Department of Biochemistry, Memorial University of Newfoundland, St. John's, Newfoundland, Canada A1B 3X9
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ABSTRACT |
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The rates of oxidation of arginine and ornithine that
occurred through a reaction pathway involving the enzyme ornithine
aminotransferase (EC 2.6.1.13) were determined using
14C-labeled amino acids in the isolated nonrecirculating
perfused rat liver. At physiological concentrations of these amino
acids, their catabolism is subject to chronic regulation by the level of protein consumed in the diet. 14CO2
production from [U-14C]ornithine (0.1 mM) and
from [U-14C]arginine (0.2 mM) was increased
about fourfold in livers from rats fed 60% casein diets for 3-4
days. The catabolism of arginine in the perfused rat liver, but not
that of ornithine, is subject to acute regulation by glucagon
(107 M), which stimulated arginine
catabolism by ~40%. Dibutyryl cAMP (0.1 mM) activated arginine
catabolism to a similar extent. In retrograde perfusions, glucagon
caused a twofold increase in the rate of arginine catabolism,
suggesting an effect of glucagon on arginase in the perivenous cells.
hepatic zonation; high-protein diet; antegrade and retrograde perfusion
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INTRODUCTION |
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ARGININE OCCUPIES A CENTRAL role in intermediary metabolism. In addition to its involvement in protein synthesis, it is an intermediate in the urea cycle and is required for the production of nitric oxide (13), creatine, polyamines, and agmatine (23). In most mammals, arginine arises from two principal sources, endogenous de novo production (43, 11) and the exogenous supply of this amino acid in the diet. In early studies, it has been stated that the definition of arginine as "essential" or "nonessential" depends on the species in question as well as the developmental stage under investigation (8). The term "conditionally essential" has since been coined (6) and is frequently used when describing the nutritional requirement for arginine. Thus, under certain physiological and pathophysiological conditions, endogenous production does not occur at a rate commensurate with optimum growth or recovery from disease. This has been borne out in studies that demonstrate the beneficial effects on immune function of supplying supradietary amounts of arginine (1) and recovery from trauma in rats (33). These studies have prompted debate as to whether the current criteria for assessing arginine requirements are appropriate (39).
The mechanisms that regulate whole body arginine levels have not been characterized in great detail. Arginine balance is a function of the supply of this amino acid relative to its utilization. Our own studies on rats (9) show that endogenous renal arginine synthesis is unaffected by dietary arginine. Studies in humans (4, 5) demonstrate that, under conditions in which dietary arginine is restricted, the body reduces the rate of oxidative catabolism of this amino acid. This homeostatic mechanism serves to spare arginine for its participation in the various metabolic pathways. In these experiments, there is no alteration in the rate of de novo synthesis of arginine. Both our own group (9) and Castillo and co-workers (4, 5) have made the case for a better characterization of the regulation of the catabolism of this amino acid within specific organs.
Rat liver contains all the enzymes necessary for the complete oxidation of arginine to CO2 (26). This pathway also accomplishes ornithine catabolism. The importance of ornithine aminotransferase (OAT, EC 2.6.1.13) is demonstrated in humans by the genetic disorder known as "gyrate atrophy." OAT activity is diminished, and there is an associated increase in the circulating levels of ornithine (38) that can be decreased by restricting dietary arginine. Also, in adult mice in which the OAT gene has been inactivated, there is a marked increase in tissue ornithine concentrations (40). With respect to other possible routes of utilization, it should be emphasized that the urea cycle is not a route for the oxidation of these amino acids, because, as a cycle, it produces one molecule of ornithine for every one of arginine. Neither nitric oxide synthesis (41) nor polyamine production (34) consumes a significant amount of these substrates in the normal rat liver on a daily basis; therefore, we regard catabolism via OAT as the major route for the oxidation of these amino acids in the rat liver.
The concept of zonation of hepatic metabolism is well established (21, 30) and is of particular importance in nitrogen metabolism (18). With regard to arginine catabolism, it is clear that hepatic ornithine aminotransferase is limited to a population of hepatocytes surrounding the hepatic vein (22). We have shown by means of retrograde perfusions that these cells also contain an arginase that permits the entire catabolism of arginine in these cells (26).
Regulation by dietary and hormonal factors is a common feature of mammalian amino acid metabolism, with responses to these stimuli ranging in time from days (chronic adaptation) to minutes (acute regulation). Schimke (32) clearly demonstrated the chronic regulation of the enzymes of the urea cycle with alterations in the level of dietary protein in rats. Feeding rats a high-protein diet for four days is known to increase circulating levels of glucagon in plasma (28) more than threefold. Treatment of isolated hepatocytes with glucagon is known to stimulate the glycine cleavage system (20), glutaminase (36), and phenylalanine oxidation (12). The principal focus of this investigation is to determine whether the catabolism of arginine and ornithine in the perfused rat liver is subject to long-term regulation by the level of dietary protein and/or acute regulation by glucagon.
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MATERIALS AND METHODS |
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Animals. Male Sprague-Dawley rats (240-350 g), purchased from Charles River (Montreal, Canada), were used. They were provided with free access to water and to purified diets for 3-4 days before the experiment. The diets contained either 15% (wt/wt) casein (normal protein diet) or 60% (wt/wt) casein (high-protein diet). Rarely, an animal ate the 60% diet poorly and gained little weight; such animals (~2% of total) were excluded from the study. Gabaculine, an OAT inhibitor, was administered at a level of 50 mg/kg body wt by intraperitoneal injection 2 h before the experiment. All animals were maintained under a controlled 12:12-h light-dark cycle. Before perfusion, rats were anesthetized with pentobarbital sodium (60 mg/kg ip). All protocols involving the use of animals were approved by the Institutional Animal Care Committee at Memorial University and were in accord with the Guidelines of the Canadian Council on Animal Care.
Diets. Modified AIN 76 diets were used (3). The high-protein (60% casein) diet contained the following ingredients (in g/100 g of diet): casein, 59.8; L-methionine, 0.15; cornstarch, 6.1; sucrose, 19.2; corn oil (Mazola), 5; vitamin mix (AIN 76), 1.0; mineral mix (AIN 76), 3.5; Alphacel, 5; choline bitartate, 0.2. In the case of the normal protein (15% casein) diet, casein was decreased to 14.8 g/100 g of diet, and sucrose and cornstarch were increased to 53.3 and 17 g/100 g, respectively. Thus both diets were isocaloric.
Perfusion procedures.
Nonrecirculating perfusions of rat livers were carried out according to
the method of Sies (35). Krebs-Henseleit medium (pH 7.4),
gassed with O2-CO2 (19:1) with added lactate
and pyruvate (2.1 and 0.3 mM, respectively), served as the basic
perfusion medium. The flow rate was maintained at ~4.0
ml · min1 · g
liver
1. [U-14C]arginine and
[U-14C]ornithine were added at various
concentrations at the times indicated in RESULTS, and the
production of 14CO2 was determined in the
effluent. When the effect of glucagon was investigated, it was
dissolved in 10 mM HCl and infused at a rate sufficient to give a final
concentration in the influent perfusate of
10
7 M. In control experiments, the
vehicle (HCl) was infused. The rate of infusion was such that no change
in pH or PCO2 was discernible. When
used, dibutyryl cAMP at a concentration of 0.1 mM was added to the
perfusion medium, whereas control experiments contained butyrate (0.1 mM). To ensure that livers were viable throughout the
procedure, oxygen consumption, perfusate
(PCO2), and pH were monitored by
means of a blood gas analyzer (model 238, Ciba Corning, Bayer, Toronto,
ON, Canada). Oxygen consumption was ~2.5
µmol · min
1 · g
liver
1, and this increased by ~15% on
infusion with glucagon. Retrograde perfusions were carried out
according to methods developed by Häussinger (17). An initial
sample of each influent medium was taken. Effluent samples were
collected at 5-min intervals after that. Samples for
14CO2 analysis were taken under mineral oil.
Measurement of 14CO2 production. Twenty-five-millimeter Erlenmeyer flasks containing 0.4 ml of 1 N HCl were fitted with center wells containing filter paper and 0.4 ml of neutrophil chemotactic factor tissue solubilizer (Amersham Canada, Oakville, Ontario, Canada) and stoppered. Into each flask, 5 ml of perfusate were injected through the stopper. The flasks were incubated in a shaking water bath at 37°C for 1 h to ensure that all of the evolved CO2 would be trapped in the center wells. The center wells were transferred to scintillation vials containing 10 ml of scintillation fluid and counted. Medium blanks were prepared to ensure that no preformed 14CO2 was present in the radioactive compounds.
OAT assay and protein determination. OAT was assayed as described by Herzfeld and Knox (19). Protein concentration was determined using the Biuret method (14), after solubilization with deoxycholate and with BSA as standard.
Chemicals. [U-14C]arginine (specific activity 320 mCi/mmol) and [U-14C]ornithine (specific activity 257 mCi/mmol) were purchased from Mandel Scientific, Guelph, Ontario, Canada. Gabaculine (3-amino-2,3 dihydrobenzoate), ortho-aminobenzaldehyde, and dibutyryl cAMP were purchased from Sigma Chemical (St. Louis, MO). All reagents used in the study were of analytical grade. Diet components were purchased from ICN (Cleveland, OH), except for the L-methionine and cornstarch, which were obtained from Sigma. Scintillation fluids were purchased from Fisher Scientific (Nepean, Canada).
Calculations and presentation of data. Results are reported as means ± SD. The GraphPad computer program (GraphPad Software, San Diego, CA) was used to calculate kinetic parameters. Comparisons of data were made using Student's unpaired and paired t-tests, as appropriate, with P < 0.05 taken as indicating a statistically significant difference.
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RESULTS AND DISCUSSION |
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Characterization of processes of arginine and ornithine catabolism.
We decided to compare arginine and ornithine metabolism in livers from
animals fed a high-protein diet (60% casein) with that in livers from
animals fed a normal protein diet (15% casein) to examine the effects
of a substantial difference in protein intake. The food consumption of
rats on both these diets was similar (~5
g · day1 · 100 g body wt
1). Because the arginine
content of bovine casein is 3.7 g/100 g, we can calculate a daily
dietary arginine intake of ~55 mg/100 g body wt in the rats fed the
15% casein diet, which increased fourfold in the animals fed the 60%
casein diet. Ornithine is not a constituent of casein. Plasma levels of
arginine and ornithine were measured in rats fed on 15, 30, or 60%
casein diets for 3 days. The ornithine levels were 25.4 ± 2.5, 22.8 ± 3.4, and 29.4 ± 3.7 nmol/ml, respectively, for the animals fed
the 15, 30, and 60% casein diets and were not significantly different
from each other. The corresponding levels of plasma arginine were 56.2 ± 2.1, 59.3 ± 5.5, and 75.9 ± 8.1, with the concentration on the 60% casein diet being significantly increased (P < 0.05).
The increased plasma arginine will be experienced by the islets and this may contribute to increased glucagon secretion.
Chronic adaptation to varying dietary protein.
The effect of dietary protein on ornithine catabolism was determined in
perfused livers from rats which were fed either the normal protein diet
(15% casein) or the high-protein diet (60% casein) for a period of
3-4 days. Figure 1 shows that, at
physiological portal vein concentrations of ornithine (0.1 mM), the
livers from rats fed the high-protein diet catabolize ornithine at a
rate fourfold greater than those from rats fed a normal protein diet (63.6 ± 22.6 vs. 14.4 ± 5.3 nmol
CO2 · min1 · g
wet liver
1 at the 29-min time point).
Figure 2 demonstrates that the oxidative catabolism of arginine (0.2 mM) also increases with increasing dietary
protein about fivefold (13.8 ± 4.9 vs. 74.5 ± 22.5 nmol CO2 · min
1 · g
wet liver
1 at the 29-min time point).
The marked stimulation in the rates of arginine and ornithine
catabolism observed upon feeding rats a high-protein diet could occur
as a result of either enzyme or transporter induction. For example, it
is known that both OAT (29) and the irreversible enzyme
1-pyrroline-5-carboxylate dehydrogenase (24) are induced in rat liver
under conditions of high dietary protein. In this study, the OAT
activities in livers from rats fed normal protein and high-protein
diets were found to be 4.12 ± 0.76 and 17.32 ± 3.45 µmol · min
1 · g
liver protein
1, respectively. The relatively low
clearance of the cationic amino acids during a single circulatory pass
of the liver (27) is thought to be due to the rather low activity of
the high-capacity low-affinity y+ transporter (42) recently
characterized as the MCAT2A transporter (7). Regulation of this
transporter may also be an effective means of increasing flux through
the catabolic process. It is possible that the raised circulating
levels of glucagon observed in rats fed a high-protein diet may be
responsible for such an alteration, as Handlogten and Kilberg (16)
demonstrated that intraperitoneal administration of glucagon to rats
stimulates y+ transporter activity in isolated rat
hepatocytes. Increased dietary supply of amino acids such as arginine
and glutamine over a 3-day period has been shown to increase
y+ transporter activity as much as fourfold (10).
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Acute regulation by glucagon infusion.
The short-term effect of a glucagon infusion was investigated (Fig.
3). A typical experiment on ornithine
catabolism (0.1 mM) shows that the infusion of glucagon does not alter
the rate of CO2 production from this amino acid (Fig.
3A), whereas it stimulates arginine catabolism (Fig.
3B). We carried out four such experiments with ornithine or
arginine and analyzed them statistically by comparing the values at 39 min (before glucagon infusion) with those at 60 min. In the ornithine
experiments, the results were 94.4 ± 25.3 nmol · min1 · g
liver
1 at 39 min and 96.1 ± 29.5 nmol · min
1 · g
liver
1 at 60 min (not significant). In
the arginine experiments the results were 64.9 ± 15.3 nmol · min
1 · g
liver
1 at 39 min and 92.6 ± 24.5 nmol · min
1 · g
liver
1 at 60 min (P < 0.05). Control experiments in which the glucagon vehicle alone
was infused demonstrated no changes. We also carried out a series of
experiments in livers from gabaculine-treated rats that were perfused
with 0.2 mM arginine. We measured ornithine production in the perfusate
effluent. In the control experiments, in which saline was infused from
39 to 60 min, ornithine production was unchanged (63.1 ± 7.0 nmol · min
1 · g
liver
1 at 39 min compared with 64.0 ± 8.5 nmol · min
1 · g
liver
1 at 60 min; n = 4).
However, when glucagon (10
7 M) was
infused from 39 to 60 min, there was a significant increase in
ornithine production (P < 0.05) with 72.6 ± 31.8 nmol · min
1 · g
liver
1 at 39 min and 116.2 ± 30.3 nmol · min
1 · g
liver
1 at 60 min. This experiment
confirms that glucagon stimulates arginine catabolism at a site before
ornithine aminotransferase.
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Localization of the glucagon effect on the catabolism of arginine.
In vivo, rat liver is supplied with blood from the portal vein and the
hepatic artery; this blood then flows through the liver and leaves
through the central vein. The cells surrounding the portal inflow are
known as periportal cells, and those surrounding the central vein are
called perivenous cells (30). Previous studies carried out in our
laboratory (26) involving retrograde perfusions have shown that the
processes of arginine and ornithine catabolism in the rat liver can be
carried out in their entirety in the cells of the perivenous region
and, therefore, that an arginase must exist in those cells. Our next
experiments were designed to determine whether glucagon's effect on
hepatic arginine catabolism was occurring in the perivenous region or
whether glucagon was exerting an effect in the upstream periportal
region that could then be communicated to the downstream perivenous
region. In the perfusions described so far, the direction of perfusion has been in the physiological antegrade direction (i.e., from the
periportal to the perivenous regions). It is, however, possible to
perfuse from the perivenous to the periportal regions [retrograde perfusion (17)]. If glucagon must first exert an effect in the cells of the periportal region, there will be no stimulation of arginine's catabolism by glucagon in a retrograde perfusion, because the signal will occur after this catabolic process. Figure
5 shows that infusion of glucagon
stimulates the production of CO2 from arginine in the
perfusions carried out in the retrograde direction. The data
demonstrate a marked increase in the rate of CO2 production from arginine. We carried out four such experiments and analyzed them
statistically. The mean rate of 14CO2
production was 41.9 ± 23.0 nmol · min1 · g
liver
1 at 29 min (before glucagon was
infused) and 74.5 ± 23.3 nmol · min
1 · g
liver
1 at 49 min. Five minutes of
exposure to glucagon was sufficient to produce a significantly
different rate of CO2 production (P < 0.05) as
determined by Student's paired t-test. Control experiments, in
which the vehicle was infused, produced no alteration in the rate of
catabolism of arginine (data not shown); thus glucagon can stimulate
perivenous cells to give an enhanced rate of catabolism of the amino
acid arginine. Because perivenous cells are well supplied with glucagon
receptors (2), the most likely mechanism would be a direct effect of
glucagon on these cells that results in arginase stimulation. However,
we cannot exclude the possibility that glucagon may act on periportal
cells that may transmit signals to the perivenous cells via gap
junctions. It has been shown that two forms of arginase are present in
rat liver, A1 and A2. A1 is known
to be present in the periportal cells, where it functions in the urea
cycle. Recently, the A2 form has been demonstrated in human
and mouse liver (15, 25); however, the specific location of this enzyme
within the liver is not known. We suggest, as discussed previously
(26), that this arginase is likely to function in the catabolism of
arginine in the perivenous region, and it is possible that this enzyme
is subject to acute regulation by glucagon in vivo. This requires
further investigation.
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ACKNOWLEDGEMENTS |
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Dan O'Sullivan thanks the School of Graduate Studies, Memorial University of Newfoundland, for a graduate fellowship. Technical assistance provided by B. Hall is gratefully acknowledged.
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FOOTNOTES |
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This work was supported by grants from the Medical Research Council of Canada.
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. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: M. Brosnan, Department of Biochemistry, Memorial University of Newfoundland, St. John's, Newfoundland, Canada A1B 3X9 (E-mail:mbrosnan{at}morgan.ucs.mun.ca).
Received 14 December 1998; accepted in final form 25 October 1999.
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