Download Role of Carnitine in Lipid Metabolism

Lipids in Modern Nutrition, edited by
M. Horisberger and U. Bracco. Nestk Nutrition,
Vevey/Raven Press, New York © 1987.
Role of Carnitine in Lipid Metabolism
Peggy R. Borum
Departments of Food Science and Human Nutrition and Biochemistry,
Gainesville, Florida 32611
A major function of lipids in modern nutrition is to serve as a substrate for production of metabolic energy. Mechanisms regulating the production of metabolic
energy under a wide variety of physiological conditions are required for survival
of the species. The critical role of carnitine in the production of energy from longchain fatty acids is well recognized. As illustrated in Fig. 1, carnitine also has a
role in the production of metabolic energy from several substrates in addition to
long-chain fatty acids. Thus, adequate carnitine status and carnitine nutriture are
essential in maintaining health (1).
ROLE OF CARNITINE IN (3-OXIDATION OF
LONG-CHAIN FATTY ACIDS
In the late 1950s and early 1960s, the role of carnitine in the transport of longchain fatty acids into the matrix of the mitochondria was documented (2,3). Experimental work of the last 20 years has enhanced our knowledge of the role of carnitine palmitoyltransferase I, carnitine acylcarnitine translocase, and carnitine palmitoyltransferase II, as diagrammed in Fig. 2. The role of carnitine and the three
proteins needed for transport of long-chain fatty acids into the mitochondrial matrix has been reviewed (4) and will not be repeated at this time. The discovery that
malonyl CoA is an inhibitor of carnitine palmitoyltransferase I has added to our
understanding of the coordinated metabolic regulation of fatty acid oxidation and
fatty acid synthesis. Many questions remain concerning the regulation of the carnitine transport process during the normal physiological cycles of feasting and fasting as well as during a variety of disease states. Since the first description of human carnitine deficiency in 1973 (5), many camitine deficient patients have been
described with a wide variety of symptoms. In addition to patients with what appears to be a genetic carnitine deficiency, there are a large number of patients who
have a carnitine deficiency that is secondary to their primary disease. Our understanding of the carnitine transport system for long-chain fatty acids allows us to
explain some of the symptoms that appear to be the result of impaired fatty acid
oxidation. However, many of the symptoms are unexpected, and we have diffi57
52
CARN1T1NE IN LIPID METABOLISM
PRODUCTION
OF
METABOLIC
ENERGY
Substrates
Oxidized in
Peroxisomes
FIG. 1. Role of camitine in the production of metabolic energy from a variety of substrates.
culty rationalizing how camitine deficiency results in the observed physiological
abnormalities. These unexpected symptoms have raised questions that have resulted in an expanded view of the role of camitine in energy metabolism.
ROLE OF CARNITINE IN OXIDATION OF
MEDIUM-CHAIN FATTY ACIDS
It is usually assumed that medium chain fatty acids are oxidized via a camitine
independent pathway. In fact, dietary medium chain triglycerides have been suggested as a nutritional intervention modality to bypass the camitine transport mechanism in patients at risk for impaired camitine status. However, more than a decade ago Groot and Hulsmann (6) demonstrated that the oxidation of octanoate by
rat skeletal muscle mitochondria required camitine. Data from several investigators
(4) indicate that the requirement for camitine results from the activation of octanoate to the coenzyme A level outside the inner mitochondrial membrane barrier
CYTOSOL
Palmltate
Long Chain • ATP
Acyl CoA •Coenzyme A
Synthataae
PalmitoyI CoA
E
s
' " r m c ' t l o n » Tn.cyi8iyc.ro..
PalmitoyI CoA + Camitine
Carnitina PalmitoyI
Transfer.™ A
Camitine Acylcarnitine Translocase
INNER
MITOCHONDRIA
MEMBRANE
Camitine Palm
T .niurM. V a l
tbyl
MITOCHONDRIA!.
MATRIX
PalmitoyI CoA ——
-oxidation
B-o
FIG. 2.
Acetyl CoA
Role of camitine in the (3-oxidation of long-chain fatty acids in the mitochondria.
54
CARNITINE IN UP1D METABOLISM
as diagrammed in Fig. 3. In skeletal muscle, the activation of both long-chain fatty
acids and medium-chain fatty acids appear to be catalyzed by the same enzyme at
a site exterior to the inner mitochondrial membrane. Thus, utilization of either palmitate or octanoate as an energy source by skeletal muscle requires camitine for
transport of the acyl coenzyme a moiety into the mitochondrial matrix.
A vast quantity of data support the camitine independent oxidation of octanoate
by hepatic tissues. However, a recent report by Otto (7) suggests that when the
ATP/ADP ratio is decreased, octanoate oxidation by either hepatocytes or mitochondria isolated from hepatic tissue is shifted from an almost total reliance upon a
camitine independent pathway to an increased reliance upon a camitine dependent
pathway. The data indicate that this increased reliance of octanoate oxidation upon
a camitine dependent pathway reflects an increased reliance upon extramitochondrial activation of octanoate. Although the exact mechanism for the inhibition of
intramitochondrial fatty acid activation by a depressed extra- or intramitochondrial
ATP/ADP ratio is unknown, the author has proposed two hypotheses (7). First,
some metabolite or other unknown factor, the level of which is determined by the
ATP/ADP ratio, might directly inhibit the matrix medium-chain fatty acyl CoA
synthetase. Second, the inhibition of this enzyme may result from a decreased
availability of the intramitochondrial ATP required for fatty acid activation, as a
consequence of the reduced intramitochondrial ATP/ADP ratio and/or the rapid
transport of extramitochondrial ADP in exchange for intramitochondrial ATP.
Many questions remain to be answered concerning the role of camitine in the
oxidation of medium-chain fatty acids. However, available data demonstrate that
in the clinical setting we can no longer assume that nutritional support of patients
with medium-chain triglycerides will be successful, regardless of the camitine status of the patient. Similarly, in the biochemical laboratory we can no longer routinely use octanoate in comparison with long-chain fatty acids to distinguish between metabolic effects occurring before or after the camitine dependent steps of
fatty acid oxidation.
ROLE OF CARNITINE IN PEROXISOMES
P-Oxidation of long-chain fatty acids occurs in peroxisomes as well as in mitochondria. The peroxisomal 3-oxidation system oxidizes saturated and unsaturated
acyl CoAs with chain lengths from 7 to 22 or more carbons. The (3-oxidation system of peroxisomes differs from the 3-oxidation system of mitochondria in several
ways. The enzymes that catalyze the reactions of the 3-oxidation process in mitochondria differ from the enzymes that catalyze the reaction of 3-oxidation in peroxisomes. The intermediates of the 3-oxidation process in the two locations also
differ (8). Camitine functions in the mitochondrial 3-oxidation process by transporting into the mitochondria long-chain acyl CoA moieties formed in the cytoplasm. In contrast to mitochondria, peroxisomes have a significant capability to
activate long-chain fatty acids to the coenzyme A level. As a result, the free long-
CYTOSOL
Octanoate
OctanoyI CoA
OUTER
MITOCHONDRIALj
MEMBRANE
OctanoyI CoA + Carnitine
Carnitinye
+
Coenzyme A
ine Acylcarnitine Translocase
INNER
MITOCHONDRIA!.
MEMBRANE
MITOCHONORIAL
MATRIX
OctanoyI CoA
FIG. 3.
Role of carnitine in the p-oxidation of medium-chain fatty acids in the mitochondria.
CARNITINE IN UP1D METABOLISM
56
chain fatty acids enter the peroxisomes and are activated within the peroxisomal
interior. Peroxisomes contain carnitine octanoyltransferase of a high specific activity and with peak specific activities for 5 to 8 carbon acyl CoA derivatives with
gradually decreased activity for longer chain acyl CoA derivatives (9). Evidence
is mounting to support involvement of carnitine in shuttling acetyl residues and
medium chain acyl residues out of the peroxisome. Thus, a long-chain fatty acid
enters the peroxisome in a carnitine independent manner and is shortened to several acetyl CoA moieties and a medium-chain CoA moiety that are transported out
of the peroxisome in a carnitine-dependent manner (Fig. 4).
ROLE OF CARNITINE IN KETONE BODY METABOLISM
Ketone bodies are a critically important source of metabolic energy during extended periods of little or no carbohydrate intake. However, uncontrolled ketogenesis leads to ketoacidosis and death. Thus, the inability to initiate ketogenesis or
to discontinue ketogenesis results in severe pathophysiological consequences.
Hepatic ketogenesis is known to be stimulated by increased hepatic carnitine
concentration and decreased malonyl CoA concentration (10,11). The physiological control mechanism increasing the hepatic carnitine concentration remains unidentified. Whether or not the increased carnitine has any effect in addition to that
of increasing the concentration of a substrate for carnitine palmitoyltransferase I
CYTOSOL
PEROXISOMAL
MEMBRANE
INTERIOR OF
PEROXISOME
Long
Cham
Fatty
Acid
Coenzyme A
Long
Chain
Acyl
CoA
Carnitine Acetyl
Transferase
•Carnitine
Acetyl .
Carnitine
.Acetyl
CoA
.Acetyl
CoA
i
,.
..
Carnitine Medium
Medium
Chain
Acyl
Carnitine
Chain Acyl
^
Transferase
+Carnitine
-m
Medium
. Chain M
Acyl
CoA
FIG. 4. Role of carnitine in the oxidation of fatty acids in peroxisomes.
CARNITINE IN L1PID METABOLISM
57
also remains uncertain. Elucidation of the role of carnitine in the production of
ketone bodies, utilization of ketone bodies, and the interrelationship of ketogenesis
and gluconeogenesis are exciting areas for further research.
ROLE OF CARNITINE IN THE PRODUCTION OF
ENERGY FROM AMINO ACIDS
Although amino acids are not generally considered a major energy source, they
may become a significant energy source during periods of catabolism. The
branched-chain amino acids have been proposed as a good energy source for peripheral tissues during a variety of metabolic stresses. The nitrogen moiety can be
transaminated to keto acids such as pyruvate to form alanine. The alanine is transported to the liver where the amino group is metabolized to urea for excretion, and
the carbon chain is metabolized to glucose for use as an energy source in a variety
of tissues. The keto acids of the branched-chain amino acid can then be utilized
for metabolic energy by a process that is stimulated by carnitine (12,13). The
mechanism of stimulation remains to be completely elucidated but appears to involve the conversion of a CoA metabolite to a carnitine linked metabolite that is
transported out of the mitochondria and leaves behind free coenzyme A (14,15) to
be utilized in the continued metabolism of the branched-chain keto acids for metabolic energy. It is easy to speculate that during a carnitine deficiency the catabolism of branched-chain keto acids may be slowed, which may in turn affect the
transamination step and possibly impact upon the glucose alanine cycle. Such
speculations begin to implicate carnitine having a role in the production of metabolic energy involving pathways usually associated with carbohydrate and protein
metabolism.
ROLE OF CARNITINE IN THE PRODUCTION OF
ENERGY FROM PYRUVATE
Pyruvate is an excellent source of metabolic energy and can itself be derived
from either carbohydrate sources or amino acids. The utilization of pyruvate for
energy is modulated by the activity of the pyruvate dehydrogenase complex. The
regulation of the pyruvate multienzyme complex has been investigated in complex
metabolic preparations under a variety of different metabolic states. The regulatory
process appears to vary with different types of tissues and under different physiological conditions. The ratio of free coenzyme A to coenzyme A bound to fatty
acids, branched-chain keto acids, or short-chain organic acids exerts regulatory
control on the activity of pyruvate dehydrogenase (16-18). Since carnitine in turn
influences the ratio of free coenzyme A to bound coenzyme A, carnitine has a role
in the production of metabolic energy from pyruvate. Once again carnitine's role
in energy metabolism involves carbohydrate and protein sources for metabolic energy in addition to its better known role in the production of metabolic energy
from lipid sources.
58
CARNITINE IN UPID METABOLISM
CONCLUSIONS
A more detailed understanding of the critical role of carnitine in regulating the
production of metabolic energy from lipid sources is emerging. Carnitine also has
a regulatory role in the production of metabolic energy from protein and carbohydrate sources. The role of carnitine in the integrated regulation of the production
of metabolic energy from all fuel sources is probably of greater physiological consequence than has been realized in the past.
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