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Supplement: Arginine Metabolism: Enzymology, Nutrition, and Clinical Significance

Arginine Transport in Catabolic Disease States^1,2

Department of Surgery at the Penn State College of Medicine and the Hershey Medical Center, Hershey, PA 17033

³To whom correspondence should be addressed. E-mail: wsouba{at}psu.edu.

	ABSTRACT

TOP ABSTRACT LITERATURE CITED

 
Arginine appears to be a semiessential amino acid in humans during critical illness. Catabolic disease states such as sepsis, injury, and cancer cause an increase in arginine utilization, which exceeds body production, leading to arginine depletion. This is aggravated by the reduced nutrient intake that is associated with critical illness. Arginine depletion may have negative consequences on tissue function under these circumstances. Nutritional regimens containing arginine have been shown to improve nitrogen balance and lymphocyte function, and stimulate arginine transport in the liver. We have studied the effects of stress mediators on arginine transport in vascular endothelium, liver, and gut epithelium. In vascular endothelium, endotoxin stimulates arginine uptake, an effect that is mediated by the cytokine tumor necrosis factor- (TNF-) and by the cyclo-oxygenase pathway. This TNF- stimulation involves the activation of intracellular protein kinase C (PKC). A significant increase in hepatic arginine transport activity also occurs following burn injury and in rats with progressive malignant disease. Surgical removal of the growing tumor results in a normalization of the accelerated hepatic arginine transport within days. Chronic metabolic acidosis and sepsis individually augment intestinal arginine transport in rats and Caco-2 cell culture. PKC and mitogen-activated protein kinases are involved in mediating the sepsis/acidosis stimulation of arginine transport. Understanding the regulation of plasma membrane arginine transport will enhance our knowledge of nutrition and metabolism in seriously ill patients and may lead to the design of improved nutritional support formulas.

KEY WORDS: • arginine • membrane transport • catabolism

The transport of amino acids across the plasma membrane of mammalian cells has come to be appreciated in recent years as less of a passive, constitutive event and more as a dynamic, tissue-specific adaptive process with the potential for regulatory control of organ substrate utilization and inter organ metabolic flows. It is well established that amino acids in the extracellular space bind to membrane bound carrier proteins that act to "transport" the substrate into the cytoplasm. This event (bind-translocate-release-reposition-bind again) is thought to occur extremely rapidly and with considerable precision and specificity. Distinct hepatic amino acid transport systems have been identified on the basis of amino acid selectivities and physicochemical properties (1) and, more recently, molecular tools. The recent success in cloning the genes that encode for a number of these amino acid plasma membrane transporter proteins has substantially improved our ability to study regulation of amino acid transport at the molecular level. Each system presumably relates to a discrete, putative, membrane-bound transporter protein.

In the world of amino acids, the dibasic, cationic, amino acid L-arginine plays a multitude of diverse and sometimes unique roles (2). Arginine’s importance in overall nitrogen metabolism is highlighted by its key position as an intermediate in the urea cycle and its significance in amino acid biosynthesis. All tissues require arginine for cytoplasmic protein biosynthesis. Interest in the regulation of arginine metabolism increased several years ago when its exclusive role as the precursor in nitric oxide (NO)⁴ biosynthesis was identified (3). This observation has led to a number of studies that have attempted to define how arginine transport and NO biosynthesis are controlled and how arginine transport is altered by catabolic disease states.

L-arginine is considered semiessential in the mammalian diet. The requirement for dietary arginine in catabolic disease states such as starvation, injury, or sepsis becomes more apparent when the various roles of arginine in metabolism are considered. The purpose of this article is to provide a review of how plasma membrane arginine transport is regulated during catabolic stress states such as trauma, infection, inflammation, and cancer. The focus will be on the liver, vascular endothelium, and gut epithelium, 3 tissues that occupy important roles in arginine homeostasis.

Arginine transport in vascular endothelium

Endothelial arginine transport has been characterized in rat pulmonary artery endothelial cells, porcine, and bovine aortic endothelial cells (4–7). Seventy percent of the arginine uptake in rat pulmonary artery endothelial cells occurred via a carrier-mediated Na⁺-independent process (System y⁺) with the remainder contributed largely by the Na⁺-dependent carrier System B^0,+.

Subsequent studies were designed to test the hypothesis that endotoxin stimulates carrier-mediated arginine transport by the pulmonary endothelium, as a mechanism of ensuring adequate delivery of arginine during sepsis when decreased circulating arginine levels are diminished (8). Endotoxin stimulated y⁺-mediated arginine transport 2-fold to 5-fold, a response that was time and dose dependent. The accelerated transport was detectable within 2 h and maximal at 12 h. Kinetic studies revealed that the accelerated arginine transport was the result of a 70% increase in the maximal transport velocity without a significant change in transport affinity. The endotoxin-mediated increase in arginine uptake was abrogated by actinomycin D and cycloheximide.

To further investigate these observations, Cendan et al. (9) hypothesized that lipopolysaccharide stimulation of plasma membrane L-arginine transport is mediated via an autocrine cytokine loop involving tumor necrosis factor- (TNF-) and interleukin-1 (IL-1). Confluent endothelial cells with various concentrations of lipopolysaccharide (LPS), TNF-, or IL-1 and arginine uptake was determined by assaying the uptake of ³H-L-arginine at different time points. Cells were also incubated with lipopolysaccharide or saline solution after pretreatment with either anti-TNF- antibody or IL-1-receptor antagonist. The investigators reported that LPS, IL-1, and TNF- all increased both Na⁺-dependent and Na⁺-independent carrier-mediated L-arginine transport in a fashion that was both time and dose dependent. Maximal increases in stimulated arginine uptake occurred 8 h after exposure to the cytokines and 12 h after exposure to lipopolysaccharide. Pretreatment of endothelial cells with anti-TNF- antibody blocked LPS stimulation of both Na⁺-independent and Na⁺-dependent transport. In addition, IL-1-receptor antagonist inhibited LPS stimulation of both Na⁺-independent and Na⁺-dependent transport. The marked increase in carrier-mediated L-arginine transport activity produced by LPS, IL-1, and TNF- may represent an adaptive response by the pulmonary endothelium to support arginine-dependent biosynthetic pathways during sepsis. It appears that endotoxin stimulation of arginine transport is mediated in part through an autocrine mechanism involving IL-1 and TNF-.

Similar observations were made in a human endothelial cell line (10–12). In confluent human umbilical vein endothelial cells, arginine transport is mediated by 2 Na⁺-independent transporters, System y⁺ (80% of total transport) and System b^0,+ (20% of transport). TNF- increased System y⁺-mediated arginine transport in a time- and dose-dependent manner by augmenting System y⁺ transport maximal capacity more than 2-fold without affecting transporter affinity. This TNF--mediated augmentation of arginine transport required the activation of the intracellular messenger intracellular protein kinase C (PKC) (12).

Arginine transport in liver

Because of its central role in amino acid metabolism, the liver has been a focus of investigation with respect to amino acid transport and arginine has been no exception. The availability of the extracellular arginine pool to the hepatocyte is restricted to a large degree in the liver as a result of a low plasma membrane transport activity, which forms a kinetic barrier between extracellular arginine and the cytoplasmic space.

Inoue and colleagues (13) were among the first to characterize plasma membrane arginine transport in hepatic plasma membrane vesicles (HPMVs) and in hepatocytes isolated and cultured from human liver biopsy specimens. They also studied the effects of the NO synthase inhibitors -nitro-L-arginine methyl ester (L-NAME) and N-methylarginine on arginine transport in HPMVs and in cultured cells. Kinetic and inhibition studies indicated that arginine transport by human hepatocytes is mediated primarily by the Na⁺-independent transport System y⁺. Arginine transport by both vesicles and cultured hepatocytes was significantly attenuated by NO synthase inhibitors, suggesting that the arginine transporter and the NO synthase enzyme may share a structurally similar arginine binding site. Treatment of rats with LPS resulted in a 2-fold stimulation of saturable arginine transport in the liver (14). This LPS-induced hepatic arginine transport activity was also inhibited by L-NAME. Thus, besides inhibition of the NO synthase enzyme, the ability of arginine derivatives to block NO production may also be due to their ability to competitively inhibit arginine transport across the hepatocyte plasma membrane.

Inoue and colleagues (14,15) also examined the effects of endotoxin on the activities of the other major Na⁺-independent amino acid transporters in rat liver using HPMVs. The use of vesicles offers the advantage of being able to discriminate membrane transport activity clearly from other confounding influences such as intracellular metabolism. Further, vesicles allow the examination of alterations of transport activity as they occurred under in vivo conditions, because such changes are adequately preserved during the preparation of vesicles. Rats were treated with a single dose of endotoxin and HPMVs were prepared by Percoll density gradient centrifugation at various timepoints after LPS administration. The activities of the Na⁺-independent amino acid transport Systems y⁺ and b^o,+ (arginine), asc (alanine and cysteine), L (leucine), and n (glutamine) were evaluated by measuring the uptake of radiolabeled amino acids using a rapid mixing/filtration technique. Interestingly, endotoxin administration did not alter the activities of Systems n, asc, or L but resulted in a time- and dose-dependent stimulation of saturable arginine transport. Arginine transport increased within 2 h of LPS administration and exhibited a return towards basal levels by 24 h. The augmented transport activity was due to a 73% increase in the V_max of the low affinity carrier (System y⁺, CAT-2A) and a 25% increase in the V_max of the high affinity transporter (System b^o,+). While the physiologic significance of an increase in the low affinity transporter is unclear, the data indicate selective stimulation of Na⁺-independent arginine transport in the liver during endotoxemia, which may serve to support important arginine-dependent pathways during sepsis.

As a consequence of the Inoue study (15), Pacitti et al. (16) postulated that cytokines play a role in mediating arginine availability to the hepatocyte intracellular space during a septic insult by influencing transport activity at the plasma membrane level. They examined the effect of TNF- on the activity of hepatic arginine transport employing HPMVs. In vivo treatment with a single injection of TNF- resulted in a stimulation of saturable, Na⁺-independent, System y⁺-mediated arginine transport activity in the liver in a time- and dose-dependent fashion. Whether TNF- stimulates System y⁺-mediated transport directly or indirectly was unclear from the data. While the source of arginine precursor to support sepsis-induced NO synthesis in the liver is debatable, when one considers the very low levels of hepatic intracellular arginine, one might postulate, based on the results of this work, that circulating arginine is used in part for NO biosynthesis. This TNF--induced stimulation of hepatic arginine transport may serve to increase the normally restricted availability of extrahepatic arginine to the hepatocyte intracellular space during a septic insult to support important arginine-dependent pathways in the liver.

Watkins and associates made similar observations in rats receiving prostaglandin E₂ (PGE₂), an important by-product of the cyclo-oxygenase pathway (17). Treatment of rats with a single dose of PGE₂ resulted in a 50% increase in system y⁺ activity in the liver, again due to an increase in transporter V_max. This observation may be important because endotoxin and cytokines have been shown to increase PGE₂ production by macrophages and endothelial cells. Thus, local production of PGE₂ by Kupffer cells or sinusoidal cells in the liver may play a key role in regulating System y⁺ activity.

Similarly, burn injury causes a marked induction in hepatic arginine transport, the magnitude of which is dependent on burn size and is temporally variable. Both Systems y⁺ and B^o,+ contributed to this enhancement of arginine uptake after burn injury, and the accelerated hepatic arginine transport that occurs after burn injury was mediated, at least in part, by the cytokine TNF- (18). This burn-induced increase in arginine transport establishes a link between enhanced transmembrane uptake and accelerated intracellular arginine metabolism via NO synthase.

Studies in a more chronic catabolic model, the sarcoma-bearing rat model, have also demonstrated an increase in arginine uptake by the liver. In rats implanted subcutaneously with fibrosarcomas allowed to grow to different sizes before sacrifice, arginine uptake by HPMVs was mediated by saturable carrier-mediated System y⁺ and passive diffusion (19). The presence of the growing tumor resulted in a 40–120% increase in System y⁺-mediated arginine transport activity in HPMVs with no significant changes in passive diffusion. This increase of arginine transport activity was dependent on tumor size and was due to a stimulation of carrier maximal velocity (V_max) and a consistent transport affinity (K_m), suggesting an increase in the number of functional System y⁺ carriers in the hepatocyte plasma membranes. This accelerated transport may amplify the availability of arginine to support key arginine-dependent metabolic pathways in the hepatocyte. Following resection of the tumor, hepatic arginine transport normalized within 3 days (20).

Arginine has been proposed as a dietary supplement that may be of benefit to certain groups of critically ill patients. Espat and colleagues (21) hypothesized that feeding supradietary amounts of arginine would enhance carrier-mediated transmembrane transport in the liver. Surgical patients (n = 8) and rats (n = 6) were fed one of 3 diets: a regular diet, an enteral liquid diet supplemented with arginine and glutamine or an enteral diet supplemented with pharmacologic amounts of glutamine and arginine. Diets were isocaloric and were administered for 3 d. Hepatic plasma membrane vesicles were prepared from rat liver and from human wedge biopsies obtained at laparotomy. Provision of both a standard enteral liquid diet and one enriched with glutamine and arginine increased the activities of Systems N and n (glutamine) and y⁺ (arginine) in rat and human liver compared to a control diet. The diet supplemented with glutamine and arginine was the most effective in increasing transport activity, indicating that the liver responds to diets enriched with specific amino acids by increasing membrane transport activity. The study could provide a biochemical rationale for the use of formulas that are enriched with conditionally essential nutrients.

Arginine transport in gut epithelium

The intestinal epithelium plays a central role in maintaining the arginine homeostasis by providing exogenous arginine into the system. Arginine, transported into the epithelium from the intestinal lumen, is either metabolized inside the epithelium or transported across the basolateral membrane into circulation as metabolites or free arginine. Changes of the intestinal epithelial brush border membrane arginine transport activity reflect the status of both local enterocyte’s arginine metabolism as well as whole organ system arginine metabolism.

Animal studies showed that arginine was predominantly transported across the intestinal membrane via a Na⁺-independent System y⁺ [CAT-1, (22–24)]. Pan et al. (25) further investigated the arginine transport systems in a well-controlled cell culture environment using differentiating intestinal epithelial Caco-2 cell line. Similar to the in vivo studies, arginine was transported largely via the Na⁺-independent transport Systems y⁺ (70%) and b^o,+, or y⁺L (D4/NBAT/4F2hc, 30%) in both undifferentiated and differentiated states. Cell differentiation downregulated the arginine transport activity by several folds without changing the relative contribution of each transport system (25). Phorbol ester activation of PKC stimulated arginine transport in both undifferentiated and differentiated Caco-2 cells via a mechanism of activating transporter mRNA and translational processes (26). This PKC-activation of arginine transport in Caco-2 cells involved the mitogen-activated protein kinase (MAPK) pathways (27). Increased arginine transport was also observed in nitric oxide producing metastatic colon cancer line as compared to its primary colon cancer counterpart (28), indicating the possible link between arginine transport and the nitric oxide production.

The intestinal epithelium is continuously exposed to dietary components, metabolic by-product, bacteria, and associated products (endotoxin), and inflammatory mediators (cytokines) from both the intestinal lumen and circulation. Arginine transport in the intestinal epithelium is regulated by various local and systemic factors. The presence of extracellular arginine specifically and reversibly stimulated arginine transport activity in a time- and dose-dependent fashion in cultured Caco-2 cells (29). Only the amino acids that share the same arginine transport systems stimulated the arginine transport activity while the amino acids that are transported by other amino acid transport systems did not have any effect on the arginine transport. The increase of both kinetic parameters—maximal transport capacity (Vmax) and transport affinity (K_m)—indicated that this stimulation was consistent with a trans-stimulation mechanism. Unlike sugar and other neutral amino acid transport systems, prolonged extracellular arginine exposure did not result in synthesis of new transporter units, suggesting that the rate of maximal arginine transport is constitutively regulated.

Increased intestinal epithelial metabolism, protein synthesis, and proliferation have been reported in catabolic states (30,31). Recent studies performed in the authors’ lab showed that the total arginine transport across rat jejunal brush border membrane increased nearly 5-fold in rats with intraabdominal abscess caused by bacteria implants, compared to rats under sham laparotomy and sterile implants (unpublished results). Similar stimulation of arginine transport was observed in cultured intestinal epithelial Caco-2 cells exposed to septic mediators such as lipopolysaccharide and interferon- (32).

Epler et al. examined the effects of chronic extracellular acidosis on the activity of arginine transport in the cultured intestinal Caco-2 cells. Chronic extracellular acidosis (>6 h) resulted in a 4-fold increase of arginine transport activity and a 3-fold increase of arginine transporter CAT-1 mRNA levels (unpublished results, M. J. Epler, W. W. Souba, E. M. Copeland & D. S. Lind, 2003). This acidosis-induced arginine transport activity increase was due to an increase of transporter maximal transport capacity rather than a change of transporter affinity (K_m). This acidosis-stimulated arginine transport was individually blocked by actinomycin-D and cycloheximide, suggesting the involvement of transcription and de novo protein synthesis. Furthermore, the nitric oxide synthase inhibitor L-NAME inhibited this acidosis-stimulated arginine transport activity, linking the induced arginine transport activity to nitric oxide synthesis. Choudry et al. further identified protein kinase C and MAPK ERK1 as the intracellular signaling mediators involved in this acidosis-induced stimulation of arginine transport in Caco-2 cells (unpublished results, H. Choudry, Q. Meng, A. M. Karinch, C. Lin, W. W. Souba, & M. Pan, 2004). Similar stimulation of arginine transport across the rat jejunal brush border membrane was observed in acidotic rats (unpublished results, M. Pan et al., 2003). Unlike in Caco-2 cells, chronic acidosis downregulated the individual arginine transport Systems y⁺, y⁺L, and b^0,+ activities in proliferating rat crypt IEC-6 cells (unpublished results, Choudry Q. Meng, A. M. Karinch, C. Lin, W. W. Souba, & M. Pan, 2004).

Summary

Marked changes of arginine transport and metabolism in vascular endothelium, liver, and intestine occur in a wide variety of catabolic states: sepsis, burn injury, acidosis, and cancer. The increase in membrane arginine transport activity in these organs may reflect an increased arginine requirement in critical illness. An increase in arginine transport provides additional arginine to support key intracellular pathways such as nitric oxide biosynthesis and those involved in immune function. Under these circumstances, plasma arginine availability may become rate limiting. Exogenous arginine administration, either through enteral tract or total parental nutrition, may be beneficial in selected circumstances.

	FOOTNOTES

 
¹ Prepared for the conference "Symposium on Arginine" held April 5–6, 2004 in Bermuda. The conference was sponsored in part by an educational grant from Ajinomoto USA, Inc. Conference proceedings are published as a supplement to The Journal of Nutrition. Guest Editors for the supplement were Sidney M. Morris, Jr., Joseph Loscalzo, Dennis Bier, and Wiley W. Souba.

² This work was supported in part by Society for Surgery of Alimentary Tract Career Development grant (M.P), National Institute of Diabetes and Digestive and Kidney Disease grant K08DK-62165 (M.P), and National Institute of General Medical Sciences grant T32GM64332 (W.W.S).

⁴ Abbreviations used: HPMV, hepatic plasma membrane vesicle; IL-1, interleukin-1; L-NAME, -nitro-L-arginine methyl ester; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; NO, nitric oxide; PGE₂, prostaglandin E₂; PKC, protein kinase C; TNF-, tumor necrosis factor-.

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