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Department of Nutritional Sciences, Cook College, Rutgers University, New Brunswick, NJ
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ABSTRACT |
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 TOP ABSTRACT Role of the liverPathways of hepatic glutamine...The liver lobuleLiver heterogeneity and...Regulation of hepatic glutamine...Balance of glutamine synthesis...REFERENCES |
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KEY WORDS: • liver • glutamine • glutamate • glutaminase • glutamine synthetase • urea cycle • ammonia
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Role of the liver |
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TOPABSTRACTRole of the liverPathways of hepatic glutamine...The liver lobuleLiver heterogeneity and...Regulation of hepatic glutamine...Balance of glutamine synthesis...REFERENCES |
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first described the synthesis and hydrolysis of
glutamine in extracts of mammalian liver. However, defining the precise
role of the liver in glutamine metabolism in vivo has been somewhat
controversial. Functional hepatectomy results in elevated glutamine
levels in the circulation (Blackshear et al. 1975
), and studies with the perfused liver demonstrated
very high rates of glutamine utilization with resultant synthesis of
glucose and urea (Ross et al. 1967
, Saheki and Katunuma 1975
). Conversely, studies of hepatic glutamine
synthesis showed low rates of release, well below the maximal glutamine
synthetase activity (Lund 1971
). Further work with
isolated hepatocytes (Lund and Watford 1976
)
confirmed the low rates of glutamine synthesis, but also noted that
high rates of glutamine utilization were seen only with medium
glutamine concentrations >2 mmol/L, with little net change at more
physiologic levels (0.5–1.0 mmol/L). Vincent et al. (1989)
demonstrated that glutamine synthesis and degradation
were occurring simultaneously in such preparations.
Portal-arterial-venous difference measurements in vivo show either no
net exchange, a slight net output or a slight net utilization of
glutamine by liver in control-fed rats. Net glutamine uptake is
seen in diabetes, sepsis, with dietary glutamine supplementation and
after high protein feeding, although the last-mentioned may be true
only during the absorptive phase (Aikawa et al. 1973
,
Brosnan et al. 1983
, Ewart and Brosnan 1993
, Lopez et al. 1998
, Matsutaka et al. 1973
, Moundras et al. 1993a
and 1993b
,
Rémésy et al. 1978
and 1997
, Schrock and Goldstein 1981
, Souba and Austgen 1990
, Yamamoto et al. 1974
). In
contrast, net glutamine production by rat liver is observed in
metabolic acidosis, in tumor-bearing rats and during some phases of
starvation (Matsutaka et al. 1973
, Schrock and Goldstein 1981
, Souba et al. 1988
,
Welbourne, 1987
). In unanesthetized dogs, there is
clearly glutamine uptake by the liver in absorptive, postabsorptive and
early starvation (24 h) conditions, but this changes to net glutamine
release later in starvation (96 h) (Cersosimo et al. 1986
). Metabolic acidosis increases net glutamine
release by dog liver, but this can be decreased by infusion of
bicarbonate (Cersosimo et al. 1987
); similar findings
have been reported in sheep (Heitmann and Bergman, 1978
). In pigs, there is evidence of net glutamine uptake,
which increases in response to the trauma of major surgery
(Hulsewe et al. 1997
) but can change to net glutamine
release after infusion of growth hormone (Balteskard et al. 1998
).
In humans, the situation is far from clear due to difficulties in
sampling hepatic portal venous blood. In one study of control subjects,
Felig et al. (1973b)
reported a mean net uptake of
glutamine of 65 µmol/L across the splanchnic bed
(artery and hepatic vein), and in a different group of controls, a mean
net glutamine uptake of 38 µmol/L across the
portal-drained viscera (artery and portal vein). This difference
suggests that at least 50% of the glutamine used by the splanchnic bed
was occurring in the portal-drained viscera but also supports net
uptake by the liver. In a second study using diabetic subjects
(Felig et al. 1973a
), the results were less clear;
subsequently, however, both studies were interpreted to indicate that
all splanchnic glutamine utilization was occurring in the
portal-drained viscera, with no glutamine uptake by the liver
(Felig 1975
). Regardless of the net exchange of
glutamine across human liver, the likelihood of simultaneous glutamine
degradation and synthesis means that this organ must remove some
glutamine from the circulation.
Interestingly, although most glutamate flux is restricted to
intracellular pathways, some reports show a small net release of
glutamate from the liver (Lopez et al. 1998
,
Heitmann and Bergman 1980
, Lund and Watford
1975, Rémésy et al. 1997
). However,
most published studies do not report glutamate values, and those that
do are complicated by uncertainties regarding the exchange of glutamate
between plasma and blood cells across different organs (Aoki et al. 1972
, Elwyn 1966
, Heitmann and Bergman 1980
).
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Pathways of hepatic glutamine and glutamate metabolism |
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TOPABSTRACTRole of the liverPathways of hepatic glutamine...The liver lobuleLiver heterogeneity and...Regulation of hepatic glutamine...Balance of glutamine synthesis...REFERENCES |
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).
The liver possesses a unique isozyme of glutaminase, first described by
Krebs (1935)
, who noted that the hydrolysis of glutamine
in liver extracts, in contrast to extracts of brain and kidney, was not
inhibited by relatively low levels of the product glutamate. Subsequent
studies confirmed that two forms of glutaminase exist in mammalian
tissues, i.e., the kidney (or brain) type, found
in all glutamine-utilizing tissues (with the exception of postnatal
liver parenchymal cells, although it is present in fetal liver), and
liver-type, which is found only in a limited population of
postnatal liver parenchymal cells (it is not expressed before birth).
 |
The glutaminase isozymes are the products of different genes, but
the amino acid sequences deduced are 73% identical (86% similar),
indicating that they likely arose from a common ancestor
(Chung-Bok et al. 1997
, Curthoys and Watford 1995
). The fate of glutamine hydrolyzed in hepatocytes is to
provide substrate (ammonia and glutamate) to urea synthesis and
gluconeogenesis. Meijer (1985)
showed that the ammonia
liberated by hepatic glutaminase is channeled preferentially to the
first enzyme of urea synthesis, carbamoyl phosphate synthase I. Further
metabolism of the glutamate formed in the liver can be via either
glutamate dehydrogenase or transamination (probably to aspartate) and
subsequent flux to urea synthesis and gluconeogenesis (Meijer et al. 1990
, Meijer 1995
) (see Fig. 1
).
|
 |
Glutamate metabolism is principally intracellular and is involved
in almost all amino acid metabolism through transamination or the
glutamate dehydrogenase (Meijer et al. 1990
,
Meijer, 1995
). Important components of glutamine and
glutamate metabolism in the liver are specific transporters; these are
discussed in detail below regarding their heterogeneous distribution
within the liver.
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The liver lobule |
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TOPABSTRACTRole of the liverPathways of hepatic glutamine...The liver lobuleLiver heterogeneity and...Regulation of hepatic glutamine...Balance of glutamine synthesis...REFERENCES |
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showed that
glutamine synthetase was localized to a small (1- to 3-cell thick)
layer of cells surrounding the venous exit, and Haussinger (1990)
established a functional periportal location for
glutaminase. This was confirmed in discrete populations of isolated
perivenous and periportal hepatocytes (Racine et al. 1995
, Watford and Smith, 1990
) and from in situ
hybridization experiments in rat and mouse liver in which expression of
liver-type glutaminase mRNA was found to be limited to a small
population of periportal hepatocytes (Moorman et al. 1994
). Given the very strict perivenous location of glutamine
synthetase in these livers, there exists a large zone of hepatocytes in
the center of the lobule that appears to play no quantitative role in
glutamine metabolism. It is not known whether conditions that induce
hepatic glutaminase (see below) increase expression only in this
existing population of glutaminase positive cells, or whether the
glutaminase-containing zone expands.
Glutamate dehydrogenase can be involved in pathways of both glutamine
utilization and synthesis. The activity in liver is relatively high,
and the enzyme is usually considered to catalyze a reaction close to
equilibrium. This latter fact suggests that net flux can be in either
direction, depending on the provision or removal of substrates and
products. Glutamate dehydrogenase is found throughout the liver lobule,
but is higher in perivenous cells [although relatively high periportal
expression with an intermediate zone of low expression has also been
reported (Lamers et al. 1988
)]. Other enzymes of amino
acid catabolism, especially the transaminases such as alanine
aminotransferase, are more abundant in the periportal region as are the
enzymes of the urea cycle (Haussinger 1990
). An
exception is ornithine aminotransferase which, like glutamine
synthetase, is expressed only in perivenous cells (Kuo et al. 1991
).
Glutamine is transported in periportal cells on a sodium-linked
carrier known as system N (Haussinger 1990
,
Meijer et al. 1990
). However, there is also evidence of
some bidirectional sodium-independent transport, possibly on system
L (Low et al. 1993
), termed "n" in some studies
(Inoue et al. 1995
), which is probably located in the
perivenous cells. Glutamate and aspartate are transported primarily by
a perivenous sodium-linked system (Stoll et al. 1991
), with a minor role played by a sodium-independent
carrier, which may be more prevalent in periportal cells.
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Liver heterogeneity and glutamine metabolism |
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TOPABSTRACTRole of the liverPathways of hepatic glutamine...The liver lobuleLiver heterogeneity and...Regulation of hepatic glutamine...Balance of glutamine synthesis...REFERENCES |
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proposed the following scenario
(Fig. 2
) for hepatic glutamine metabolism. Portal blood delivers large amounts
of glutamine and ammonia to the liver. The periportal cells (the bulk
of the cells and the site of glutaminase and other amino acid
catabolism enzymes and the urea cycle) take up some glutamine and most
of the ammonia. Interestingly, hepatic glutaminase has an absolute
requirement for activation by ammonia, and thus glutamine utilization
is stimulated at times of ammonia excess. Glutamine and ammonia are
metabolized in periportal cells to urea by a high capacity/low affinity
system. The capacity of the urea cycle is many fold that of hepatic
glutamine synthesis, as determined in perfused organs, but the
Km of carbamoyl phosphate synthetase I
for ammonia is ~1–2 mmol/L. Therefore, some ammonia is not utilized
by the periportal cells and reaches the perivenous (glutamine
synthetase–containing) cells, where it is efficiently detoxified by a
low capacity/high affinity glutamine synthesizing system (the
Km of glutamine synthetase for ammonia
is 0.2 mmol/L). Thus, the presence of glutamine synthesis in the last
few cells ensures total ammonia detoxification, a hypothesis supported
by studies in vivo showing that hyperammonemia results from selective
destruction of perivenous hepatocytes and the clinical observation of
hyperammonemia occurring in a patient with reported glutamine
synthetase deficiency (Tuchman et al. 1997
).
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). Glutamate derived from intracellular proteolysis is probably released
by periportal cells and may be the source of the glutamate released by
liver (Meijer et al. 1990
). However, this glutamate is
unlikely to contribute significantly to perivenous glutamine synthesis
because the Vmax of the
sodium-linked glutamate transport system in such cells is very low.
Furthermore, some of the properties of this transport system (e.g., it
is down-regulated in acidosis) seem to be incompatible with known
features of glutamine synthesis regulation. Perivenous cells may take
up 
-ketoglutarate or other -carboxylic acids from the circulation
(Stoll et al. 1991
), but the abundance of such
substrates is very low. Similarly, the provision of glutamate directly
from proteolysis would be minor in perivenous cells (Meijer et al. 1990
). Other sources of glutamate, such as synthesis from
glucose or lactate, have been proposed (Almond et al. 1991
). One interesting hypothesis is that ornithine
transaminase, also exclusively perivenous, plays a role. In this
scenario, arginine taken up by perivenous cells would be converted to
ornithine, which would then be transaminated to pyrroline
5-carboxylate. This product would then yield glutamate through the
action of pyrroline 5-carboylate dehydrogenase (Kuo et al. 1991
). Although this notion is supported by the occurrence of
arginase activity in perivenous cells (O’Sullivan et al. 1998
), there are unresolved issues at present, i.e., the
pathway requires glutamate/-ketoglutarate recycling to function (for
the transamination reaction), and the quantity of arginine or ornithine
available for this pathway would be relatively small.
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Regulation of hepatic glutamine and glutamate metabolism |
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TOPABSTRACTRole of the liverPathways of hepatic glutamine...The liver lobuleLiver heterogeneity and...Regulation of hepatic glutamine...Balance of glutamine synthesis...REFERENCES |
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used control strength analysis
to determine that glutamine (control strength 0.96) and system N
transport (control strength 0.5) were important in changing the rate of
glutamine utilization. However, these were countered by glutamine
efflux from the cell (control strength -0.4), which could effectively
decrease the rate of glutamine degradation. Thus, changing any one of
these variables will bring about large changes in the rate of glutamine
degradation.
Short-term stimulation of glutaminase [see Brosnan et al. (1995)
] is
seen in response to hormones such as glucagon or epinephrine, acting
via cAMP, and vasopressin, acting via calcium. Interestingly, these
increases are maintained in mitochondria isolated from liver after
treatment in vivo or in vitro, but are lost on disruption of the
mitochondria. Similarly, from work in isolated, perfused livers or
hepatocytes, agents such as ammonia or bicarbonate (as well as
increasing pH) stimulate glutamine breakdown and urea synthesis.
Purified hepatic glutaminase exhibits a flat pH curve and is not
affected by many of the agents that appear to regulate it in intact
cells or mitochondria (Smith and Watford 1988
). Indeed,
McGivan (1988)
proposed that the tight association of
the enzyme with the mitochondrial inner membrane is responsible for
many of its kinetic characteristics in vivo. There is also extensive
evidence of acute regulation of glutamine synthetase activity in intact
cell or tissue preparations, with increased flux during acidosis and
decreased flux at higher pH levels (Haussinger, 1990
,
Lueck and Miller 1970
). However, the mechanisms involved
have not yet been defined, and such changes have not been demonstrated
in vivo (see below).
The long-term regulation of rat hepatic glutaminase is well
documented (Curthoys and Watford 1995
). Increased
activity occurs in diabetes, starvation and with the feeding of high
protein diets, whereas decreased activity occurs with the feeding of
low protein diets. To date, all such changes suggest transcriptional
regulation of the glutaminase gene to be the major control point.
Studies with the promoter region 5' to the hepatic glutaminase gene
confirmed that dexamethasone was a strong inducer of expression in
HepG2 cells (Chung-Bok et al. 1997
), with the response
requiring a region -252 to -103 upstream of the start site of
transcription. Surprisingly, in contrast to the evidence from
experiments in vivo, ammonium chloride repressed gene expression
(Chung-Bok and Watford 1997
), whereas glucagon and cAMP
analogs did not affect the activity of the promoter. However, this
negative finding may be due to the short (1000 bp) promoter sequence
analyzed.
Hepatic glutamine synthetase activity appears unresponsive to
physiologic and pathophysiologic changes in vivo (it is unchanged in
diabetes, acidosis or after changes in dietary protein intake),
although a slight increase has been reported in starvation
(Arola et al. 1991). The activity is lower in
hypophysectomized, adrenalectomized and thyroidectomized rats, and can
be restored by growth hormone, glucocorticoids or thyroid hormones
(respectively), but these hormones have no effect in intact animals
[see Lie-Venema (1997)
]. Hepatic glutamine synthetase
activity is decreased in conditions of liver atrophy brought about by
energy or protein restriction, but the effect follows from an
interesting mechanism, i.e., a decrease in the number of glutamine
synthetase–positive cells [rather than a reduction in enzyme activity
within the cells themselves; see Lie-Venema (1997)
].
Glutamine transport on system N has been proposed to be a major control
site for hepatic glutamine utilization. Consistent with such a role,
system N is up-regulated in conditions of increased urea synthesis,
such as diabetes and burn injury (Lohmann et al. 1998
,
Meijer et al. 1990
), and some evidence indicates that
the sodium-independent system "n" is up-regulated in
tumor-bearing rats (Inoue et al. 1995
). Perivenous
sodium-linked glutamate transport has also been reported to decline
in response to acidosis, an action at odds with the increased
requirement for glutamate in such cells [ see Meijer et al. (1990)
].
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Balance of glutamine synthesis and degradation across the liver |
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TOPABSTRACTRole of the liverPathways of hepatic glutamine...The liver lobuleLiver heterogeneity and...Regulation of hepatic glutamine...Balance of glutamine synthesis...REFERENCES |
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and 1992
). This effect is illustrated in studies with rats fed high
or very low protein diets, in which glutamine synthesis and net release
during low protein feeding has been termed "nitrogen salvage"
(Rémésy et al. 1997
). When the rate of
hepatic glutamine release in such animals is expressed as a percentage
of the total nitrogen released as glutamine + urea, the proportion
exiting as glutamine does increase with low protein feeding. However,
on careful examination of the data, it is apparent that although the
liver does becomes a site of net glutamine synthesis in low
protein–fed animals, the absolute rate of glutamine synthesis is
unchanged, and it is the rate of urea synthesis that is decreased (and
thus conserves the nitrogen). In summary, the separation of glutaminase and glutamine synthetase within different regions of the liver lobule allows this organ to remove excess glutamine when necessary, but also enables it to release glutamine at times when glutamine is required by other tissues. The principal mechanism responsible for the liver’s ability to switch from net glutamine utilization to net glutamine synthesis is by modulating the rate of glutamine utilization, with the rate of glutamine synthesis remaining relatively constant.
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FOOTNOTES |
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REFERENCES |
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TOPABSTRACTRole of the liverPathways of hepatic glutamine...The liver lobuleLiver heterogeneity and...Regulation of hepatic glutamine...Balance of glutamine synthesis...REFERENCES |
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