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. 2013 Jan 14;94(1):47–55. doi: 10.1111/iep.12002

Changes in liver gluconeogenesis during the development of Walker-256 tumour in rats

Carolina Campos Lima Moreira *, Priscila Cassolla *, Ana Paula Segantini Dornellas *, Hely Morais *, Camila Oliveira Souza *, Glaucia Regina Borba-Murad *, Roberto Barbosa Bazotte †, Helenir Medri Souza *
PMCID: PMC3575873  PMID: 23317353

Abstract

Few studies have investigated liver gluconeogenesis in cancer and there is no agreement as to whether the activity of this pathway is increased or decreased in this disease. The aim of this study was to evaluate gluconeogenesis from alanine, pyruvate and glycerol, and related metabolic parameters in perfused liver from Walker-256 tumour-bearing rats on days 5 (WK5 group), 8 (WK8 group) and 12 (WK12 group) of tumour development. There was reduction (P < 0.05) of liver glucose production from alanine and pyruvate in WK5, WK8 and WK12 groups, which was accompanied by a decrease (P < 0.05) in oxygen consumption. Moreover, there was higher (P < 0.05) pyruvate and lactate production from alanine in the WK5 group and a marked reduction (P < 0.05) of pyruvate and urea production from alanine in the WK12 group. In addition, liver glucose production and oxygen consumption from glycerol were not reduced in WK5, WK8 and WK12 groups. Thus the, the results show inhibition of hepatic gluconeogenesis from alanine and pyruvate, but not from glycerol, on days 5, 8 and 12 of Walker-256 tumour development, which can be attributed to the metabolic step in which the substrate enters the gluconeogenic pathway.

Keywords: alanine, cancer, gluconeogenesis, glycerol, liver perfusion, pyruvate, Walker-256 tumour

Cancer is a disease characterized by marked weight loss (cachexia) and by various metabolic abnormalities, caused by several factors produced by the tumour and the tissues of the tumour-bearing (Bennani-Baiti & Davis 2008; Tisdale 2008a,b, 2010a,b; Glass 2010). Despite the fact that many abnormalities in the metabolism of proteins, lipids and carbohydrates are well established features of cancer, few studies have investigated liver gluconeogenesis in cancer and there is no agreement as to whether the activity of this pathway is increased or decreased in this disease.

There are reports about stimulation of liver gluconeogenesis in patients with cancer, which would provide greater release of glucose into the circulation and increased glucose supply for tumour cells (Bongaerts et al. 2006; Yalcin et al. 2009; Ferreira 2010; ). In fact, gluconeogenesis from glycerol (Lundholm et al. 1982), alanine (Waterhouse et al. 1979) or lactate (Shapot & Blinov 1974) was increased in patients with cancer. In agreement, gluconeogenesis from lactate (Shearer et al. 1983) and the activity of phosphoenolpyruvate carboxykinase (PEPCK), one of the key enzymes of gluconeogenesis, was enhanced in tumour-bearing rats (Noguchi et al. 1989). Moreover, isolated hepatocytes from tumour-bearing rats showed higher gluconeogenesis when incubated with lactate, alanine (Roh et al. 1984; Blumberg et al. 1993) or glutamine (Fisher et al. 1997). However, there are also reports that gluconeogenesis from alanine was reduced in perfused liver from Walker-256 tumour-bearing rats (Corbello-Pereira et al. 2004; Acco et al. 2007). Accordingly, conversion of alanine to glucose was decreased in livers of mammary adenocarcinoma-bearing rats (Liu et al. 1990).

As this lack of consensus could be attributed, among other factors, to the tumour stage, the aim of this investigation was to evaluate liver gluconeogenesis from alanine, pyruvate and glycerol, and related metabolic parameters, in Walker-256 tumour-bearing rats in the initial, intermediary and final stages of tumour development.

Materials and methods

Chemicals

Gluconeogenic precursors and all other chemicals (98–99.8% purity) were purchased from Sigma Chemical Co. (St Louis, MO, USA), Acros Organics (New Jersey, NJ, USA), Reagen (Rio de Janeiro, Brazil) and Merck (Darmstad, Germany).

Animals and Walker-256 tumour implantation

Male Wistar rats (220–230 g) fed with a standard rodent chow (Nuvilab®) were used in all experiments. For tumour implantation, Walker-256 cells suspended in phosphate buffered saline (PBS; 16.5 mM phosphate, 137 mM NaCl, 2.7 mM KCl, pH 7.4) were inoculated subcutaneously (8.0 × 107 viable cells/rat) into the right flank after an assessment of cell viability by the method of trypan blue exclusion. Control rats were inoculated with PBS in the same place.

As the rats survived an average of 14 days after tumour implantation, the experiments were carried on days 5 (initial stage), 8 (intermediary stage) and 12 (final stage) of tumour development.

Ethical Approval

The experimental protocols with animals were executed in accordance with Brazilian law and aproved by the Ethics Comittee of the State University of Londrina (registration number 23/09).

Liver perfusion experiments

Walker-256 tumour-bearing rats on days 5 (WK5 group), 8 (WK8 group) and 12 (WK12 group) after tumour implantation and control rats, fasted for 24 h for depletion of liver glycogen, were weighed, anesthetized with sodium pentobarbital (40 mg/kg) and submitted to in situ liver perfusion as previously described (Borba-Murad et al. 2005; Bassoli et al. 2008; Borba-Murad; Leonardo et al. 2009; Mario et al. 2009). The perfusion fluid, Krebs-Henseleit buffer (KHB), pH 7.4, at 37 °C and saturated with a 95%:5% O2:CO2 mixture, was introduced (4 ml/min per gram weight of liver) through a cannula inserted into the portal vein, while a second cannula in the inferior vena cava was used to collect the effluent perfusate. The composition of the KHB was as follows: 115 mM NaCl, 25 mM NaHCO3, 5.8 mM KCl, 1.2 mM Na2SO4, 1.18 mM MgCl2, 1.2 mM NaH2PO4 and 2.5 mM CaCl2. The livers were perfused with KHB for 10 min and then with KHB plus alanine (2.5 mM), pyruvate (5 mM) or glycerol (2 mM) during 30 min. The effluent perfusate of the liver, after passing through the Clark electrode to evaluate the oxygen uptake, was collected at intervals of 2 min to assess glucose, urea, lactate and pyruvate production. At the end of the perfusion the liver was removed and weighed, allowing precise metabolic calculations and correction of flow rates. In addition, tumour masses were carefully removed and weighed.

Analytical procedures

Glucose (Bergmeyer & Bernt 1974), urea (Gutmann & Bergmeyer 1974), pyruvate (Czok & Lamprecht 1974) and lactate (Gutmann & Wahlefeld 1974) in the effluent perfusion fluid of the liver were assayed by standard enzymatic methods. Oxygen uptake was monitored continuously with a platinum electrode (Bracht et al. 2003). Metabolic rates (Δ) were calculated as described in the legend of the figures.

Statistical procedures

Normal distribution and variance homogeneity were tested, and the Student's t-test was employed to analyse the results. Statistical analysis was carried out with the programs Statistica 6.0 Stat Soft Inc., Tulsa, OK, USA and GraphPad Prism 4.0 (GraphPad Software Inc., San Diego, CA, USA), at the 5% level of significance (P < 0.05). Data are expressed as mean ± standard error of the mean (SEM).

Results

Walker-256 tumour-bearing rats showed progressive tumour growth (Table 1), as previously demonstrated in our studies (Cassolla et al. 2012).

Table 1.

Comparison of glucose, urea, pyruvate and lactate production and oxygen uptake from alanine, pyruvate and glycerol in perfused liver of rats on days 5 (WK5), 8 (WK8) and 12 (WK12) after the implantation of Walker-256 tumour with the respective controls. Tumour mass is also illustrated

Variable WK5 (%) WK8 (%) WK12 (%)
Alanine (2.5 mM) Glucose production − (38.81) − (54.05) − (55.81)
Oxygen uptake − (53.17) − (50.00) − (69.44)
Urea production = = − (65.33)
Pyruvate production + (57.93) = − (43.66)
Lactate production + (71.62) = =
Pyruvate (5 mM) Glucose production − (29.02) − (25.06) − (41.67)
Oxygen uptake = − (67.70) − (118.72)
Glycerol (2 mM) Glucose production = = =
Oxygen uptake = = =
Tumour mass (g) – 6.93 ± 0.83 18.01 ± 1.27 32.62 ± 2.35
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Results (%) were obtained from data of Figures 6. The symbols − (decreased), + (increased) and = (unchanged) are in comparison with the respective controls. Values of tumour mass are the mean ± SEM (n = 8–12).

Infusion of alanine (2.5 mM) increased liver glucose production and oxygen uptake in Walker-256 tumour-bearing and controls rats. However, this increase was lower (P < 0.05) in WK5, WK8 and WK12 groups, as shown by their metabolic rates (Δ) (Figure 1). The reduction percentage of glucose production and oxygen uptake from alanine was more pronounced in WK12 group (Table 1).

Figure 1.

Figure 1

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Glucose production (a,c,e) and oxygen uptake (b,d,f) from alanine in livers from 24 h fasted rats on days 5 (WK5), 8 (WK8) and 12 (WK12) of development of Walker-256 tumour and controls. The livers were perfused as described in Materials and methods. Δ = metabolic rate, calculated as the difference between the mean of the last 6 min after and before the infusion of alanine. Data are mean ± SEM of 5–12 experiments. *P < 0.05, **P < 0.01 and ***P < 0.001 vs. control (unpaired Student's t-test).

Infusion of alanine also increased the liver production of urea (Figure 2), pyruvate (Figure 3) and lactate (Figure 4) in Walker-256 tumour-bearing and controls rats. However, the urea production was lower (P < 0.05) in the WK12 group, the pyruvate production was higher (P < 0.05) in the WK5 group and lower (P < 0.05) in the WK12 group, and the lactate production was higher (P < 0.05) in the WK5 group (Table 1).

Figure 2.

Figure 2

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Urea production from alanine in livers from 24 h fasted rats on days 5 (WK5), 8 (WK8) and 12 (WK12) of development of Walker-256 tumour and controls. The livers were perfused as described in Materials and methods. Δ = metabolic rate, calculated as the difference between the mean of the last 6 min after and before the infusion of alanine. Data are mean ± SEM of 4–12 experiments. **P < 0.01 vs. control (unpaired Student's t-test).

Figure 3.

Figure 3

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Pyruvate production from alanine in livers from 24 h fasted rats on days 5 (WK5), 8 (WK8) and 12 (WK12) of development of Walker-256 tumour and controls. The livers were perfused as described in Materials and methods. Δ = metabolic rate, calculated as the difference between the mean of the last 6 min after and before the infusion of alanine. Data are the mean ± SEM of 4–12 experiments. *P < 0.05 vs. control (unpaired Student's t-test).

Figure 4.

Figure 4

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Lactate production from alanine in livers from 24 h fasted rats on days 5 (WK5), 8 (WK8) and 12 (WK12) of development of Walker-256 tumour and controls. The livers were perfused as described in Materials and methods. Δ = metabolic rate, calculated as the difference between the mean of the last 6 min after and before the infusion of alanine. Data are the mean ± SEM of 4–12 experiments. ***P < 0.001 vs. control (unpaired Student's t-test).

Similarly to alanine, liver glucose production from pyruvate (5 mM) was lower (P < 0.05) in the WK5, WK8 and WK12 groups (Figure 5). Oxygen uptake during pyruvate infusion was lower (P < 0.05) in the WK8 and WK12 groups (Figure 5). The reduction percentage of liver glucose production and oxygen uptake from pyruvate was also more pronounced in the WK12 group (Table 1).

Figure 5.

Figure 5

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Glucose production (a,c,e) and oxygen uptake (b,d,f) from pyruvate in livers from 24 h fasted rats on days 5 (WK5), 8 (WK8) and 12 (WK12) of development of Walker-256 tumour and controls. The livers were perfused as described in Materials and methods. Δ = metabolic rate, calculated as the difference between the mean of the last 6 min after and before the infusion of pyruvate. Data are the mean ± SEM of 4–13 experiments. *P < 0.05 and **P < 0.01 vs. control (unpaired Student's t-test).

Finally, the infusion of glycerol (2 mM) resulted in similar increase in glucose production and oxygen uptake in the livers from WK5, WK8 and WK12 rats, when compared with the control group (Figure 6, Table 1).

Figure 6.

Figure 6

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Glucose production (a,c,e) and oxygen uptake (b,d,f) from glycerol in livers from 24 h fasted rats on days 5 (WK5), 8 (WK8) and 12 (WK12) of development of Walker-256 tumour and controls. The livers were perfused as described in Materials and methods. Δ = metabolic rate, calculated as the difference between the mean of the last 6 min after and before the infusion of glycerol. Data are the mean ± SEM of 4–6 experiments.

Discussion

Our results showed a reduction in liver glucose production and oxygen uptake from alanine and pyruvate in all stages of Walker-256 tumour development (WK5, WK8 and WK12 groups), thus revealing inhibition of gluconeogenesis from these precursors, which was more pronounced on day 12 of tumour development (Table 1).

In addition, we observed increased production of pyruvate and lactate from alanine in WK5 group (Table 1), indicating that the inhibition of gluconeogenesis from alanine did not involve inhibition of alanine aminotransferase at this stage of tumour development. It is possible that the increased pyruvate and lactate production could be due to the increased hepatic uptake of alanine. In fact, low concentrations of alanine were found in the blood (Inculet et al. 1987) while high concentrations were detected in the liver (Rivera et al. 1988) of tumour-bearing animals, suggesting high hepatic uptake of alanine in this condition. In agreement with this hypothesis, tumour necrosis factor α (TNFα), a cytokine which is increased in cancer, stimulated amino acid transport in hepatocytes (Inoue et al. 1995).

However, our results showed a reduction in the production of pyruvate and urea from alanine in WK12 group (Table 1), which is indicative of a reduction in the activity of alanine aminotransferase at this late stage of tumour development. The inhibition of alanine aminotransferase is reinforced by greater reduction in liver glucose production from alanine than from pyruvate in the WK12 group (Table 1). A reduction in the activity of alanine aminotransferase on day 12 of tumour development would explain the reduced conversion of alanine to pyruvate and the decreased urea production, even with the possibility of increased hepatic uptake of alanine in tumour-bearing rats. Accordingly, other studies demonstrated a reduction in the activity of alanine aminotransferase (Herzfeld & Greengard 1972) and inhibition of liver gluconeogenesis from alanine (Corbello-Pereira et al. 2004; Acco et al. 2007) in Walker-256 tumour-bearing rats.

Inhibition of gluconeogenesis from alanine in tumour-bearing rats probably involves changes in other steps of gluconeogenic pathway (Figure 7) in addition to the reduced conversion of alanine to pyruvate. This is reflected in the inhibition of gluconeogenesis from pyruvate seen in the WK5, WK8 and WK12 groups (Table 1).

Figure 7.

Figure 7

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Schematic representation of gluconeogenesis in the hepatocyte. Plasma membrane is represented by the greatest circle and mitochondria by the smallest circle. (Inline graphic) Decreased gluconeogenesis and (Inline graphic) unchanged gluconeogenesis on days 5 (WK5), 8 (WK8) and 12 (WK12) of development of Walker-256 tumour in rats. OAA, oxaloacetate; PEP, phosphoenolpyruvate; 2-PGA, 2-phosphoglycerate; 3-PGA, 3-phosphoglycerate; 1,3-DPGA, 1,3-diphosphoglycerate; GAP, glyceraldehyde 3-phosphate; DHAP, dihydroxyacetone phosphate; Glycerol-P, glycerol phosphate; Fru-1,6-P2, fructose 1,6-bisphosphate; Fru-6-P, fructose 6-phosphate; Glu-6-P, glucose 6-phosphate; PEPCK, phosphoenolpyruvate carboxykinase; ATP, adenosine triphosphate; AMP, adenosine monophosphate.

Inhibition of gluconeogenesis from pyruvate probably did not involve a reduction in its hepatic uptake, as there was inhibition of gluconeogenesis from alanine in the WK5 group, in a condition of higher availability of pyruvate within the hepatocytes (Table 1). Inhibition of gluconeogenesis from pyruvate may have involved, among other factors, inhibition of gluconeogenic enzymes, which catalyse reactions after the pyruvate step (Figure 7), and pro-inflammatory cytokines such as TNFα and interleukins IL1β and IL10 produced by the tumour and the tissues of the tumour-bearing host (Fearon et al. 1991; Moldawer et al. 1992; Yanagawa et al. 1995; Noguchi et al. 1996; Matthys & Billiau 1997; Metzger et al. 1997; Mantovani et al. 2000; Yerkovich et al. 2004; Caton et al. 2009; Carson & Baltgalvis 2010; Silvério et al. 2011).

However, the unchanged gluconeogenesis from glycerol in the WK5, WK8 and WK12 groups (Table 1) excludes the possibility of inhibition of fructose 1,6-biphosphatase and glucose 6-phosphatase, enzymes that catalyse reactions after the entry of glycerol in the gluconeogenic pathway (Figure 7). Moreover, the unchanged gluconeogenesis from glutamine in other studies of liver perfusion in Walker-256 tumour-bearing rats (Corbello-Pereira et al. 2004) suggests that PEPCK, which catalyses reactions after the entry of glutamine in to the gluconeogenic pathway (Figure 7), was also unchanged.

Thus, inhibition of gluconeogenesis from pyruvate and also of alanine in tumour-bearing rats may have involved reduced conversion of pyruvate to oxaloacetate by pyruvate carboxylase, an ATP-dependent mitochondrial step (Figure 7). This is consistent with the observation that TNFα increased the levels of mRNA of uncoupling proteins (UCP2 and UCP3) (Busquets et al. 1998) and induced the uncoupling of mitochondrial respiration (Busquets et al. 2003), an effect that reduces ATP synthesis and inhibits gluconeogenesis.

Although it has been proposed that increased gluconeogenesis increases energy expenditure and can contribute to cancer cachexia (Bongaerts et al. 2006), the present study demonstrated an inhibition of gluconeogenesis from alanine and pyruvate. Nevertheless, our study employed a technique in which the liver is isolated from the circulation. Therefore, it is possible that for in vivo conditions, the hepatic gluconeogenesis could be stimulated by increased blood levels of free fatty acids and gluconeogenic precursors in carriers of cancer (Baracos 2000; Veiga et al. 2008; Cassolla et al. 2012). For example, hepatic infusion of high concentration of fatty acid and lactate/pyruvate, which predominate in Walker-256 tumour-bearing rats (Cassolla et al. 2012), practically normalized the inhibition of gluconeogenesis found in perfused liver of these animals (Veiga et al. 2008).

It can be concluded that Walker-256 tumour-bearing rats show inhibition of liver gluconeogenesis from alanine and pyruvate, but not from glycerol, in all stages of tumour development, which can be attributed to the metabolic step in which the substrate enters the gluconeogenic pathway.

Acknowledgments

We gratefully thank Adelar Bracht for his helpful technical assistance. This research is supported by Fundação Araucária (PRONEX).

Conflict of Interest

The authors declare that there are no conflicts of interest.

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