
of reactions that involve the transfer of acyl is present outside the liver (mainly skeletal
groups from acyl coenzyme A (CoA). These acyl muscle).11 The sequence for carnitine biosynthe-
groups vary in length from short chain (acetyl) to sis from extrahepatic trimethyllysine involves
long chain (palmitoyl). Typically, in healthy hu- protein degradation to release free trimethyl-
mans, approximately 80% to 85% of carnitine lysine, then conversion to trimethylammonio-
exists as the free form in plasma. Physiological butanoate (␥-butyrobetaine), followed by trans-
abnormalities caused by inadequate carnitine may port in the plasma with ultimate hydroxylation to
be associated with either a decreased absolute carnitine in the liver (Fig 2). This latter step
content of free carnitine or a greater than normal
ratio of acylated carnitine to free carnitine. These
conditions have been described variously as car- From the Departments of Pharmacology and Medicine,
Louis Stokes Cleveland Department of Veterans Affairs
nitine deficiency and insufficiency, respectively; Medical Center, Case Western Reserve University, Cleve-
however, the two conditions may coexist, for land, OH.
example, in patients with kidney failure undergo- Supported in part by an unrestricted educational grant
ing dialysis. from Sigma-Tau Pharmaceuticals.
L-Carnitine normally is present in plasma in Address reprint requests to Charles Hoppel, MD, VA
Medical Center, GRECC 111C(W), 10701 East Blvd, Cleve-
the form of free carnitine at concentrations of land, OH 44106. E-mail: [email protected]
approximately 40 to 50 ␮mol/L in healthy adult © 2003 by the National Kidney Foundation, Inc.
men. Dietary sources of L-carnitine primarily 0272-6386/03/4104-0402$30.00/0

S4 American Journal of Kidney Diseases, Vol 41, No 4, Suppl 4 (April), 2003: pp S4-S12
CARNITINE IN FATTY ACID METABOLISM S5

tems, including skeletal muscle and heart. Di-

etary fat is digested and transformed into triglyc-
erides for subsequent storage in adipose tissue, a
process stimulated by insulin. When required,
stored triglycerides are hydrolyzed to free fatty
acids and glycerol; this process of lipolysis is
regulated by epinephrine and glucagon. Fatty
acids are released into the circulation and trans-
ported to various tissues by attachment to albu-
Fig 1. Structural formula for L-carnitine. min. Within the cell, fatty acids enter the mito-
chondria through the carnitine system as
serves as a regulatory point in the carnitine acylcarnitines and are metabolized by ␤-oxida-
synthesis pathway because in humans, the liver tion. In this pathway, energy is released, acetyl
and kidney are the major sites of carnitine produc- CoA is produced, and the fatty acid chain is
tion.12 However, the rate of protein turnover, shortened by two carbons with each cycle. The
which produces trimethyllysine, is the limiting released acetyl CoA then enters the citric acid
step in the biosynthesis of carnitine.13 Carnitine cycle, during which further energy is generated.
is turned over rapidly in the kidney, which is the
main site of regulation of plasma carnitine con- Mitochondrial Fatty Acid Transport
centrations.6 In rat kidneys, more than 95% of The typical steps involved in fatty acid trans-
carnitine is reabsorbed, and the reabsorption port are shown in Fig 3, using palmitate as an
mechanism appears to have relatively low speci- example. The activation of long-chain fatty acid
ficity.14 to form acyl CoA occurs in the microsomal
fraction of the endoplasmic reticulum and on the
PHYSIOLOGICAL ROLES OF CARNITINE outer surface of the mitochondrial outer mem-
Physiological actions of carnitine are appreci- brane. Acyl CoA then must transverse the outer
ated best in the overall context of normal fatty membrane into the mitochondrial intermem-
acid metabolism. In mammals, fatty acids are a brane space, an important process that uses the
primary source of energy in a number of sys- voltage-dependent anion channel (porin).15,16 Acyl

Fig 2. Endogenous carni-

tine biosynthesis has a mod-
est role in carnitine ho-
meostasis. The essential
amino acid lysine is con-
verted in various tissues to
trimethyllysine (TML). In a se-
ries of metabolic steps, the
primarily protein-bound TML
is converted to butyrobe-
taine. Enzymes for the path-
way to this point are present
in most tissues. The final
conversion of butyrobetaine
to carnitine is catalyzed by
an enzyme found primarily
in the liver and kidneys.
S6 CHARLES HOPPEL

Fig 3. The mitochondrial carnitine system has an obligatory role in ␤-oxidation of long-chain fatty acids by
catalyzing their transport into the mitochondrial matrix. This transport system consists of the malonyl-CoA–
sensitive CPT-I localized in the mitochrondrial outer membrane; the carnitine:acylcarnitine translocase, an integral
inner membrane protein; and CPT-II localized on the matrix side of the inner membrane. Acyl CoAs formed in the
mitochondrial outer membrane are converted to acylcarnitines, catalyzed by CPT-I. These long-chain acylcarnitines
are then translocated into the mitochondrial matrix in an exchange reaction catalyzed by the carnitine-acylcarnitine
translocase. Within the matrix, acylcarnitines then are converted to the respective acyl-CoAs by CPT-II. Acyl-CoAs
are then available to enter the ␤-oxidation process in the mitochondrial matrix.

CoA between the outer and inner boundary mem- carnitine acyltransferases represent important
branes is converted to acylcarnitine by the malo- regulatory targets in fatty acid metabolism. There
nyl-CoA–sensitive carnitine palmitoyltransferase are three groups of acyltransferases, distin-
I (CPT-I). Acylcarnitine next is transported across guished primarily by their substrate specificity.18
the mitochondrial inner membrane by a carnitine- The generally accepted nomenclature, substrate
acylcarnitine translocase, an important regula- specificity, and localization are listed in Table 1.
tory site that is responsive to intramitochondrial Carnitine acetyltransferase has been purified
carnitine content.17 In the matrix, acylcarnitine from many sources, and the mammalian en-
acts as a substrate for carnitine palmitoyltrans- zymes show activity with a broad range of sub-
ferase II (CPT-II), with resulting transfer of the strates: maximal reaction velocity is obtained
acyl group to CoA and the release of carnitine. with propionyl CoA, whereas lower activities are
Acyl CoA then enters the fatty acid ␤-oxidation seen with acetyl CoA and butyryl CoA.18 Carni-
pathway. tine octanoyltransferase, a peroxisomal enzyme,
From the pathway described, it is clear that has been purified from rat liver and shows a

Table 1. Carnitine Acyltransferases and Their Subcellular Localization

Enzyme Group Substrate Location

Carnitine acetyltransferase Short-chain acyl groups (C1-C4) Mitochondria

Peroxisomes
Microsomes
Carnitine octanoyltransferase Medium-chain acyl groups (C5-C12) Peroxisomes, microsomes
Carnitine palmitoyltransferase Long-chain acyl groups (⬎C12) Mitochondria
CARNITINE IN FATTY ACID METABOLISM S7

broad substrate specificity. The greatest activity Removal of Acyl Groups

is seen with hexanoyl CoA, but longer chain acyl A high kidney carnitine content enhances the
CoAs also show activity.19,20 Conversely, acyl- excretion of acylcarnitines in urine. In rat liver, a
transferase in intact peroxisomes and mitochon- decrease in liver carnitine accompanies the en-
dria shows maximal activity with decanoyl and hanced formation and efflux of short-chain acyl-
myristoyl CoA.19,20 carnitines.26 An extension of this buffering effect
Carnitine palmitoyltransferase exists as a ma- occurs when the normal metabolic pathway of an
lonyl-CoA–sensitive form, CPT-I, present in the acyl CoA is blocked or when an acyl CoA is
mitochondrial outer membrane. The other form, formed that cannot be metabolized further. The
CPT-II, is located on the inner surface of the occurrence of ␣-methyl medium-chain acylcar-
inner membrane. There are two different iso- nitines in human urine indicates a role for carni-
forms of CPT-I, a liver-specific and a muscle- tine in the excretion of these acyl derivatives.27
specific isoform, which are encoded by different Accumulation of propionate or its metabolic
genes. By virtue of their sensitivity to malonyl- product propionyl CoA can disrupt normal cellu-
CoA, CPT-I is considered an important regula- lar metabolism by inhibiting short-chain fatty
tory step, whereas CPT-II is not considered to acid oxidation, as well as other metabolic path-
have a regulatory role in fatty acid oxidation.16 ways. Carnitine can partially reverse this inhibi-
tion by generating propionylcarnitine, thereby
Buffering of the Acyl CoA-CoA Ratio decreasing propionyl CoA concentrations and
The interaction between carnitine and the tis- increasing the availability of free CoA.28 These
sue CoA pool is of considerable interest. Studies studies support the concept that carnitine’s inter-
in fed and fasted rats injected with carnitine action with the cellular CoA pool can have a
suggest that production of acylcarnitine is charac- beneficial effect on cellular metabolism under
teristic of the metabolic state of the rat.21 The conditions of unusual fatty acid accumulation.
acylcarnitine-carnitine ratio was different in fasted
rats compared with controls, and this difference Peroxisomal Fatty Acid Oxidation
was maintained or enhanced after carnitine injec- The ␤-oxidation system of fatty acids in the
tion, suggesting that the state of the hepatic peroxisomes follows a pathway distinct from
carnitine pool reflects metabolic state, rather that in the mitochondria. A characteristic feature
than the previously held assumption that changes of the peroxisomal pathway is that long-chain
in the carnitine pool can influence hepatic metab- fatty acids are chain-shortened with incomplete
olism.21 Similarly, it was shown that the carnitine ␤-oxidation of fatty acyl groups, leading ulti-
pool does not cause major changes in the mito- mately to chain-shortened fatty acyl CoAs and
chondrial CoA pool or mitochondrial palmitoyl- acetyl CoA. Because carnitine acetyltransferase
carnitine metabolism.22 and octanoyltransferase activity are found in
Other studies have shown that carnitine can peroxisomes, there is considerable interest in
directly modulate the short-chain acyl CoA-CoA defining a role for carnitine in peroxisomal ␤-oxi-
ratio, implying that the system can transfer acyl dation. Studies of rat hepatocytes suggest that the
groups (as acylcarnitine derivatives) from one activity of peroxisomes contributes significantly
compartment to another in a tissue- and substrate- to the free acetate generation known to occur
dependent fashion.23,24 A key example of the during fatty acid oxidation.29 Subsequently, it
buffering action of carnitine occurs during exer- was shown that peroxisomes oxidize medium-
cise, when acetylcarnitine accumulates at work- chain–length fatty acids by a carnitine-indepen-
loads greater than the lactate threshold, but no dent mechanism, whereas they oxidize long-
change in skeletal muscle carnitine occurs under chain fatty acids by a carnitine-dependent
low-intensity exercise.25 These increases in the mechanism.30 The exact role of carnitine remains
acetylcarnitine-carnitine ratio reflect the in- to be clarified; however, recent studies have
creased production of acetyl CoA as a result of provided further insight into the mechanism by
increased pyruvate generation during high- which carnitine can transfer activated acyl groups
intensity exercise. in and out of peroxisomes.31,32
S8 CHARLES HOPPEL

Branched-Chain Amino Acid Metabolism Organic acidurias represent a class of genetic

Carnitine also has a role in the oxidation of disorders of mitochondrial metabolism. These
branched-chain amino acids, shown by its ability disorders result in the accumulation of fatty acids
to enhance the oxidation of leucine and valine in tissues and plasma. Because the short-chain
derivatives.33 Extramitochondrial free carnitine fatty acids cannot be catabolized, they are ex-
rapidly interacts with matrix short-chain ali- creted in urine. Secondary carnitine deficiency
phatic acyl CoAs generated from alpha-keto ac- has been identified as a consequence of short-,
ids of branched-chain amino acids and pyruvate medium-, and long-chain acyl CoA dehydroge-
in the presence and absence of malate.23 This nase deficiency, isovaleric acidemia, glutaric acid-
effect appears to involve a mechanism similar to uria, and propionic and methylmalonic acid-
the buffering effect of carnitine on other meta- emia.6,39,40 In all these deficiencies, it appears
bolic processes. Using perfused rat kidneys, hy- that carnitine is used as a means of removing
droxy acids and acylcarnitines are excreted pref- excess fatty acids, confirming its role in the
erentially in the urine, whereas branched-chain buffering of the acyl CoA-CoA ratio.6
amino acids are preferentially excreted in the Defects in ␤-oxidation are the most frequent
perfusate; L-carnitine accumulates rapidly in the genetic disorders that result in secondary carni-
kidney when it is added to the perfusate.34 tine deficiency. They typically are caused by
abnormalities in the acyl CoA dehydrogenase
Other Roles for Carnitine enzymes that catalyze the initial step in the
oxidation of fatty acids. Short- and long-chain
As more research is conducted into carnitine
acyl CoA dehydrogenase deficiencies are rela-
function, other potential roles for carnitine in
tively uncommon and have been identified in
normal metabolism have emerged. Carnitine is
only a few patients.42,43 Conversely, more than
believed to have a protective role by removing
100 cases of medium-chain acyl CoA defects
long-chain acyl CoAs from cell membranes,
have been reported.39,41 More than 90% of these
thereby stabilizing them.35,36 Fatty acid oxidation
patients showed low levels of tissue and plasma
mediated by carnitine is believed to be an impor-
carnitine, together with the accumulation of me-
tant component of gluconeogenesis.12 Other func-
dium-chain acylcarnitines in plasma and
tions for carnitine include energy storage in sperm
urine.39,41
and macrophages and calcium transport.37,38
In some cases, a combination of carnitine
deficiencies may exist because of multiple fac-
DISORDERS OF CARNITINE METABOLISM
tors that result in altered carnitine metabolism. In
The growing body of research into carnitine the next section, we briefly review two of the
function has led to increased understanding and most common disease states associated with al-
identification of disorders associated with altered tered carnitine metabolism: myocardial disease
carnitine metabolism. These disorders can in- and kidney failure.
clude a variety of carnitine deficiency syn-
dromes, abnormalities in fatty acid oxidation Carnitine and Cardiac Disease
pathways, organic acidurias, and lipid storage Because fatty acid oxidation is the primary
myopathies. Primary carnitine deficiencies are energy source for cardiac tissue, adequate levels
caused directly by insufficient carnitine content, of carnitine are required to support its role in
typically characterized by impaired fatty acid normal fatty acid metabolism in heart muscle.
oxidation, and are not associated with any other Carnitine deficiency associated with myocardial
systemic disease state.39 They are classified fur- diseases has been described in both experimental
ther into systemic and myopathic deficiencies.40 models and humans and typically involves de-
Secondary carnitine deficiencies include both fects in the metabolism of long-chain fatty ac-
genetic and acquired conditions that result in a ids.39-41 Total and free myocardial carnitine is
decrease in plasma or tissue carnitine levels.39,41 reduced significantly in patients with dilated car-
They are more common than primary carnitine diomyopathy and congestive heart failure,44 a
deficiencies and largely related to disorders in condition that appears responsive to treatment
fatty acid metabolism. with L-carnitine.45 A decreased rate of transport
CARNITINE IN FATTY ACID METABOLISM S9

caused by lower serum carnitine levels may be molecule, it is freely dialyzed, and a typical
responsible for the reduced content of carnitine hemodialysis session can result in as much as a
seen in myocardial cells in diabetic animals.46 75% reduction in plasma free carnitine concentra-
The increased plasma concentrations of carnitine tion, but by 8 hours after dialysis, concentrations
seen in adult patients with heart failure have been have returned to predialysis values. During a
attributed to leakage of carnitine from the heart long period of undergoing hemodialysis, this has
or skeletal muscle.47 pronounced effects on skeletal muscle and myo-
Several abnormalities of lipid metabolism have cardial tissue.6,58 Complications of carnitine dis-
been shown in cardiac ischemia, including in- orders in these patients are aggravated further by
creased lipolysis and phospholipid hydrolysis dietary restrictions, low protein supply, and ane-
and accumulation of myocardial acylcar- mia.41,58
nitines.48,49 In addition, congestive heart failure Several abnormalities of fatty acid metabo-
has been associated with abnormal oxidative lism have been documented in dialysis patients.
stress, measured by such indicators of lipid per- Hemodialysis patients show high concentrations
oxidation as malondialdehyde.50 of plasma free fatty acids, a condition that has
Abnormalities of fatty acid metabolism corre- been attributed to enhanced degradation of tri-
late with the clinical symptoms, severity, and glycerides and increased generation of free fatty
duration of cardiac disease and often have far- acids with heparin administration during hemodi-
reaching effects beyond the cardiovascular sys- alysis.60 This condition correlates with cardiac
tem. Accumulation of acylcarnitines is believed arrhythmias and is reversible by L-carnitine treat-
to contribute directly to arrhythmogenesis through ment, presumably by restoring impaired oxida-
alterations in the biophysical properties of the tion of free fatty acids.61 Hemodialysis patients
sarcolemmal membrane.51 Increased acylcarni- also show decreased free and acetyl carnitine
tine content also alters mitochondrial membrane concentrations in both plasma and skeletal muscle
permeability and has been suggested to promote compared with control values, and the decrease
apoptosis.52,53 Altered membrane permeability in muscle carnitine content progresses with dialy-
has been implicated in modifying the activity of sis vintage.62 This dialysis-associated decrease in
various hormone receptors, including the insulin tissue carnitine also leads to the abnormalities in
receptor.54 Malondialdehyde content, as an indi- cardiac fatty acid metabolism discussed in the
cator of lipid peroxidation, has been found to previous section.63 Increased oxidative stress,
correlate with the duration, severity, and func- indicated by increased lipid peroxidation, is com-
tional state in congestive heart failure.50,55,56 Mi- mon in chronic hemodialysis patients, which
tochondrial membrane phospholipid injury in may constitute a greater risk for cardiovascular
patients with heart failure is reported to correlate disease.64,65
with the prognosis of patients with dilated cardio- The abnormalities in fatty acid metabolism
myopathy.57 described are exacerbated further by other com-
plications of chronic kidney failure, which often
Carnitine and Kidney Failure have an additive effect. For example, animal
Carnitine homeostasis depends significantly studies have shown that high concentrations of
on the glomerular filtration of free carnitine and parathyroid hormone can impair ␤-oxidation of
its reabsorption by renal tubules. As glomerular fatty acids through a reduction in carnitine palmi-
function declines with progressive kidney dis- toyltransferase activity.66 It also has been re-
ease, plasma carnitine concentrations are el- ported that the increased lipid peroxidation and
evated. Further decreases in kidney function lead oxidative stress seen in hemodialysis patients is
to an accumulation of acylcarnitines in plasma.58 largely a result of anemia of kidney failure,
In addition, incomplete fatty acid oxidation also implying that anemia management can improve
leads to accumulation of acylcarnitines.58 The this condition.67 However, these results must be
combined effect for patients who are not on examined in the context of other studies that
dialysis therapy is that the ratio of acylcarnitines implicate oxidative stress as a cause of erythro-
to free carnitine is abnormally high.58,59 poietin resistance in hemodialysis patients.68
Because carnitine is a small water-soluble Carnitine status in dialysis patients has been
S10 CHARLES HOPPEL

correlated with several clinical indicators. Mea- for the beneficial effects of L-carnitine replace-
sures of exercise performance have been exam- ment in secondary deficiency conditions, further
ined and correlated with total muscle carnitine research is needed to elucidate which set of
content in hemodialysis patients.69 Decreased patients might have measurable clinical benefits
plasma carnitine levels in hemodialysis patients from L-carnitine therapy. It is our hope that the
correlated inversely with cardiothoracic ratio and information presented in this review will stimu-
were implicated as a cause of cardiomegaly.70 late further evaluation of the clinical uses of
Serum total, free, and acylated carnitine concen- L-carnitine.
trations correlated with indicators of erythrocyte
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