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Department of Gastroenterology, Hepatology and Infectiology, Heinrich Heine University, Düsseldorf, Germany
2To whom correspondence should be addressed. E-mail: haeussin{at}uni-dusseldorf.de
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONGlutamine-induced hepatocyte...Cell volume sensing and...Glutamine signaling and...Glutamine signaling and biliary...CONCLUSIONSLITERATURE CITED |
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KEY WORDS: • proteolysis • bile formation • glutamine • MAP kinases • signal transduction
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONGlutamine-induced hepatocyte...Cell volume sensing and...Glutamine signaling and...Glutamine signaling and biliary...CONCLUSIONSLITERATURE CITED |
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, Häussinger 1998
). However, it also
became clear that this amino acid exerts regulatory properties
independent of its own metabolism, such as modulation of protein and
glycogen turnover, gene expression or transport. Subsequently,
glutamine-induced alterations of cell hydration were recognized as
one major trigger for such effects, when it became clear that
nutrient-, hormone- and osmolarity-induced changes of cell
hydration act as independent and potent signals that modify cell
function and gene expression [for reviews see Häussinger (1996)
and Lang et al. (1997)
]. Osmoregulation
of cell function has been studied in detail in liver, and the present
article focuses on the role of glutamine-induced hydration changes
on hepatic proteolysis and bile secretion. |
Glutamine-induced hepatocyte swelling |
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TOPABSTRACTINTRODUCTIONGlutamine-induced hepatocyte...Cell volume sensing and...Glutamine signaling and...Glutamine signaling and biliary...CONCLUSIONSLITERATURE CITED |
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). In the perfused rat liver, glutamine-induced hepatocyte swelling
is half-maximal and maximal at portal glutamine concentrations of
0.7 and 2 mmol/L, respectively. Thus, physiologic fluctuations of
portal glutamine are expected to modulate hepatocyte hydration
effectively. Also, other amino acids such as the system A substrates,
glycine and alanine, produce hepatocyte swelling, which is additive to
the swelling induced by glutamine (Table 1
). The extent of amino acid–induced hepatocyte swelling is determined
by the intra/extracellular amino acid concentration gradient, which
largely depends upon the activity of the concentrative transport
systems in the plasma membrane, as well as the osmorelevance of
intracellular amino acid metabolism. The latter is under complex
control by hormones and the nutritional state. Accordingly,
upregulation of the amino acid transport systems A and N during
starvation enhances the swelling potency of their respective substrates
(Table 1)
. In view of the potent control of liver function by cell
hydration, the role of concentrative amino acid transport systems not
only resides in the translocation of amino acids across the plasma
membrane, but these transporters also act as transmembrane signaling
systems, which allow, via changes of cell hydration, a rapid adaptation
of cell function in response to changes in the amino acid load.
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Cell volume sensing and signaling |
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TOPABSTRACTINTRODUCTIONGlutamine-induced hepatocyte...Cell volume sensing and...Glutamine signaling and...Glutamine signaling and biliary...CONCLUSIONSLITERATURE CITED |
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, Maeda et al. 1995
, Posas et al. 1996
, Sugiura et al. 1994
, Verna et al. 1997
), whereas no counterparts have thus far been identified in
mammalian cells. However, there is some evidence that integrins [for
reviews see Giancotti and Ruoslahti (1999)
and
Plow et al. (2000)
] are involved in osmosensing in
skeletal muscle. In particular, a hexameric peptide (GRGDTP) derived
from fibronectin and comprising an arginine-glycine-aspartate
(RGD)3
adhesion motif blocks regulation of glycogen metabolism as well as
system N activity (i.e., glutamine uptake) by cell volume in rat
primary rhabdomyocytes (Low et al. 1997
, Low and Taylor 1998
). RGD peptides are believed to disrupt integrin
interaction with extracellular matrix (ECM) proteins, although this has
not been addressed experimentally. Preliminary results suggest an
involvement of integrin/ECM contacts in hepatic hydration sensing as
well (see below). It is likely that multiple osmosensing structures
exist in mammalian cells, which allow transduction not only of
information on the extent and kinetics of cell hydration changes, but
also on the nature of the cell volume challenge. Much more is known
about the osmosignaling pathways, which are activated in response to
hepatocyte hydration changes [for review see Häussinger and Schliess (1999)
]. Hypoosmotic swelling of cultured
hepatocytes, perfused liver or H4IIE hepatoma cells results within 1
min in an activation of mitogen-activated protein kinases (MAPK)
(Noé et al. 1996
), which are also activated in
response to growth factor signaling (Davis 1993
).
Hypoosmotic extracellular signal-regulated kinase (ERK) activation
occurs in a pertussis and cholera toxin– as well as genistein- and
erbstatin-sensitive, but protein kinase C-independent way,
suggestive of G-proteins and a tyrosine kinase as upstream elements
in the osmosignaling pathway toward ERK (Noé et al. 1996
, Schliess et al. 1997
). Within 5–10 min,
there is also a transient activation of p38MAPK;
however, the upstream signaling events are not yet known
(Häussinger et al. 1999
). Jun-kinase (JNK)
activation is found only after 60 min of hypoosmotic exposure of
perfused rat liver; however, in H4IIE hepatoma cells, c-jun
induction occurs earlier. In freshly isolated hepatocyte suspensions,
hypoosmotic and glutamine-induced activation of
phosphatidylinositol-3-kinase has been described (Krause et al. 1996
), whereas ERK activation was not detectable. The latter
may be explained by the fact that ERK are already highly preactivated
due to the cell isolation stress, which may mask the activation of
specific osmoregulated MAPK modules (Schaeffer and Weber 1999
) and the requirement of cell-cell or cell-matrix
contacts for proper osmosignaling. Indeed, osmoregulation of
proteolysis is not detectable in freshly prepared hepatocyte
suspensions, but is restored when microtubules reorganize after 24-h
cultivation of the cells (vom Dahl et al. 1995
).
ERK and p38MAPK activation is also observed when
hepatocytes swell in response to glutamine or glutamine plus glycine
(Häussinger et al. 2000
). In addition, a transient
activation of JNK occurs. In isolated hepatocytes, ERK activation is
observed in response to L-glutamine, whereas
D-glutamine is ineffective (F. Schliess and D.
Häussinger, unpublished results), and glutamine-induced ERK
activation was also shown in intestinal cells (Rhoads et al. 2000
). MAPK activation in response to glutamine addition to
perfused rat liver is shown in Figure 2
.
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Glutamine signaling and proteolysis control |
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TOPABSTRACTINTRODUCTIONGlutamine-induced hepatocyte...Cell volume sensing and...Glutamine signaling and...Glutamine signaling and biliary...CONCLUSIONSLITERATURE CITED |
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, Pösö et al. 1982
). The
antiproteolytic effect of glutamine can be explained largely by its
effect on liver cell hydration. Indeed, cell hydration is a major
determinant of hepatic proteolysis (Häussinger et al. 1991 and 1993
, vom Dahl and Häussinger 1996
) in healthy volunteers (Berneis et al. 1999
). There is a close relationship between the extent of
effector-induced hepatocyte swelling and the antiproteolytic
potency. This occurs regardless of whether cell hydration changes are
induced by anisoosmolarity, insulin, glucagon, ethanol, blockers of ion
transport, bile salts or amino acids such as glutamine, glycine or
alanine (Häussinger et al. 1991 and 1993
,
vom Dahl and Häussinger 1996
). A 1% increase of
cell water yields an inhibition of proteolysis of 2%, irrespective
of the mechanism underlying the cell hydration change. Thus,
proteolysis inhibition by glutamine and glycine can be mimicked
quantitatively by hypoosmotic swelling of liver cells. (Fig. 3
). Modulation of the swelling potency of glutamine and glycine by the
nutritional state affects their antiproteolytic effect in parallel
(vom Dahl and Häussinger 1996
). Proteolysis
inhibition by hypoosmotic or glutamine/glycine-induced cell swelling is
accompanied by a significant decrease of autophagic vacuoles in liver,
suggesting that cell volume control of proteolysis occurs at the
sequestration step of autophagic proteolysis (Häussinger et al. 1999
). Inhibition of osmosignaling toward ERK has no
effect on the antiproteolytic effect of cell swelling, whereas
inhibition of p38MAPK by the imidazole SB203580
abolishes proteolysis inhibition, but not the cell hydration increase.
The important role of p38MAPK activation for
proteolysis control by cell hydration is also underlined by the fact
that SB203580 also abolishes the effect of cell swelling on autophagic
vacuoles (Häussinger et al. 2000
). Inhibition of
proteolysis and autophagic vacuole formation by cell swelling is also
sensitive to colchicine (vom Dahl et al. 1995
), whereas
disruption of microtubules has no effect on hypoosmotic or amino
acid–induced cell swelling and p38MAPK and ERK
activation (vom Dahl et al., unpublished observation). This suggests
that microtubules are involved in the osmosignaling toward autophagic
proteolysis at a site downstream of MAPK.
|
, Ruoslahti 1996
),
abolish proteolysis control by hypoosmotic or amino acid–induced
swelling (unpublished observation). This suggests the involvement of
integrins in osmosensing and osmosignaling toward autophagic
proteolysis. Figure 4A
summarizes our current knowledge on cell volume signaling toward
proteolysis. It should be emphasized that proteolysis control also
occurs independently of cell hydration. For example, phenylalanine and
asparagine are potent inhibitors of autophagic proteolysis, but exert
little effect on liver cell hydration. Such cell volume–independent
control mechanisms are neither sensitive to colchicine nor to SB203580
and therefore involve completely different signaling pathways compared
with proteolysis control by cell hydration (Häussinger et al. 1999
, vom Dahl et al. 1995
, vom Dahl and Häussinger 1996
).
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Glutamine signaling and biliary excretion |
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TOPABSTRACTINTRODUCTIONGlutamine-induced hepatocyte...Cell volume sensing and...Glutamine signaling and...Glutamine signaling and biliary...CONCLUSIONSLITERATURE CITED |
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, Häussinger et al. (2000)
,
Meier (1995)
and Oude-Elferink et al. (1995)
]. A major site of control is the excretion of
cholephilic compounds across the canalicular membrane of the hepatocyte
by means of transport ATPases, such as conjugate export pump multidrug
resistance–associated protein (MRP)2 for transport of
glutathione and glucuronide conjugates and the bile salt export pump
(BSEP) for excretion of conjugated bile acids. Canalicular secretion by
these transporters is strongly regulated by the hepatocellular
hydration state (Häussinger et al. 1992
). Roughly,
an increase of cell water by 10% almost doubles the transport capacity
for taurocholate into bile within minutes. This occurs in a
microtubule-dependent way and is explained by the rapid insertion
of MRP2 and BSEP transporter molecules, which are stored underneath the
canalicular membrane inside the cell, into the canalicular membrane
(Kubitz et al. 1997 and 1999
, Schmitt et al. 2000, 2001
). Conversely, cell shrinkage triggers cholestasis by
a rapid retrieval of these transporters from the canalicular membrane.
Similar to hypoosmotic exposure, glutamine, at physiologically relevant
concentrations, stimulates biliary excretion due to
glutamine-induced cell swelling (Häussinger et al. 1992
). Endotoxin exerts its cholestatic effect in liver on a
short-term time scale by transporter retrieval from the canalicular
membrane (Kubitz et al. 1999
) and on a long-term
time scale by downregulation of BSEP and MRP2 expression
(Trauner et al. 1997
). Under these conditions, the
canalicular excretion of leukotriene C4 metabolites, which are MRP2
substrates, is compromised, and this phenomenon may be of relevance in
septic shock. Interestingly, hepatocyte swelling by glutamine (and also
hypoosmolarity) significantly stimulates excretion of leukotriene C4
metabolites into bile under these conditions (Wettstein et al. 1995
).
The signaling events that trigger the insertion of BSEP and MRP2 into
the canalicular membrane in response to hypoosmotic hepatocyte swelling
were studied in detail and are most likely identical to those
triggering the choleretic effect of glutamine. Inhibitor studies on the
osmosignaling toward bile formation showed that both the ERK
(Noé et al. 1996
) and the
p38MAPK pathways (Kurz, A., Graf, D., Schliess,
F. and Häussinger, D., unpublished result) are involved. Indeed,
upstream inhibition of the swelling-induced ERK (but not
p38MAPK) activation at the levels of
G-proteins, the tyrosine kinase or MAPK/ERK completely abolishes
the choleretic effect of cell swelling; this is also observed when the
p38MAPK (but not the ERK) pathway is blocked by
SB203580. Disruption of microtubules by colchicine also abolishes the
choleretic effect of hepatocyte swelling, but not the
swelling-induced MAPK activation (vom Dahl, S., Schliess, F. and
Häussinger, D., unpublished result). These findings suggest that
activation of both ERK and p38MAPK is required
for mediation of the choleretic effect, with microtubules involved
downstream of these kinases. A model consistent with the experimental
data is depicted in Figure 4
B. Obviously, the molecular
targets of ERK and p38MAPK remain to be
established and one may speculate on a convergence of both signaling
pathways on a single substrate, such as MAPK signal-integrating
protein kinase or microtubule-associated proteins.
Tauroursodesoxycholate, widely used for the treatment of cholestatic
liver disease, triggers the activation of both, ERK and
p38MAPK similar to glutamine. However, in
contrast to glutamine, it produces these effects in a
swelling-independent way (Schliess et al. 1997
). The
therapeutic potential of glutamine in cholestatic liver disease has yet
to be evaluated, but it is conceivable that its beneficial effects in
septic states are due to multiple sites of action, including an
augmentation of canalicular secretion.
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CONCLUSIONS |
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TOPABSTRACTINTRODUCTIONGlutamine-induced hepatocyte...Cell volume sensing and...Glutamine signaling and...Glutamine signaling and biliary...CONCLUSIONSLITERATURE CITED |
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FOOTNOTES |
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3 Abbreviations used: BSEP, bile salt export pump;
ECM, extracellular matrix; ERK, extracellular signal-regulated
kinase; JNK, Jun-kinase; MAPK, mitogen-activated protein kinase;
MRP, multidrug resistance–associated protein; RGD,
arginine-glycine-aspartate.
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONGlutamine-induced hepatocyte...Cell volume sensing and...Glutamine signaling and...Glutamine signaling and biliary...CONCLUSIONSLITERATURE CITED |
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