From the Robert Schwartz M.D. Center for Metabolism and Nutrition, MetroHealth Medical Center, Cleveland, Ohio 44109, Departments of Pediatrics and Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, and § Department of Developmental Biochemistry, Hebrew University-Hadassah School of Medicine, Jerusalem 991120, Israel
Received for publication, July 13, 2000, and in revised form, January 2, 2001
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ABSTRACT |
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Glyceroneogenesis,
i.e. the synthesis of the glycerol moiety of
triacylglycerol from pyruvate, has been suggested to be quantitatively important in both the liver and adipose tissue during fasting. However,
the actual contribution of glyceroneogenesis to triacylglycerol synthesis has not been quantified in vivo in human studies.
In the present study we have measured the contribution of glycerol and
pyruvate to in vivo synthesis of hepatic triacylglycerol in nonpregnant and pregnant women after an overnight fast. Five
nonpregnant women were administered
[13C3]glycerol tracer as prime constant rate
infusion, and the appearance of tracer in plasma glucose and
triacylglycerol was quantified using gas chromatography-mass
spectrometry. The contribution of pyruvate to hepatic triacylglycerol
was quantified in nonpregnant and pregnant women using the deuterium
labeling of body water method. The appearance of [2H] in
hydrogens on C1 and C3 of triacylglycerol was
measured following periodate oxidation of the glycerol isolated from
hydrolyzed triacylglycerol. After a 16-h fast, ~6.1% of the plasma
triacylglycerol pool was derived from plasma glycerol, whereas 10 to
60% was derived from pyruvate in nonpregnant women and pregnant women
early in gestation. Our data suggest that glyceroneogenesis from
pyruvate is quantitatively a major contributor to plasma
triacylglycerol synthesis and may be important for the regulation of
very low density lipoprotein triacylglycerol production. Our
data also suggest that 3-glycerol phosphate is in rapid equilibrium
with the triosephosphate pool, resulting in rapid labeling of the
triose pool by the administered tracer glycerol. Because the rate of
flux of triosephosphate to glucose during fasting far exceeds that to
triacylglycerol, more glycerol ends up in glucose than in
triacylglycerol. Alternatively, there may be two distinct pools of
3-glycerol phosphate in the liver, one involved in generating
triosephosphate from glycerol and the other involved in
glyceride-glycerol synthesis.
The synthesis of triacylglycerol in the liver, adipose tissue, and
skeletal muscle following a meal is an important metabolic pathway for
the deposition of fat and in the maintenance of energy homeostasis in
all vertebrates. Even after an overnight fast in adult humans, and
following a brief fast in newborn infants, a substantial
re-esterification of fatty acids has been documented using isotopic
tracer methods (1-3). The source of glycerol for the esterification of
fatty acids in various tissues has generally been considered to be
plasma glucose or glycerol; however direct evidence for such an
inference has not been documented.
Triacylglycerol synthesis requires both fatty acids and a source of
3-glycerol phosphate. During fasting, the source of 3-glycerol phosphate can either be plasma glucose via glycolysis or glycerol released from the hydrolysis of triacylglycerol. In the adipose tissue
in particular, the glycerol released from the hydrolysis of
triacylglycerol cannot be re-utilized for the esterification of fatty
acids because of absence of glycerol kinase. It has been proposed that
during fasting adipose tissue generates the 3-glycerol phosphate
required for triacylglycerol synthesis, either from glucose via
glycolysis or, alternatively, from pyruvate via an abbreviated or
truncated version of gluconeogenesis, termed glyceroneogenesis (4-7).
The key enzyme in this pathway is the cytosolic form of phosphoenolpyruvate carboxykinase (GTP)
(PEPCK;1 EC 4.1.1.32). The
transcription of the gene for PEPCK is stimulated by cAMP during
periods of fasting (8, 9), resulting in an increase in enzyme activity
in both adipose tissue and liver. In isolated epididymal adipose tissue
from the rat, the rate of re-esterification of free fatty acids was
greatly increased by the provision of a glyceroneogenic precursor such
as pyruvate (10). In addition, hepatic glyceroneogenesis has been shown to account for ~89% of glyceride-glycerol in the triacylglycerol synthesized by rats fed a high protein diet (11).
There has not been a quantitative analysis of the relative rates of
glyceride-glycerol synthesis from its precursors, plasma glycerol,
pyruvate, or glucose in humans. In the present study we have quantified
the relative contribution of plasma glycerol and pyruvate (plus
lactate, alanine, etc.) to glyceride-glycerol in nonpregnant and
pregnant women during fasting. Pregnant women were studied because of
the higher concentration of plasma triacylglycerol during pregnancy,
particularly in the third trimester. Our data show that the source of
glyceride-glycerol following a brief fast is predominantly pyruvate.
Because the synthesis of glucose and glyceride-glycerol from plasma
glycerol share common enzymatic reactions, our data also suggest a
functional separation of the pathways of glycerol entry into the liver
and the 3-glycerol phosphate precursor pool for triacylglycerol synthesis.
Materials--
[2H]water, 99.9%
2H, and [1,2,3-13C3]glycerol,
99% 13C, were obtained from Isotech, Inc. (Miamisburg, OH).
Methods--
The respective contributions of plasma glycerol and
pyruvate were quantified in two separate groups of nonpregnant and
pregnant women. Written informed consent was obtained from each woman
and her spouse (when available) after fully explaining the procedure. The protocol was approved by the Institutional Review Board of the
University Hospitals of Cleveland.
Glycerol Incorporation in
Triacylglycerol--
[1,2,3-13C]Glycerol (over 99%
13C) was infused in five normal nonpregnant women after an
overnight fast. They were physically healthy and had a negative history
of diabetes or other metabolic disorders in their family. The tracer
glycerol was dissolved in normal saline, sterilized by Millipore
filtration, and tested for pyrogenicity and sterility. All subjects
reported to the Clinical Research Center at University of Hospitals of
Cleveland following a 12-h fast. The tracer was infused at a constant
rate of 0.03 mg/kg of body weight/min for a period of 5 h,
following a priming dose of 0.5 mg/kg. Arterialized blood samples were
obtained in heparinized syringes from the opposite arm at 30-min
intervals starting at 1 h. Blood samples were centrifuged
immediately, and the plasma samples were stored at Pyruvate Incorporation into Triacylglycerol--
The
contribution of pyruvate to glycerol in triacylglycerol was evaluated
using the total body water labeling method described for determining
the rate of gluconeogenesis in vivo (12, 13). The volunteers
had been studied previously, and the details of the experimental design
and the data on glucose turnover and gluconeogenesis have been reported
previously (12). Plasma samples for the quantification of
glyceroneogenesis were examined in four nonpregnant women, five
pregnant women in the first trimester (~11 weeks), and five women
during the third trimester (34 weeks) of pregnancy. None of the women
had any medical or obstetric illness or family history of diabetes and
were not taking any medication. The subjects ate their last meals at
6:00 p.m. the evening before the day of the study. They were given
[2H]water orally (~3 gm/kg of body water), assuming
total body water to be 55% of body weight (14), in three divided doses
at 11:00 p.m., 3:00 a.m., and 7:00 a.m. Blood samples in heparinized
syringes were obtained at frequent intervals starting at 8:00 a.m. and lasting until 12:00 noon. The samples were centrifuged immediately, and
the separated plasma was stored at Analytical Methods--
Total triacylglycerol with lipoproteins
were precipitated with 10% perchloric acid and hydrolyzed with 0.5 N alcoholic potassium hydroxide at 70 °C. The samples
were then neutralized, and glycerol, along with glucose, was isolated
by ion exchange chromatography (3). Glycerol was then separated from
glucose using HPLC by the following procedures. A Biorex Aminex column
(HPX-87P), 300 × 7.8 mm, along with an Aminex-Q-1505 (action
exchange resin in sodium form) guard column, was used. Glycerol was
eluted isocretically using HPLC grade water at a flow rate of 0.2 ml/min at a column temperature of 85 °C. The glycerol fractions
(from 52 to 60 min) were collected in a total volume of 1.6 to 1.8 ml.
[13C] Enrichment of Glycerol--
Glycerol
from the plasma was isolated by ion exchange chromatography (3) whereas
glycerol from triacylglycerol was isolated as described above. The
isotopic enrichment of glycerol was measured by gas chromatography-mass
spectrometry. A triacetate derivative of glycerol was prepared and
analyzed using a Hewlett Packard GC-MS system (Model 5985A; Hewlett
Packard Co., Palo Alto, CA) equipped with a capillary column (length,
10 m; inner diameter, 0.53 mm; film thickness, 1.2 µ; stationery
phase, AT-1; Alltech Associates, Inc., Avondale, PA) (3). The GC
conditions were as follows: injection temperature, 250 °C; initial
oven temperature, 90 °C for 3 min; final temp, 230 °C; and ramp
at 30 °C per min. Methane was used as a carrier and reactant gas.
Chemical ionization was used with selected ion monitoring software.
Peak areas for m/z 159, 160, 161, and 162, representing unlabeled and labeled isotopomer (m0,
m1-3) of glycerol, were measured.
[13C] Enrichment of Glucose--
The
m3 and m6 enrichment of glucose was measured by
GC-MS; an aldonitrile penta-acetate derivative was prepared, and
m/z 328 to 334, representing unlabeled and
labeled isotopomers (m0, m1-6) of glucose,
were quantified (15).
Measurement of Deuterium Enrichment in
Glycerol--
Carbons 1 and 3 of glycerol, along with their hydrogens,
were cleaved by periodate oxidation to form formaldehyde, which was condensed with ammonium hydroxide to form hexamethylenetetramine (16).
The latter was analyzed directly using a Hewlett Packard gas
chromatography-mass spectrometry system (HP5970 equipped with an HP5890
gas chromatograph). The GC-MS conditions were as follows: a nonpolar
polydimethyl siloxane stationary phase bonded fused-silica open-tubular
column was used (AT-1; Alltech, Deerfield, IL). The column dimensions
were length 30 m × 0.54-mm inner diameter, and film thickness was
1.2 µm. The injection temperature was 170 °C, initial temperature
was 105 °C for 6 min, and final temperature was 230 °C; ramp rate
was 45 °C per min. The retention time of hexamethylenetetramine was
~3.2 min. Electron impact ionization (70 eV) was used, and ions
m/z 140 and 141 were monitored using the
selected-ion monitoring technique. Standard solutions of
hexamethylenetetramine prepared from [1-2H]glucose of
known enrichment were run along with unknowns to correct for
instrumental variations (16). [2H] enrichment of
total body water was measured using the zinc reduction method with an
isotope ratio mass spectrometer (12).
Calculations--
The fractional contribution of glycerol to
plasma glucose and triacylglycerol was calculated by comparing the
m3 enrichment of glucose and triacylglycerol with that of
plasma glycerol. Because two trioses join together to form a glucose
molecule, the enrichment in glucose was multiplied by 0.5.
The contribution of pyruvate to triacylglycerol was calculated from the
deuterium enrichment of triacylglycerol using the following
assumptions. The major sources of glycerol for triacylglycerol include
pyruvate (plus lactate, alanine, and other gluconeogenic amino acids)
and plasma glucose or glycerol. The methyl hydrogens (C3) of pyruvate
that form C6 of glucose and C3 of glyceraldehyde-3-P exchange with
hydrogens in body water so that [2H] enrichment of
hydrogens bound to C3 of pyruvate or to phosphoenolpyruvate is similar
to that of water (Fig. 1). This
assumption was evaluated in fasting human subjects and shown to be over
80% complete (17). One hydrogen on C1 of dihydroxyacetone
phosphate (DHAP), the immediate precursor of glycerol-3-P, is obtained
from body water during the conversion of phosphoenolpyruvate to
glyceraldehyde-3-P. The second hydrogen (on C1) is also obtained from
body water during the isomerization of DHAP and glyceraldehyde-3-P so
that the [2H] enrichment of both the hydrogens on C1 of
glycerol-3-P is the same as that of body water. Thus the
[2H] enrichments of hydrogen on C1 and C3 of
triacylglycerol formed from pyruvate will be the same as that of the
body water. In contrast, the triacylglycerol formed from nonpyruvate
sources will have the hydrogens labeled only at the C1 position (Fig.
1). Periodate oxidation results in cleavage of both C1 and C3 of
glycerol, along with the attached hydrogen. Therefore the measured
2H enrichment in glycerol is the sum of the enrichments of
hydrogen from pyruvate and nonpyruvate sources. From the assumptions
presented above, i.e. the deuterium enrichment of
hydrogen on glycerol carbons from pyruvate will be the same as water
and that the deuterium enrichment of hydrogen on nonpyruvate carbon
source will be that of water (C1), and the natural abundance of
deuterium (C3), the relative flux of pyruvate and nonpyruvate carbon to
triacylglycerol can be calculated.
Contribution of Plasma Glycerol--
The mean m3
enrichments of plasma glycerol, glucose, and
triacylglycerol during 3.5 to 5 h of
[13C3]glycerol infusion are presented
in Table I. An isotopic steady state was evident in all three
metabolic pools. As shown, only 6.1% of the triacylglycerol pool was
derived from plasma glycerol in normal healthy women after 17 h of
fasting; the rest was from nonglycerol sources. The rate of appearance
of glycerol, calculated from tracer dilution, was 1.65 ± 0.6 µmol/kg/min (mean ± S.D.). Approximately 4% of the plasma
glucose pool was derived from plasma glycerol. Assuming the rate of
glucose turnover to be ~10 µmol/kg of body weight/min (12), this
would represent ~0.8 µmol of glycerol/kg/min or 50% of glycerol
turnover. In contrast, if the rate of appearance of VLDL
triacylglycerol is assumed to be ~0.5 µmol/kg/min (18), the
contribution of glycerol to triacylglycerol synthesis would represent
0.03 µmol/kg/min or less than 2% of the glycerol turnover.
Contribution of Pyruvate to Triacylglycerol--
The steady state
deuterium enrichment in body water in triacylglycerol and carbon-6 of
glucose are displayed in Table II. The
2H enrichment in triacylglycerol was measured ~5 h after
the last dose of [2H]water and does not represent an
isotopic plateau in the triacylglycerol pool. The fractional
contribution of pyruvate to triacylglycerol ranged from 10 to 46% in
nonpregnant women and from 20 to 60% during early gestation. In late
gestation, 6 to 19% of triacylglycerol was derived from pyruvate. It
was not measurable in two subjects. The 2H enrichment of
triacylglycerol was lower in women studied late in gestation, most
likely a consequence of the large plasma triacylglycerol pool at this
stage in pregnancy (19). As shown in Table II, 36 to 69% of glucose
was produced via gluconeogenesis from pyruvate. No statistically
significant differences were evident in any of the parameters between
pregnant and nonpregnant subjects.
The data from the present study show that in nonpregnant women,
6.1% of glycerol in triacylglycerol was derived from plasma glycerol
and that a significant portion (10 to 60%) of the triacylglycerol was
derived from pyruvate (glyceroneogenesis). The large variance observed
was most likely because of a lack of isotopic steady state in the
triacylglycerol pool during [2H]water studies, because
the plasma samples were obtained after a relatively short period
following tracer administration, and because of the slow turnover rate
of the triacylglycerol pool.
Data from the present study are comparable with the recently published
work by Botion et al. (11), in which the rates of glyceroneogenesis were quantified in rats in vivo. Hepatic
glyceroneogenesis accounted for 80% of the total glyceride-glycerol
formation in rats fed a high protein diet. However, they measured total
[3H] incorporation into all hydrogens of glycerol
following [3H]water administration to rats and
likely overestimated the contribution of glyceroneogenesis.
The physiological role of glyceroneogenesis from pyruvate in the
regulation of hepatic triacylglycerol synthesis remains to be
determined. Knopp et al. (20) examined the effect of
FFA availability and of insulin on VLDL triglyceride production and VLDL apoB production in healthy young men. Using the euglycemic hyperinsulinemic clamp method they showed that raising the plasma FFA
levels by infusion of intralipid could not completely counter the
inhibitory effect of insulin on VLDL triglyceride and apoB production.
In contrast, elevation of FFA alone, without insulin, acutely
stimulated VLDL production in healthy young males. The authors
concluded that the acute inhibition of VLDL production by insulin
in vivo is only partly because of the suppression of plasma
FFA release by adipose tissue and may also be because of an
FFA-independent process. Other investigators (21) have shown a
defective regulation of triacylglycerol metabolism by insulin in
noninsulin-dependent diabetic subjects and concluded that
the inability of insulin to acutely inhibit the release of VLDL
triglycerides from liver, despite efficient suppression of serum FFA,
contributes to the hypertriglyceridemia in
noninsulin-dependent diabetic subjects. We speculate that
the acute suppression of VLDL triacylglycerol synthesis by insulin is
an integrated response as a result of insulin action at multiple sites;
these include the peripheral suppression of lipolysis and suppression
of PEPCK gene expression resulting in a reduction in glyceroneogenesis,
along with a reduction in gluconeogenesis. The continued high
triacylglycerol synthesis observed in noninsulin-dependent
diabetic subjects during hyperinsulinemia may be related to hepatic
insulin resistance and lack of suppression of PEPCK gene transcription.
These findings, together with the data in the present paper, suggest
that glyceroneogenesis may play an important role in controlling VLDL
production by the liver.
During periods of starvation, glycerol is released by lipolysis in
adipose tissue. Because of the absence of glycerol kinase, this
glycerol cannot be further metabolized by adipose tissue and is
released into circulation and is taken up by the liver for the
synthesis of glucose. Because the liver also synthesizes a significant
amount of triacylglycerol during fasting, it would be logical to assume
that this glycerol would be the major source of the glyceride-glycerol
for triacylglycerol synthesis. Our data show that only a small fraction
of the glyceride-glycerol made by the liver during fasting is
synthesized from glycerol, this despite the fact that a large fraction
of the glycerol (50%) is converted to glucose.
We can think of two explanations for our findings that only a small
fraction of the plasma glycerol entering the liver is converted to
glyceride-glycerol, despite the fact that it enters a potential
precursor pool of 3-glycerol phosphate (Fig.
2). First, a single pool of 3-glycerol
phosphate is in very rapid equilibrium with the triosephosphate pool,
so that there is a rapid labeling of the triosephosphate pool by the
infused glycerol tracer. Because the flux from triosephosphate to
glucose during fasting (~10 µmol/kg/min) far exceeds that to
triacylglycerol (<1 µmol/kg/min), more glycerol will end up in
glucose than in triacylglycerol (Fig. 2A). For the same
reason, because the contribution of pyruvate to the triosephosphate pool is much greater than that of plasma glycerol, the contribution of
pyruvate to triacylglycerol will be far greater than that of glycerol,
as was observed in the present study. Second, there may be two
functional pools of 3-glycerol phosphate in the liver. One of these
pools is the precursor for triosephosphate, and the other is the
precursor pool for glyceride-glycerol synthesis (Fig. 2B).
The first suggested scenario seems more likely, because it is supported
by the observation of Siler et al. (22) that ethanol consumption by human subjects resulted in an accumulation of
[2-13C1]glycerol from plasma in hepatic
glycerol-3-P. This result was due in part to the effect of the
ethanol-induced increase in the cytosolic NADH level on the equilibrium
position of glycerol-3-phosphate dehydrogenase. As predicted, this
alteration in the cytosolic redox state markedly increased the labeled
glycerol in glyceride-glycerol, because it effectively reduces DHAP to
glycerol-3-P, which in turn serves as a precursor for triacylglycerol
synthesis. Clearly more research is required to resolve the pathways of
carbon flow responsible for the low level of conversion of plasma
glycerol to glyceride-glycerol in the livers of fasting humans.
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
REFERENCES
EXPERIMENTAL PROCEDURES
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
REFERENCES
70 °C until analysis.
70 °C until analysis.
View larger version (17K):
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Fig. 1.
Conversion of pyruvate to glycerol-3-P and
triacylglycerol and the site of labeling of the hydrogen atoms
(bold) from deuterium in body
water.TCA Cycle, tricarboxylic acid
cycle.
RESULTS AND DISCUSSION
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
REFERENCES
Contribution of plasma glycerol to glucose and triacylglycerol
Glyceroneogenesis and gluconeogenesis from pyruvate in humans
View larger version (14K):
[in a new window]
Fig. 2.
Pathway for the conversion of plasma glycerol
to triacylglycerol or glucose in the liver. Panel A,
rapid flux from the triose pool. Glycerol enters the liver and is
converted to glycerol-3-P by glycerol kinase, which is then oxidized to
DHAP by glycerol-3-phosphate dehydrogenase. The labeled glycerol-3-P is
in rapid equilibrium with DHAP. Because the flux of triosephosphate to
glucose (~10 µmol/kg/min) exceeds that to triacylglycerol (<1
µmol/kg/min), more glycerol is ultimately converted to glucose than
to triacylglycerol. Panel B, Two pools of glycerol-3-P.
Glycerol enters the liver and is converted to glycerol-3-P, which is
then oxidized to DHAP as outlined in panel A. A second pool
of glycerol-3-P formed by the reduction of some of the DHAP is
sequestered from the first pool and is utilized for the synthesis of
hepatic triacylglycerol (see "Results and Discussion").
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ACKNOWLEDGEMENTS |
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We thank the nursing staff of the General Clinical Research Center at University of Hospitals of Cleveland for invaluable help in the conduct of these studies. The secretarial assistance of Joyce Nolan is gratefully appreciated.
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FOOTNOTES |
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* The work was supported by National Institutes of Health Grants RR00080, HD11089 (to S. C. K.), and DK25541 (to R. W. H.) and by United States-Israel Binational Foundation Grant 9100268 (to L. R.).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.
To whom correspondence should be addressed: Schwartz Center for
Metabolism and Nutrition, MetroHealth Medical Center, 2500 MetroHealth
Dr., Cleveland, OH 44109-1998; Tel.: 216-778-8643; Fax: 216-778-8644;
E-mail: sck@po.cwru.edu.
Published, JBC Papers in Press, January 29, 2001, DOI 10.1074/jbc.M006186200
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ABBREVIATIONS |
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The abbreviations used are: PEPCK, the cytosolic form of phosphoenolpyruvate carboxykinase (GTP); FFA, free fatty acid; DHAP, dihydroxyacetone phosphate; HPLC, high pressure liquid chromatography; GC-MS, gas chromatography-mass spectrometry; VLDL, very low density lipoprotein.
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REFERENCES |
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