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1 McDonald Research Laboratories/iCAPTURE Centre, Department of Pathology and Laboratory Medicine, University of British Columbia and St. Paul's Hospital/Providence Health Care, Vancouver, British Columbia V6Z 1Y6; and 2 Cardiovascular Research Group, University of Alberta, Edmonton, Alberta T6G 2S2, Canada
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We tested the hypothesis that myocardial substrate supply regulates fatty acid oxidation independent of changes in acetyl-CoA carboxylase (ACC) and 5'-AMP-activated protein kinase (AMPK) activities. Fatty acid oxidation was measured in isolated working rat hearts exposed to different concentrations of exogenous long-chain (0.4 or 1.2 mM palmitate) or medium-chain (0.6 or 2.4 mM octanoate) fatty acids. Fatty acid oxidation was increased with increasing exogenous substrate concentration in both palmitate and octanoate groups. Malonyl-CoA content only rose as acetyl-CoA supply from octanoate oxidation increased. The increases in octanoate oxidation and malonyl-CoA content were independent of changes in ACC and AMPK activity, except that ACC activity increased with very high acetyl-CoA supply levels. Our data suggest that myocardial substrate supply is the primary mechanism responsible for alterations in fatty acid oxidation rates under nonstressful conditions and when substrates are present at physiological concentrations. More extreme variations in substrate supply lead to changes in fatty acid oxidation by the additional involvement of intracellular regulatory pathways.
heart; acetyl-CoA carboxylase; malonyl; 5'-AMP-activated protein kinase
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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LONG-CHAIN FATTY ACIDS are the major fuel of the heart in that fatty acid oxidation normally provides 60-70% of the energy requirements of the normoxic heart (4, 30, 36). The concentration of fatty acids in the blood or perfusate is a major determinant of the extent of myocardial fatty acid oxidation. For example, a rise in circulating levels of fatty acids such as occurs during reperfusion after ischemia leads to an increase in fatty acid oxidation. Under these circumstances, fatty acid oxidation accounts for almost all of the ATP production in the heart (20, 22).
Myocardial fatty acid oxidation is also regulated by complex intracellular mechanisms (21). Malonyl-CoA is an important intracellular regulator of fatty acid oxidation in the heart (2, 35), because it potently inhibits carnitine palmitoyltransferase 1 (CPT 1), a key enzyme involved in transporting long-chain fatty acids into the mitochondrial matrix (28). Reduced malonyl-CoA levels are associated with increases in fatty acid uptake in the heart in vivo (10) as well as with elevated rates of palmitate oxidation in isolated cardiac myocytes (2) and isolated hearts (18). Malonyl-CoA is synthesized by acetyl-CoA carboxylase (ACC), which catalyzes the carboxylation of acetyl-CoA to form malonyl-CoA (11, 15, 35, 39).
In the heart, two isoforms of ACC are present: a 265-kDa isoform and the predominating 280-kDa isoform (3, 35, 37). Phosphorylation of both ACC isoforms is an important determinant of ACC activity (5, 8) and concomitant intracellular malonyl-CoA levels. 5'-AMP-activated protein kinase (AMPK) and protein kinase A phosphorylate both isoforms of rat heart ACC and thereby cause significant inactivation of ACC (7, 8).
Myocardial ischemia increases the AMPK activity that is
associated with decreased ACC activity, decreased levels of
malonyl-CoA, and increased rates of fatty acid oxidation during
reperfusion (18). In addition, exposure of newborn rabbit
hearts to
5-aminoimidazole-4-carboxamide-1-
-D-ribofuranoside (AICAR), a cell-permeable activator of AMPK, decreases ACC activity and
increases the rate of long-chain fatty acid oxidation
(27). These findings are consistent with the concept that
activation of AMPK stimulates myocardial long-chain fatty acid
oxidation rates via the phosphorylation and inactivation of ACC
(19). In contrast, oxidation of fatty acids of shorter
chain length such as octanoate (which has eight carbons) does not
require CPT 1 for entry into the mitochondria (29). As
such, malonyl-CoA levels should not influence oxidation of these fatty acids.
The supply of acetyl-CoA to ACC is another important mechanism by which malonyl-CoA synthesis can be increased or decreased to address the metabolic demands of the heart (35). Increases in the intramitochondrial acetyl-CoA/CoA ratio caused either by decreases in metabolic demand or increases in acetyl-CoA (from increased glucose or fatty acid catabolism) will increase the flux of acetyl groups from the mitochondria into the cytosol. Intramitochondrial acetyl-CoA is transferred to the cytosol via a carnitine acetyltransferase-carnitine acetyl translocase (CAT) system that leads to formation of acetylcarnitine and acetyl-CoA in the cytosol (25, 26). This increase in cytosolic acetyl-CoA stimulates ACC-mediated synthesis of malonyl-CoA, which results in decreased fatty acid oxidation (35). Therefore malonyl-CoA links the changes in acetyl-CoA supply that arise from lowered metabolic demand or from increasing utilization of carbohydrate or lipid sources to the flux rate of long-chain acylcarnitine into the mitochondria.
We undertook the present study to test the hypothesis that alterations in acetyl-CoA supply lead to changes in malonyl-CoA levels and corresponding changes in fatty acid oxidation rates. Isolated working rat hearts were exposed to different concentrations of exogenous long-chain or medium-chain fatty acids to alter acetyl-CoA supply and to determine the effects on malonyl-CoA levels, the activities of AMPK and ACC, and fatty acid oxidation.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Materials.
Bovine serum albumin (fraction V) was obtained from Boehringer Mannheim
and human insulin was from Eli Lilly. All radiochemicals were obtained
from NEN-DuPont, with the exception of [
-32P]ATP,
which was obtained from ICN. Dowex 1-X4 (200-400 mesh) anion exchange
resin was obtained from Bio-Rad. All other chemicals were
obtained from Sigma or BDH and were of analytic grade.
Isolated working-heart preparation and perfusion protocol. Fed male Sprague-Dawley rats (weight 350-450 g) were anesthetized with 2-3% halothane. Hearts were excised and placed in ice-cold Krebs-Henseleit (KH) solution. The aortae were quickly cannulated, and the hearts were initially perfused via the aortae with oxygenated KH solution (pH 7.4) containing 5.5 mM glucose and 2.5 mM calcium at a constant pressure of 60 mmHg. During this initial 10-min aortic perfusion, hearts were trimmed of excess tissue and the left atria were cannulated.
The hearts were then switched to working mode and perfused with KH solution at a left atrial preload of 11.5 mmHg and an aortic afterload of 80 mmHg for 40 min as previously described (1, 12, 23, 24). Hearts were perfused with KH solution containing either low (0.4 mM) or high (1.2 mM) [1-14C]palmitate or low (0.6 mM) or high (2.4 mM) [1-14C]octanoate as the source of long-chain or medium-chain fatty acids, respectively. The KH solution also contained (in mM) 5.5 [5-3H]glucose, 0.5 lactate, and 2.5 calcium and 100 µU/ml insulin. The [1-14C]palmitate was prebound to 3% albumin as described previously (23), and the octanoate was added to the albumin mixture and dialyzed in a similar manner. In each fatty acid group, a series of hearts was also perfused in the presence of 0.4 mM AICAR to determine the effect of AMPK activation on fatty acid oxidation under the conditions studied. All solutions were oxygenated with 95% O2-5% CO2 and maintained at 37°C. Heart rate and peak systolic pressure were recorded with a DIREC physiological recording system (Fine Science Tools) using a pressure transducer (Viggo-Spectramed) in the aortic afterload line. Hearts with spontaneous rates of <230 beats/min were electrically stimulated to achieve rates of 250 beats/min. At the end of the perfusions, hearts were clamped with tongs that had been cooled to the temperature of liquid nitrogen. Frozen ventricular tissue was weighed, powdered (using a mortar and pestle that had been cooled to the temperature of liquid nitrogen), and stored in cryovials at
70°C until use.
Measurement of fatty acid oxidation and glycolysis.
Fatty acid oxidation was determined by quantitatively measuring the
rate of 14CO2 production from
14C-labeled fatty acids as described previously
(36). During the working-heart perfusion, hearts were
perfused in a closed system that allowed quantitative collection of
both gaseous and perfusate 14CO2 that
originated from either exogenous octanoate or palmitate. The
14CO2 liberated in the gaseous state was
trapped in 1 M hyamine hydroxide in the gas-outlet line. Samples of
this solution were injected directly into scintillation liquid for
counting. Perfusate samples were immediately injected below a 2-ml
volume of mineral oil to prevent liberation of perfusate
14CO2 and were stored at 20°C until
analyzed. The 14CO2 from the perfusate was
subsequently extracted by injection of 1 ml of perfusate into a sealed
test tube containing 1 ml of 9 N H2SO4 and 300 µl of hyamine hydroxide soaked onto filter paper and suspended in a
scintillation vial. The tubes were vortexed and then gently shaken for
30 min to release the 14CO2 present in the
perfusate as [14C]bicarbonate. For ease of comparison
among groups, fatty acid oxidation rates are expressed as nanomoles of
acetyl-CoA oxidized per minute per gram of dry weight. These rates were
calculated by multiplying the mean rate of fatty acid oxidation by the
number of two-carbon (acetyl-CoA) groups existent per fatty acid unit (i.e., eight for palmitate and four for octanoate).
Biochemical analysis. CoA esters were extracted from frozen ventricular tissue using 6% perchloric acid as described previously (35) and were then separated and quantified using a previously described HPLC procedure (16).
AMPK activity was assayed by following the incorporation of 32P into a synthetic peptide in the presence of 200 µM AMP (18). ACC activity was determined using the [14C]bicarbonate fixation assay as previously described (18).Data analysis. Data are expressed as means ± SE. Heart function and rates of glycolysis were compared using two-way ANOVA. Rates of fatty acid oxidation, measurements of CoA ester levels, and activities of AMPK and ACC were compared using two-way ANOVA after natural logarithmic transformation. If the tests indicated interaction between the two factors, post hoc t-tests were used to compare the four groups. The Bonferroni procedure was applied to all tests to correct for multiple tests and comparisons. A corrected value of P < 0.05 was considered significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Heart function.
Heart function is summarized in Table 1.
Function was stable over the duration of the perfusion in all groups
(data not shown). Functional parameters in octanoate-perfused hearts
were slightly lower than corresponding values in palmitate-perfused
hearts, although no significant differences were observed.
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Fatty acid oxidation.
Rates of fatty acid oxidation are shown in Fig.
1. Hearts perfused at a high palmitate
concentration ([palmitate]) exhibited significantly higher rates of
fatty acid oxidation than those perfused at a low [palmitate]. In the
same way, rates of octanoate oxidation were significantly increased in
hearts perfused with a high octanoate concentration ([octanoate])
compared with those perfused with a low [octanoate]. Fatty acid
oxidation was higher in octanoate-perfused hearts compared with
corresponding palmitate-perfused hearts.
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Glycolysis.
Rates of glycolysis are reported in Table
2. Glycolytic rates were significantly
decreased in hearts perfused at higher fatty acid concentrations (1.2 mM palmitate or 2.4 mM octanoate) compared with those perfused at lower
fatty acid concentrations (0.4 mM palmitate or 0.6 mM octanoate).
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Acetyl-CoA and malonyl-CoA measurements.
Figure 2, A and B,
shows the levels of acetyl-CoA and malonyl-CoA esters, respectively,
measured in palmitate- and octanoate-perfused hearts. Acetyl-CoA
content remained unchanged in hearts perfused with high [palmitate]
compared with those perfused with low [palmitate]. In contrast,
acetyl-CoA content was greater in hearts perfused with high
[octanoate] than in those perfused with low [octanoate]. Acetyl-CoA
levels in octanoate-perfused hearts were also significantly elevated
compared with those in palmitate-perfused hearts. Malonyl-CoA levels
did not differ between hearts perfused at low and high [palmitate].
However, malonyl-CoA levels were significantly elevated in hearts
perfused with 2.4 mM octanoate relative to those perfused with 0.6 mM
octanoate. Malonyl-CoA levels in octanoate-perfused hearts were also
significantly elevated compared with those in palmitate-perfused
hearts.
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ACC and AMPK activity.
ACC activity in the absence of citrate is summarized in Fig.
3. ACC activity was unaltered by
increases in [palmitate] from 0.4 to 1.2 mM. However, in hearts
perfused with high [octanoate] (2.4 mM), ACC activity was
significantly higher than that for hearts perfused with low
[octanoate] (0.6 mM) or with either [palmitate] (0.4 or 1.2 mM). In
all groups, the presence of 10 mM citrate dramatically stimulated ACC
activity to values that did not differ significantly among groups (data
not shown).
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AICAR and fatty acid oxidation.
In hearts perfused in the presence of 0.4 mM AICAR, rates of palmitate
oxidation were significantly increased compared with control regardless
of [palmitate] (see Table 4). The
presence of AICAR had no significant effect on rates of octanoate
oxidation.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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In this study, we demonstrate that increasing carbon substrate supply increases myocardial fatty acid oxidation. We also show for the first time that when the increased supply of acetyl-CoA from fatty acid oxidation leads to increased acetyl-CoA content, a corresponding increase in malonyl-CoA content also occurs. This increase in malonyl-CoA is independent of changes in the activities of ACC and AMPK (a finding that is in keeping with the substrate dependence of the 280-kDa isoform of ACC). At very high rates of acetyl-CoA production, we make the additional observation that a feedback loop exists that involves stimulation of ACC. This loop may function to increase malonyl-CoA and decrease fatty acid oxidation when acetyl-CoA supply from fatty acid oxidation exceeds tricarboxylic acid cycle demand. Finally, we demonstrate that medium-chain fatty acid oxidation occurs independent of activation by AMPK, which confirms that mitochondrial transport of medium-chain fatty acids occurs independent of CPT 1.
As expected, increased availability of exogenous fatty acids increased fatty acid oxidation rates (see Fig. 1), a finding that is in line with previously reported data (30, 36). Elevated exogenous fatty acid concentrations likely increase fatty acid oxidation rates through the increased uptake of fatty acids by the cell and by increased availability of acyl moieties for mitochondrial transport. Increases in fatty acid oxidation rates correspondingly increase acetyl-CoA production from fatty acids. The finding that acetyl-CoA did not rise with high [palmitate] (see Fig. 2A) indicates that the supply of acetyl-CoA adequately met the demand for acetyl-CoA, presumably because the increased acetyl-CoA supply from palmitate was accompanied by a corresponding decrease from glucose. In contrast, cellular acetyl-CoA content increased in hearts perfused with octanoate (see Fig. 2A). This finding suggests that acetyl-CoA production from medium-chain fatty acids (which have free access to the mitochondrial matrix) exceeded the demand of the tricarboxylic acid cycle for acetyl-CoA.
In general, increases in acetyl-CoA content were accompanied by increases in malonyl-CoA content (see Fig. 2, A and B) and were presumably a reflection of a negative feedback system: production of acetyl-CoA in excess of demand led to increased malonyl-CoA levels that subsequently limited long-chain fatty acid entry into mitochondria. The tendency for acetyl-CoA and malonyl-CoA levels to increase in concert has been reported previously (35). Saddik et al. (35) suggested that the 280-kDa ACC isoform (the predominant ACC isoform in the heart) is a substrate-driven enzyme, and that increases in the amount of acetyl-CoA available to the enzyme lead to the increased production of malonyl-CoA. Support for this view comes from results of hearts perfused with high [octanoate] where malonyl-CoA levels markedly increased as acetyl-CoA levels changed. Furthermore, because cardiac ACC is regulated by substrate supply (35) and the activity and substrate did not change in the palmitate perfusions, it is not surprising that malonyl-CoA content did not increase under these conditions.
In the presence of high mitochondrial acetyl-CoA levels, such as would occur when fatty acid supply exceeds demand (e.g., octanoate perfusions), acetyl groups will be exported out of the mitochondria as acetylcarnitine after transformation via CAT (21, 25, 26, 35). The acetylcarnitine is then converted back to acetyl-CoA in the cytosol. The acetyl-CoA so produced not only leads to increased ACC-mediated malonyl-CoA production as a feedback mechanism to lower fatty acid oxidation rates (21), but also could potentially lower fatty acid activation in the cytosol by limiting the free CoA available for this reaction (13, 31). It is conceivable that increased citrate arising from fatty acid oxidation may also have contributed to the increased malonyl-CoA levels in octanoate-perfused hearts. Citrate, which may act as a signal that fuel supply exceeds demand, could have contributed to higher malonyl-CoA levels by acting as a precursor of acetyl-CoA via the ATP-citrate lyase reaction and as an allosteric activator of ACC (32).
In addition to alterations in acetyl-CoA supply, it is also apparent that direct alterations in ACC activity contributed to the high malonyl-CoA levels seen in hearts perfused with high [octanoate]. ACC activity in hearts perfused with a high [octanoate] (2.4 mM) was significantly elevated compared with corresponding values in hearts perfused with a low [octanoate] (0.6 mM). This suggests that at very high rates of acetyl-CoA production, malonyl-CoA production is dependent on both acetyl-CoA supply and the activation state of ACC. That these increases are present only in hearts perfused with 2.4 mM octanoate and not in the presence of 1.2 mM palmitate indicates that the stimulation of fatty acid oxidation in hearts perfused with high [palmitate] is not of a sufficient magnitude for the initiation of negative feedback mechanisms. In the presence of 2.4 mM octanoate, acetyl-CoA production was 3-fold higher than in the presence of 0.6 mM octanoate, whereas acetyl-CoA and malonyl-CoA were 2.3- and 1.6-fold higher, respectively.
Alterations in the phosphorylation of ACC by AMPK may be one mechanism by which ACC activity is increased in hearts perfused with high [octanoate] (14). AMPK phosphorylation and inhibition of ACC is an important mechanism controlling fatty acid oxidation in the heart. ACC activity was significantly increased in hearts perfused with 2.4 mM octanoate, whereas AMPK activity was not significantly altered. Thus, under the conditions used in the present study, the increase in ACC activity cannot be attributed to measurable alterations in AMPK activity.
The presence of other carboxylases (e.g., pyruvate carboxylase and propionyl-CoA carboxylase) in the heart extracts could be a potential source of error when using the [14C]bicarbonate fixation method to measure ACC activity. However, we found that the [14C]bicarbonate fixation method and an HPLC method that specifically measures malonyl-CoA (the product of the ACC assay) yielded comparable results (35), which indicates that formation of nonmalonyl-CoA products via pyruvate carboxylase was not a significant factor. A possible contribution of propionyl-CoA carboxylase to malonyl-CoA production remains a potential source of error. However, the substantially greater sensitivity of ACC to acetyl-CoA compared with propionyl-CoA carboxylase (9, 38) and the citrate-dependent activity observed indicate that the malonyl-CoA production detected in the assay most likely reflects activity of ACC.
As expected, stimulation of AMPK with AICAR selectively stimulated the oxidation of long-chain fatty acids (palmitate), but not medium-chain fatty acids (octanoate) (see Table 4). This finding is consistent with the concept that AMPK-induced stimulation of myocardial fatty acid oxidation occurs via phosphorylation and inhibition of ACC with decreased malonyl-CoA production and increased CPT 1 activity. AICAR readily enters cardiac myocytes and is converted to 5-aminoimidazole-4-carboxamide riboside monophosphate (ZMP) by adenylate kinase (34). ZMP has been shown to mimic the effects of AMP on AMPK by direct allosteric activation and by promotion of phosphorylation of AMPK by the upstream AMPK kinase (6). In hearts, AICAR has been shown to produce measurable increases in myocardial AMPK activity (27, 33). The selective stimulation of palmitate oxidation by AICAR is entirely in keeping with the concept that long-chain fatty acids such as palmitate require CPT 1 for transport into the mitochondrial matrix to be oxidized, whereas shorter-chain fatty acids such as octanoate are transported independently of CPT 1. Importantly, the effects of increasing [palmitate] and AICAR levels in the perfusate are additive with respect to fatty acid oxidation rates; this observation indicates that both act through different mechanisms.
As expected, hearts perfused with higher fatty acid concentrations (1.2 mM palmitate or 2.4 mM octanoate) possessed lower rates of glycolysis compared with hearts perfused with lower fatty acid concentrations (0.4 mM palmitate and 0.6 mM octanoate). The reduction in glycolytic rates with higher fatty acid conditions likely resulted from the increased production of citrate, a well-known inhibitor of glycolysis (30). That rates of glycolysis did not decrease further as [octanoate] increased from 0.6 to 2.4 mM possibly reflects the fact that acetyl-CoA supply exceeded demand under these conditions and thereby led to a relative inhibition of glycolysis even at the lower [octanoate].
Taken together, our data suggest that myocardial substrate supply is the primary mechanism responsible for alterations in fatty acid oxidation rates under nonstressful conditions and when substrates are present at physiological concentrations. More extreme variations in substrate supply or conditions (e.g., increased workload or ischemia and reperfusion) lead to changes in fatty acid concentration by the additional involvement of intracellular regulatory pathways such as those involving AMPK phosphorylation and inhibition of ACC.
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ACKNOWLEDGEMENTS |
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The authors thank Yulia D'Yachkova for help with statistical analyses.
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FOOTNOTES |
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This study was supported by grants from the Canadian Institutes of Health Research and the Heart and Stroke Foundation of British Columbia and Yukon. S. L. Longnus is a Research Trainee of the Heart and Stroke Foundation of Canada. G. D. Lopschuk is an Alberta Heritage Foundation for Medical Research Medical Scientist. M. F. Allard is a Career Investigator of the Heart and Stroke Foundation of British Columbia and Yukon.
Address for reprint requests and other correspondence: M. F. Allard, McDonald Research Laboratories/iCAPTURE Centre, Rm. 292, St. Paul's Hospital, 1081 Burrard St., Vancouver, BC V6Z 1Y6, Canada (E-mail: mallard{at}mrl.ubc.ca).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 18 December 2000; accepted in final form 29 May 2001.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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significantly different from 0.4 mM palmitate value;
significantly different from 1.2 mM palmitate value.
