The early stimulation of glycolysis by epidermal growth factor in isolated rat hepatocytes is secondary to the glycogenolytic effect

Quintana, I; Grau, Montserrat; Moreno, F. Xavier Vila i; Soler, Concepció; Ramı́rez, Ignasi; Soley, Maria

doi:10.1042/bj3080889

Cited by 13 publications

(21 citation statements)

References 42 publications

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“…A similar controversy also exists concerning the mechanism of action of EGF in hepatocytes. A review of the literature shows that EGF‐dependent phospholipase activation, and increases in DAG, PA, inositoltrisphosphate and cytosolic calcium, were detected to various degrees when hepatocyte suspensions or glucocorticoid‐free hepatocyte cultures were used [36,39,41,46,47]. In contrast, in our dexamethasone‐treated cultures, EGF had no effect on DAG levels, which is in agreement with the results of Dajani et al .…”

Section: Discussionsupporting

confidence: 91%

“…1B). Similar results have been reported before for other hepatocyte culture systems [27,41]. Furthermore, transforming growth factor-a (TGF-a) completely mimicked EGF action in the lower concentration range (0.1-3 ngAEmL )1 ); however, it elicited an extrastimulatory response (+30%) at higher concentrations (Fig.…”

Section: Metabolic Effectssupporting

confidence: 86%

“…ATP and exogenous PLC, which both stimulate DAG formation [36][37][38], were used as positive controls. In addition, EGF, an insulin-mimetic as well as an insulin-antagonistic factor [39][40][41], was included in some experiments.…”

Section: Resultsmentioning

confidence: 99%

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The diacylglycerol and protein kinase C pathways are not involved in insulin signalling in primary rat hepatocytes

Probst

Beuers²,

Drabent

et al. 2003

European Journal of Biochemistry

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Diacylglycerol (DAG) and protein kinase C (PKC) isoforms have been implicated in insulin signalling in muscle and fat cells. We evaluated the involvement of DAG and PKC in the action of insulin in adult rat hepatocytes cultured with dexamethasone, but in the absence of serum, for 48 h. Our results show that although insulin stimulated glycolysis and glycogen synthesis, it had no effect on DAG mass or molecular species composition. Epidermal growth factor showed the expected insulin-mimetic effect on glycolysis, whereas ATP and exogenous phospholipase C acted as antagonists and abolished the insulin signal. Similarly to insulin, epidermal growth factor had no effect on DAG mass or molecular species composition. In contrast, both ATP and phospholipase C induced a prominent increase in several DAG molecular species, including 18:0/20:4, 18:0/20:5, 18:0/22:5 and a decrease in 18:1/18:1. These changes were paralleled by an increase in phospholipase D activity, which was absent in insulin-treated cells. By immunoblotting or by measuring PKC activity, we found that neither insulin nor ATP translocated the PKCa, -d, -e or -f isoforms from the cytosol to the membrane in cells cultured for six or 48 h. Similarly, insulin had no effect on immunoprecipitable PKCf. Suppression of the glycogenic insulin signal by phorbol 12-myristate 13-acetate, but not by ATP, could be completely alleviated by bisindolylmaleimide. Finally, insulin showed no effect on DAG mass or translocation of PKC isoforms in the perfused liver, although it reduced the glucagon-stimulated glucose output by 75%. Together these results indicate that phospholipases C and D or multiple PKC isoforms are not involved in the hepatic insulin signal chain.Keywords: hepatocytes; insulin; ATP; diacylglycerol molecular species; protein kinase C.Among the three major insulin-sensitive organs, i.e. liver, muscle and fat tissue, the liver plays a key role in the regulation of blood glucose homeostasis by channelling excess glucose into glycogen after food uptake and by producing glucose through glycogenolysis and gluconeogenesis in the states of hunger and starvation. Insulin, the dominant hormone of the absorptive phase, acts via receptor-mediated tyrosine phosphorylation of insulin receptor substrates (IRSs). Two well established signalling cascades are initiated when adaptor proteins are recruited to the IRSs through their src homology 2 domains (a) the growth factor receptor binding protein activates the ras/ mitogen-activated protein kinase pathway and (b) phosphatidylinositol 3-kinase activates the protein kinase B/glycogen synthase kinase-3 cascade. Recent data suggest that a third signalling pathway, downstream of phosphatidylinositol 3-kinase, may also be involved: phospholipase D (PLD)-dependent generation of phosphatidic acid (PA) and diacylglycerol (DAG), with subsequent activation of DAG-insensitive atypical protein kinase C (PKC) isozymes such as f and k, as well as activation of DAG-sensitive PKC isozymes [1][2][3]. These studies, which were performed on m...

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Section: Discussionsupporting

confidence: 91%

Section: Metabolic Effectssupporting

confidence: 86%

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The diacylglycerol and protein kinase C pathways are not involved in insulin signalling in primary rat hepatocytes

Probst

Beuers²,

Drabent

et al. 2003

European Journal of Biochemistry

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“…Interaction of neurotensin with its receptor, a G protein-coupled receptor, results in the activation of phospholipase C and its downstream signaling cascades, including an increase in [Ca 2+ ] i that is known to mediate stimulation of cellular metabolism (glycolysis) in a number of cell types (14,15). The EGF receptor, a tyrosine kinase, mediates the intracellular signals via two robustly activated pathways: phospholipase C and the ras-raf-MEK-ERKs axis.…”

Section: Molecular Mechanism Of Action Of Anthocyanidins/ Anthocyaninsmentioning

confidence: 99%

Neurotensin- and EGF-Induced Metabolic Activation of Colon Carcinoma Cells Is Diminished by Dietary Flavonoid Cyanidin but Not by Its Glycosides

Briviba¹,

Abrahamse²,

Pool‐Zobel³

et al. 2001

Nutrition and Cancer

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Dietary polyphenols, including anthocyanidins and their glycosides anthocyanins, are suggested to be involved in the protective effects of fruits and vegetables against cancer. Very few data are available concerning the effects of anthocyanidins/anthocyanins on cellular processes induced by growth factors such as neurotensin and epidermal growth factor (EGF), which are implicated in the pathophysiology of colon cancer. Here, we show that neurotensin and EGF caused an increase in the extracellular acidification rate, which could reflect the activity of cellular metabolism, in the human carcinoma cell line HT29 clone 19A. Neurotensin and EGF also caused a strong rise in the intracellular Ca2+ concentration, induced phosphorylation of extracellular signal-regulated kinases (ERK1 and ERK2), and stimulated growth of human carcinoma cells. Cyanidin (10 microM), but not its glycosides cyanin and idaein, was able to inhibit the neurotensin- and EGF-induced increased rate of extracellular acidification. In contrast to N-ethyl-N-isopropyl amiloride, an inhibitor of Na+/H+ exchange, cyanidin did not alter the rate of intracellular pH recovery of cells loaded by NH3/NH4+, indicating that cyanidin inhibits cellular metabolism, rather than directly altering Na+/H+ exchange. Cyanidin, but not cyanin and idaein, was able to inhibit an increase in intracellular Ca2+ concentration induced by neurotensin. Neurotensin- and EGF-induced phosphorylation of ERKs was not affected by cyanidin, cyanin, and idaein at < or = 100 microM. Only cyanidin (100 microM), but not cyanin and idaein, was able to inhibit cellular growth induced by EGF. Thus these findings suggest that a dietary polyphenol cyanidin, but not its glycosides, is a potent inhibitor of mitogen-induced metabolic activity, increase in free intracellular Ca2+, and cellular growth of cultured colon carcinoma cells.

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“…We assessed the changes in biochemical and pathological parameters over time following induction of apoptosis. In addition, we addressed whether changes in energy metabolism could be reversed when the liver was protected against apoptosis using epidermal growth factor (EGF) which is known to rapidly affect liver glucose metabolism [24][25][26].…”

Section: Introductionmentioning

confidence: 99%

Hepatocellular apoptosis in mice is associated with early upregulation of mitochondrial glucose metabolism

et al. 2011

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Hepatocyte death due to apoptosis is a hallmark of almost every liver disease. Manipulation of cell death regulatory steps during the apoptotic process is therefore an obvious goal of biomedical research. To clarify whether metabolic changes occur prior to the characteristic apoptotic events, we used ex vivo multinuclear NMR-spectroscopy to study metabolic pathways of [U-(13)C]glucose in mouse liver during Fas-induced apoptosis. We addressed whether these changes could be associated with protection against apoptosis afforded by Epidermal Growth Factor (EGF). Our results show that serum alanine and aspartate aminotransferase levels, caspase-3 activity, BID cleavage and changes in cellular energy stores were not observed before 3 h following anti-Fas injection. However, as early as 45 min after anti-Fas treatment, we observed upregulation of carbon entry (i.e. flux) from glucose into the Krebs-cycle via pyruvate dehydrogenase (PDH) and pyruvate carboxylase (PC) (up to 139% and 123% of controls, respectively, P < 0.001). This was associated with increased glutathione synthesis. EGF treatment significantly attenuated Fas-induced apoptosis, liver injury and the late decrease in energy stores, as well as the early fluxes through PDH and PC which were comparable to untreated controls. Using ex vivo multinuclear NMR-spectroscopic analysis, we have shown that Fas receptor activation in mouse liver time-dependently affects specific metabolic pathways of glucose. These early upregulations in glucose metabolic pathways occur prior to any visible signs of apoptosis and may have the potential to contribute to the initiation of apoptosis by maintaining mitochondrial energy production and cellular glutathione stores.

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The early stimulation of glycolysis by epidermal growth factor in isolated rat hepatocytes is secondary to the glycogenolytic effect

Cited by 13 publications

References 42 publications

The diacylglycerol and protein kinase C pathways are not involved in insulin signalling in primary rat hepatocytes

The diacylglycerol and protein kinase C pathways are not involved in insulin signalling in primary rat hepatocytes

Neurotensin- and EGF-Induced Metabolic Activation of Colon Carcinoma Cells Is Diminished by Dietary Flavonoid Cyanidin but Not by Its Glycosides

Hepatocellular apoptosis in mice is associated with early upregulation of mitochondrial glucose metabolism

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