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We conducted an extensive mass isotopomer analysis of citric
acid cycle and gluconeogenic metabolites isolated from livers of
overnight fasted rats perfused with 4 mM glucose, 0.2 mM octanoate, 1 mM [U-
Volume 270,
Number 17,
Issue of April 28, pp. 10027-10036, 1995
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
REVERSIBILITY OF ISOCITRATE DEHYDROGENASE AND INVOLVEMENT OF
ATP-CITRATE LYASE IN GLUCONEOGENESIS
C
]lactate, and 0.2 mM [U-C
]pyruvate, in the
anterograde or retrograde mode. In both perfusion modes, two distinct
isotopomer patterns were observed: (i) those of phosphoenolpyruvate,
glucose, malate, and aspartate and (ii) those of citrate,
-ketoglutarate, glutamate, and glutamine. Key citric acid cycle
parameters and, hence, rates of gluconeogenesis, calculated (Lee, W.-N.
P. (1989) J. Biol. Chem. 264, 13002-13004 and Lee, W.-N.
P. (1993) J. Biol. Chem. 268, 25522-25526) from our mass
isotopomer data did not only vary, but lead to conclusions inconsistent
with Lee's citric acid cycle model. Compared to lactate and
pyruvate uptake, which sets an upper limit to glucose production, rates
of gluconeogenesis calculated (i) with the phosphoenolpyruvate and
citrate data were similar, but those calculated (ii) with the glutamate
data amounted to only 60%, which is unlikely. All these conclusions are
independent of the perfusion modes. We provide evidence that the
following processes contribute to the observed labeling discrepancy:
(i) the reversibility of the isocitrate dehydrogenase reaction and (ii)
an active citrate cleavage pathway for the transfer of the oxaloacetate
carbon skeleton from mitochondria to the cytosol. Also, a good fit of
our labeling data was obtained with a model of citric acid cycle and
gluconeogenesis which we developed to incorporate the above reactions
(Fernandez, C. A., and Des Rosiers, C. (1995) J. Biol. Chem. 270, 10037-10042). The following conclusions can be drawn
from the calculated reaction rates: (i) about half of the lactate
conversion to glucose occurs via the citrate cleavage pathway, (ii) the
flux through the reversal of the isocitrate dehydrogenase reaction is
almost as fast as that through the citrate synthase reaction, and (iii)
the flux through citrate synthase and -ketoglutarate dehydrogenase
is 1.6- and 3.2-fold that through pyruvate carboxylase, respectively.
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