Regional acetate kinetics and oxidation in human
volunteers
B.
Mittendorfer1,
L. S.
Sidossis1,3,
E.
Walser2,
D. L.
Chinkes1, and
R. R.
Wolfe1,3
Departments of 1 Surgery and
2 Radiology, University of Texas
Medical Branch, and
3 Metabolism Unit, Shriners Burns
Institute, Galveston, Texas 77550
 |
ABSTRACT |
We have used a 3-h primed continuous infusion of
[1,2-13C]acetate in
five fasted (24 h) volunteers to quantify splanchnic and leg acetate
metabolism (protocol 1). Fractional
extraction of acetate by both tissues was high (~70%), and
simultaneous uptake and release of acetate were observed. Labeled
carbon recovery in CO2 was 37.9 ± 2.3% at the whole body level, 37.7 ± 1.5% across the
splanchnic bed, and 37.3 ± 2.9% across the leg. Furthermore, we
calculated whole body labeled carbon recovery during 15 h of [1,2-13C]acetate
infusion in three volunteers (protocol
2). Whole body acetate carbon recovery in
CO2 was significantly higher (66.7 ± 4.5%) after 15 h of tracer infusion than after 3 h. We conclude that acetate is rapidly taken up by the leg and splanchnic tissues and
that the percent recovery of CO2
from the oxidation of acetate is heavily dependent on the length of
acetate tracer infusion. In the postabsorptive state, labeled carbon
recovery from acetate across the leg and the splanchnic
region is similar to the whole body
CO2 recovery.
fatty acids; liver; muscle; acetate correction factor
 |
INTRODUCTION |
DETERMINATION of the rate of recovery of labeled
CO2 from labeled acetate allows
the calculation of a correction factor for use in the estimation of
plasma fatty acid oxidation (13). The present studies were performed to
determine whole body and regional (splanchnic and leg) acetate kinetics
and oxidation in normal human volunteers after 3 h of infusion of
labeled acetate (protocol 1) to
obtain "acetate correction factors" across the splanchnic region
and the leg and to compare those values with the whole body values.
Metabolic pathways differ among various tissues, so it is possible that
the carbon label recoveries differ as well. For example, a rapid rate
of gluconeogenesis might cause exchange of acetate label via the
oxaloacetate pool in the liver but not in muscle. Regional differences
in recovery could be obscured at the whole body level. It is therefore
of importance to determine the recoveries of
13CO2
from the oxidation of labeled acetate at the regional level, not only
for the determination of acetate oxidation by different tissues, but
also to verify the validity of the acetate correction factor for the calculation of whole body free fatty acid
oxidation using carbon-labeled free fatty acids. Because the length of
tracer infusion influences carbon label recovery (17), we also
determined acetate carbon recovery in
CO2 in the whole body after 15 h
of labeled acetate infusion (protocol
2).
The major sites of acetate uptake and release in humans are still not
known, and the role of acetate in intermediary metabolism is unclear.
Acetate is formed endogenously from acetyl-CoA by two enzymes,
acetyl-CoA synthetase and acetyl-CoA hydrolase. Both are present in the
cytosol and the mitochondrial fraction of different tissues in mammals
(6). In rat and sheep, for example, acetate is produced by liver and
heart slices from pyruvate or fatty acid precursors. Liver
mitochondrial fractions do not form acetate from either substrate but
instead convert acetate into acetoacetate (6). Heart mitochondrial
fractions, on the other hand, form acetate from pyruvate or fatty acid
precursors (6).
It has long been believed that the liver is the primary site of acetate
metabolism in humans. However, acetate is utilized by peripheral
tissues in humans, as evidenced by the fall in acetate concentration
between arterial and venous blood in the forearm in fasting subjects
(4, 8, 9). Furthermore, it has recently been proposed that there is
considerable oxidation of
[2-14C]acetate
to
14CO2
in muscle (12).
Whole body oxidation of acetate has been suggested to account for up to
10% of energy expenditure (16), and it has been proposed that acetate
serves to redistribute oxidizable substrate throughout the body (11),
especially under conditions of caloric deprivation (1). To clarify some
of these aspects, we quantified whole body and regional acetate
kinetics after 3 h of labeled acetate infusion
(protocol 1).
 |
METHODS |
Experimental Design
Eight healthy volunteers (7 male, 1 female, age 29 ± 2 yr, weight
76 ± 5 kg) were recruited to participate in the studies, which were
approved by the Institutional Review Board and the General Clinical
Research Center of the University of Texas Medical Branch in Galveston.
After informed consent had been obtained, all subjects were given a
comprehensive physical examination and were considered in good health
at the time of the study. Two experimental protocols were performed.
Each volunteer participated in one of the protocols. In
protocol 1, regional and whole body
acetate kinetics were quantified during a 3-h infusion of
[1,2-13C]acetate at
the end of 24 h of fasting. In protocol
2, whole body recovery of acetate carbon in
CO2 was determined at the end of a
15-h infusion of
[1,2-13C]acetate.
Protocol 1 (n = 5).
The subjects were given a standardized meal in the evening of
day 1 and were then fasted (24 h)
until the end of the tracer infusion the following day
(day 2). The next morning
(day 2), a catheter for tracer
infusion was placed in a peripheral vein and sampling catheters were
placed in a femoral artery and a femoral vein as described in
Procedures. After baseline blood
samples were collected (6:00 PM, day
2), a primed (45 µmol/kg) continuous (1.5 µmol · kg
1 · min
1)
infusion of
[1,2-13C]acetate
(Cambridge Isotope Laboratories, Andover, MA) was started and
maintained for 3 h with a calibrated Harvard syringe pump (Harvard
Apparatus, Natick, MA). At the beginning of the study, a 150-µmol/kg
NaH13CO3
bolus was given to prime the bicarbonate pool. The exact tracer infusion rates were determined by measurement of concentration of the
infusion mixture.
Breath samples were taken every 30 min for the initial 150 min of
tracer infusion and every 10 min for the remaining 30 min. During the
last 20 min of isotope infusion, blood samples (2 ml each) from the
artery and the femoral and hepatic veins were taken simultaneously with
the breath samples at 10-min intervals. Whole body oxygen consumption
(
O2) and carbon dioxide
production (
CO2) were
measured at 140-160 min of tracer infusion by means of indirect calorimetry. Four blood samples for the determination of blood flow
(see Procedures) were obtained at
105, 110, 115, and 120 min after the start of tracer infusion.
Protocol 2 (n = 3).
Before the start of the tracer infusion, each subject was given a
standardized meal on day 1 and was
then fasted (15 h) until the end of the tracer infusion the next day
(day 2). After dinner (9:00 PM) a
catheter for tracer infusion was placed in a forearm vein. After
baseline blood and breath samples were collected, a primed (15 µmol/kg) continuous infusion (0.5 µmol · kg
1 · min
1)
of [1,2-13C]acetate
(Cambridge Isotope Laboratories) was started and maintained for 15 h by
use of a calibrated Harvard syringe pump (Harvard Apparatus). The exact
tracer infusion rates were determined by measurement of concentration
of the infusion mixture.
Breath samples were taken every hour for 14 h and every 10 min during
the last hour of tracer infusion.
O2 and
CO2 were measured during a
20-min period 2 h before the end of tracer infusion.
Procedures
Catheter placement.
On the morning of the study, volunteers were brought to a vascular
radiology suite at the University of Texas Medical Branch, where the
right groin was prepared and draped in a sterile fashion. A lead glove
was placed over the genitalia before the procedure. After patient
preparation, the right common femoral vein was punctured, and a 6-Fr
sheath was placed. Through this sheath, a straight 5-Fr catheter with
several side holes near its tip was manipulated into the right or
middle hepatic vein. This catheterization was performed by using a
deflecting-tip 0.035" guidewire within the straight catheter. After the
catheter was positioned into the hepatic vein, a digital venogram was
performed to verify placement, and both the sheath and catheter were
infused with heparinized saline to maintain patency. The position of
the catheter was confirmed again by a plain view abdominal X ray
immediately after the end of the study. A short, straight 4-Fr catheter
was then placed retrograde into the right common femoral artery, and it
too was connected to a pressurized flush setup. After both catheters
and the sheath had been sutured in place, a sterile transparent
dressing was used to cover the vascular entry sites.
Blood flow.
Blood flow was determined 60 min before the end of the study using a
constant infusion of indocyanine green dissolved in 0.9% saline. The
dye was infused through the femoral artery catheter at the rate of 0.5 mg/min for 55 min during the 2nd hour of protocol 1, and blood samples were taken at 40, 45, 50, and 55 min after the start of dye infusion simultaneously from the hepatic
vein, the femoral vein, and a peripheral vein. The concentrations of the dye in the infusate and in serum samples were determined using a
spectrophotometer set at 805 nm. Leg plasma flow was determined by
dividing the infusion rate of the dye by the concentration difference
of the dye in femoral venous and peripheral venous serum. The
peripheral venous concentration of the dye was subtracted from the
concentration in the femoral vein to account for recycling of the dye
into the artery. Splanchnic plasma flow was determined by dividing the
infusion rate of the dye by the concentration difference in arterious
and hepatic venous serum. Leg and splanchnic blood flows were then
calculated by dividing the plasma flow by 1 minus the hematocrit. With
this method, we have found that the SE of the mean is generally within
±3% of the mean values.
Analysis of samples.
Analytic procedures for breath samples have been previously described
(14). Briefly, breath samples were collected by inflation of an
anesthesia bag and then transferred to Vacutainers.
13CO2
enrichment was then determined by isotope ratio mass spectrometry (IRMS; SIRA Series II, VG Isogas, Middlewich, Cheshire, UK, with an HP
3392A integrator). A Sensor Medics 2900 Metabolic Cart (Thermodex Instruments, Pittsburgh, PA) was used to determine expired
CO2. All blood samples for
CO2 analysis were collected into
prechilled tubes containing heparin sodium. Blood
CO2 concentration was measured immediately using a 965 Ciba Corning
CO2 analyzer, and the remaining blood samples were kept frozen until further analysis. Blood samples for acetate analysis were collected in iced heparinized tubes and
centrifuged immediately at 4°C. Plasma was separated and stored at
70°C. For the determination of blood
CO2 enrichment, 5-10 µl
phosphoric acid, 85%, were added to 1 ml blood in a sealed tube to
release the CO2 into the headspace
of the tube. The headspace represents free
CO2 and
CO2 bound to bicarbonate. The
13C-to-12C
ratio of the CO2 in the headspace
was then determined by IRMS. Plasma acetate concentration and
enrichment were determined by gas chromatography-mass spectrometry
(GC-MS; Hewlett Packard, Palo Alto, CA) using a recently described
method (10). Briefly, a known amount of
[1,2-13C-2,2,2-2H3]acetate
was added to 200 µl plasma. After direct derivatization with
difluoroaniline, the samples were extracted with ethyl acetate, dried
over N2, and redissolved in 70 µl ethyl acetate. One microliter was injected into the GC-MS, and
isotopic enrichment was determined using electron impact ionization.
Ions at mass-to-charge ratio (m/z)
171, 173, and 176, representing the molecular ions of unlabeled and
enriched acetyl derivatives, respectively, were selectively monitored,
and their corresponding peaks were integrated. The ion at
m/z 173 results from the tracer
infusion, and m/z 176 represents the
internal standard that we used for the calculation of plasma acetate
concentration.
Calculations
In protocol 1,
CO2, plasma acetate, and
blood CO2 concentrations and
enrichments at 160, 170, and 180 min after the beginning of the labeled
acetate infusion were averaged for each sampling site for use in
subsequent calculations. In protocol
2, the values for breath
CO2 enrichment and
CO2 obtained at 14:40,
14:50, and 15:00 h after the start of the tracer infusion were averaged for the calculation of acetate kinetics. The following equations were
used for rate of appearance of acetate, whole body acetate carbon
recovery, organ fractional extraction, uptake and release of acetate,
percent acetate taken up by the tissues that was oxidized, and net
balance across the tissues
|
(1)
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(2)
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(3)
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(4)
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(5)
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(6)
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(7)
|
where
F is the tracer infusion rate, and
ECO2 and
CCO2 stand
for the isotopic enrichment and the concentration of
CO2, respectively. Eacet is the isotopic enrichment
of acetate in plasma, and Cacet is
the concentration of acetate. Subscript a indicates artery, subscript v
indicates vein. PF is plasma flow, and BW is body weight. Fractional
extraction is abbreviated as fe. Regional acetate carbon label recovery
(Eq. 3) is the release of
carbon-labeled CO2 (labeled
CO2 arteriovenous balance) by the
tissue divided by the uptake of acetate tracer (labeled acetate
arteriovenous balance) by that tissue. The labeled
CO2 arteriovenous balance is
divided by 2 because the oxidation of 1 mole of
[1,2-13C]acetate
produces 2 moles of
13CO2.
Statistical comparisons were made using Student's
t-test. Data are expressed as means ± SD.
 |
RESULTS |
Protocol 1

View larger version(8K)
Steady states for plasma acetate enrichment, breath
CO2 enrichment, and blood
CO2 enrichment were achieved
within 90-120 min after the start of tracer infusion and were
maintained until the end of the study period (Fig.
1). Average breath
CO2 enrichment at steady state was
0.0088 ± 0.0007 (tracer/tracee ratio), and average
CO2 was 130.1 ± 15.6 µmol · kg
1 · min
1.
Average arterial and venous plasma acetate concentrations and enrichments, as well as blood CO2
concentrations and enrichments, are presented in Table
1. Average splanchnic blood flow was 1.097 ± 0.195 l/min; average leg blood flow was 0.467 ± 0.036 l/min.
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Table 1.
Enrichment and concentration of plasma acetate and blood
CO2 after 3 h of [1,2-13C]acetate infusion
(protocol 1)
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Labeled carbon recovery as CO2
across the splanchnic region and the leg was not different from whole
body carbon label recovery (Table 2). Whole
body acetate Ra, clearance, and
fractional extraction by the tissues are presented in Table 2.
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Table 2.
Whole body and regional acetate kinetics and labeled carbon
recovery from acetate after 3 h of [1,2-13C]acetate
infusion (protocol 1)
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Isotopic data indicated there was simultaneous uptake and release of
acetate across both the splanchnic region (Table
3) and the leg (Table
4). The absolute amount of uptake of
acetate by both the leg and the splanchnic region was strongly
correlated with the delivery of acetate to the tissue (Pearson's
R > 0.9, P < 0.001) (Fig.
2). Net acetate uptake by the leg was
observed in all subjects. In contrast, net acetate release was observed in some subjects across the splanchnic bed, whereas other subjects had
net uptake. Individual and mean values are presented in Table 3 and
Table 4.

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Fig. 2.
Acetate uptake by tissues as a function of delivery (blood flow to
tissue × blood acetate concentration).
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Protocol 2

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Breath CO2 enrichment increased
with time (Fig. 3). Percent acetate carbon
recovery was significantly higher (P < 0.05) at 15 h (66.7 ± 4.5%) after the start of tracer infusion
than at 3 h.
 |
DISCUSSION |
Interpretation of acetate kinetics, as with lactate kinetics (3), is
complicated by the likelihood that isotopic exchange occurs within
intracellular pools. However, the fact that the isotopic exchange
reactions involving acetate should be the same as for acetyl-CoA makes
acetate a useful substrate for kinetic studies of substrate oxidation
by use of tracers. In fact, labeled CO2 recovery from labeled acetate
infusion can be used as a correction factor for the estimation of
plasma fatty acid oxidation (13). Briefly, the acetate correction
factor accounts for label fixation that might occur at any step between
the entrance of labeled acetyl-CoA into the tricarboxylic acid (TCA)
cycle until the recovery of label in breath
CO2. This unique characteristic
makes the acetate correction factor preferable to the bicarbonate
correction factor for correcting isotopic estimates of plasma fatty
acid oxidation (13).
At the end of 3 h of labeled acetate infusion
(protocol 1), we calculated whole
body recovery of acetate carbon in
CO2 to be ~40%. This value
differs from earlier reports in which acetate recoveries of 90% (16),
70% (9), and 50% (13) have been obtained using
[1-14C]- or
[1-13C]acetate in the
postabsorptive state. The lower recovery of labeled carbon atoms from
acetate in our study can be explained by the use of doubly labeled
[1,2-13C]acetate as
opposed to singly labeled acetate, and also by the relatively short
infusion time. As previously reported, the recovery of label from the
two position of acetate is less than recovery from the one position
(17). This is because the two position has a much greater opportunity
to participate in exchange reactions in the TCA cycle before it is
excreted as CO2. Thus doubly
labeled acetate will result in lower recoveries over the same period of time than acetate labeled only in the one position. Furthermore, recovery increases with length of infusion (17). This finding is
evidenced by the data from our 15-h infusion study
(protocol 2) and follows from the
expectation that labeled carbon atoms that participate in exchange
reactions will eventually recycle and go to
CO2. Therefore, the value of label
recovery calculated in protocol 1 represents an underestimate of the final labeled carbon recovery,
because a true steady state was not achieved within 3 h of tracer
infusion. Rather, a "pseudo"-plateau was achieved at a value
somewhat less than the ultimate true plateau. However, the same is true
for labeled carbons from fatty acid tracers as well. Thus the
appropriate acetate correction factor for use in isotopic estimates of
plasma fatty acid oxidation is obtained when labeled acetate is infused
over the same period of time as are the labeled fatty acids.
Acetate carbon recoveries across the leg and the splanchnic region were
not different from whole body acetate recoveries. Therefore, whole body
acetate recovery can be used to correct substrate oxidation estimates
across the leg and splanchnic region in the postabsorptive state.
However, regional differences could be obscured at the whole body level
under other conditions. In lipogenic states, for example, some acetate
may be incorporated into newly synthesized fatty acids (5). Thus a
significant amount of labeled acetate may be lost before the possible
exchange with the bicarbonate and/or glutamate/glutamine pool.
During lipogenesis, the application of the acetate correction factor
may therefore overestimate substrate oxidation (13), because the
incorporation of acetate into fatty acids occurs before the TCA cycle.
The extent of overestimation depends on the rate of de novo fatty acid
synthesis.
Ketogenesis should not interfere with the acetate correction factor,
because ketone bodies are oxidized in all tissues (e.g., liver, leg)
rather than "stored." The only significant storage pool for
ketone bodies is the plasma. Therefore, as long as the plasma
concentration of ketones is not changing during the time course of the
experiment, we can be confident that our assumption regarding ketone
oxidation is reasonable.
The plasma acetate concentrations in our study (Table 1) compare well
with other studies in human subjects (4, 7-9, 15, 16). Also, our
data indicating simultaneous uptake and release of acetate across the
splanchnic region and the leg are consistent with previous studies
carried out in perfused rat livers (10) and in dogs (1, 2). The
observation is analogous to the situation with lactate (3), and the
interpretation of this observation is difficult. Nonetheless,
simultaneous uptake and release indicate rapid intracellular exchange
of acetate with the intracellular acetyl-CoA pool.
In response to the tracer infusion, we observed an increase in plasma
acetate concentration that corresponded to the infusion rate (i.e., the
contribution of infused tracer to the observed concentration). Hence,
the endogenous Ra was likely not
affected by the rapid infusion rate used in protocol
1.
The absolute amount of acetate uptake by both the leg and the
splanchnic region was strongly correlated with the delivery of acetate
to the tissue (Fig. 2). This is similar to earlier studies in the sheep
(6) and in humans (16) in which uptake was observed when arterial
acetate concentrations were high and release was observed when arterial
concentrations of acetate were low. Acetate uptake presumably occurs by
simple diffusion, and thus exchange of acetate between the plasma and
the tissue depends only on the concentration gradient.
Net uptake of acetate across the leg occurred in all our studies. The
same has been proposed previously across the forearm in human
volunteers in the postabsorptive state (4, 8). However, in another
study in human volunteers (16), net release as well as uptake of
acetate from the leg was reported. Across the splanchnic region, which
represents the gut and the liver, we found net uptake in some subjects
and net release in other subjects. Data from dogs (1) showed that the
liver was the main site of acetate uptake, whereas the intestine was
the major source of acetate release in the postabsorptive state.
We are unable to account for the whole body
Ra of acetate by the net rate of
release from the leg and the splanchnic region. However, any acetate
that is released by the gut into the portal vein and is subsequently
taken up by the liver was not accounted for by our whole body
Ra value. Such unlabeled acetate
does not appear in the systemic circulation. Consequently, it will not "dilute" the acetate tracer in the systemic circulation. The
kidneys and adipose tissue are an unlikely source of
Ra acetate, because net acetate
uptake by the kidneys has been reported in dogs (1) and by the adipose
tissue in humans (4). Therefore, the best candidate for systemic
acetate appears to be the gut.
In summary, acetate is rapidly metabolized in human subjects by the
liver as well as by peripheral tissues (leg). This notion is supported
by the high fractional extraction of acetate from the plasma. Oxidation
of labeled acetate results in similar labeled carbon recoveries across
the leg, the splanchnic region, and the whole body during fasting.
Therefore, we conclude that whole body acetate recoveries can be used
to correct substrate oxidation by these two tissues, as suggested
previously for the whole body (13).
 |
ACKNOWLEDGEMENTS |
The authors appreciate the help of the nursing staff of the General
Clinical Research Center (GCRC) in the performance of the experiments
and thank Dr. Y. Zheng for excellent technical assistance.
 |
FOOTNOTES |
This work was supported by National Institute of Diabetes and Digestive
and Kidney Diseases Grants DK-34817-12 (R. R. Wolfe) and DK-51969 (L. S. Sidossis), Shriners Hospital Grant 8490 (R. R. Wolfe), and GCRC
Grant 00073.
Address for reprint requests: R. R. Wolfe, Metabolism Dept., Shriners
Burns Institute, 815 Market St., Galveston, TX 77550.
Received 14 August 1997; accepted in final form 16 February 1998.
 |
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