Uncoupling effect of polyunsaturated fatty acid deficiency in isolated rat hepatocytes:effect on glycerol metabolism

Piquet, Marie-Astrid; Fontaine, Éric; Sibille, Brigitte; Filippi, Céline; Kériel, Christiane; Leverve, Xavier

doi:10.1042/bj3170667

Cited by 24 publications

(16 citation statements)

References 34 publications

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“…In other words, the number of ATP moles produced per O 2 consumed (energy yield of O 2 ) could be lower in n-3-depleted versus control animals, irrespective of the substrate used, as a result of wasting processes. Studies in both isolated mitochondria and intact cells have shown that n-3 PUFA deficiency causes an increase in proton permeability of the inner mitochondrial membrane, similar to that caused by the classical protonophore 2,4-dinitrophenol (18). Thirdly, the n-3 PUFA deficient diet could alter energy transfer from mitochondria to sites of energy utilization through an effect on phosphotransfer kinases (19).…”

Section: Discussionmentioning

confidence: 99%

Acute in vivo administration of a fish oil-containing emulsion improves post-ischemic cardiac function in n-3-depleted rats

Peltier

Malaisse²,

Portois³

et al. 2006

Int J Mol Med

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Abstract.A novel i.v. lipid preparation (MCT:FO) containing 80% medium chain-triacylglycerols and 20% fish oil was recently developed to rapidly replenish cell membrane phospholipids with omega 3 (n-3) polyunsaturated fatty acids (PUFA). In regard of this property, we investigated the effect of a single i.v. administration of MCT:FO on the recovery of cardiac function after ischemia in control and n-3-depleted rats. Results were compared with those obtained either with a control preparation, where FO was replaced by triolein (MCT:OO), or with saline. Saline (1 ml) or lipid preparation (also 1 ml) was injected as a bolus via the left saphenous vein. After 60 min the heart was removed and perfused for 20 min in normoxic conditions according to Langendorff. Thereafter, the heart was subjected to a 20 min zero-flow normothermic ischemia, followed by 40 min reperfusion. Cardiac mechanical and metabolic functions were monitored. In control rats, the previous administration of a lipid preparation (MCT:FO or MCT:OO) versus saline improved cardiac function during aerobic reperfusion post-ischemia. N-3-depleted rats showed decreased basal cardiac function and impaired recovery following ischemia. However, the bolus injection of MCT:FO opposed the deleterious effect of longterm n-3-deficiency and, in this respect, was superior to MCT:OO over the first 20 min of reperfusion. This novel approach to rapidly correct n-3 PUFA-deficiency might be clinically relevant and offer interesting perspectives in the management of acute ischemic accidents.

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Section: Discussionmentioning

confidence: 99%

Acute in vivo administration of a fish oil-containing emulsion improves post-ischemic cardiac function in n-3-depleted rats

Peltier

Malaisse²,

Portois³

et al. 2006

Int J Mol Med

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“…Proteins in the perifusate were denatured by heating the samples (80°C for 10 min) before centrifugation (36). Glucose, lactate, and pyruvate were measured in the perifusate and DHAP; glucose 6-phosphate; fructose 6-phosphate; 3-phosphoglycerate; and PEP were measured in the cellular fraction as described previously (31)(32)(33)(34)(35). The net fluxes (micromoles/min/g of dry cells) of gluconeogenesis (J glucose ), glycolysis (J lactate ϩ pyruvate ), and DHA metabolism (J DHA ), were calculated from the total cell content of the perifusion chamber, the perifusate flow rate, and the concentration of glucose, lactate, and pyruvate in the perifusate.…”

Section: Methodsmentioning

confidence: 99%

“…Hepatocytes were perifused at 37°C at a flow rate of 5 ml⅐min Ϫ1 with Krebs bicarbonate buffer (pH 7.4) continuously saturated with O 2 /CO 2 (19:1) and containing calcium (1.3 mM) (32)(33)(34)(35).…”

Section: Methodsmentioning

confidence: 99%

“…The most striking finding of this work is a significant decrease of lactate-plus-pyruvate production resulting from a potent inhibition of pyruvate kinase. Cytosolic adenine nucleotides are potent regulators of glycolysis, but given the decrease in cytosolic ATP-to-ADP ratio following exogenous Mg-ATP, an activation of glycolysis would actually have been predicted (32,34,35). The increased cytosolic NADH/NAD ratio as shown by the increased lactate-to-pyruvate ratio (Fig.…”

Section: Table II Effect Of Exogenous Mg-atp On Cytosolic and Mitochomentioning

confidence: 99%

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Exogenous Mg-ATP Induces a Large Inhibition of Pyruvate Kinase in Intact Rat Hepatocytes

Ichaï¹,

El-Mir²,

Nogueira

et al. 2001

Journal of Biological Chemistry

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Mg-ATP infusion in vivo has been reported to be beneficial both to organ function and survival rate in various models of shock. Moreover, a large variety of metabolic effects has been shown to occur in several tissues due to purinergic receptor activation. In the present work we studied the effects of exogenous Mg-ATP in rat liver cells perifused with dihydroxyacetone to investigate simultaneously gluconeogenetic and glycolytic pathways. We found a significant effect on oxidative phosphorylation as characterized by a decrease in oxygen consumption rate and in the cellular ATP-to-ADP ratio associated with an increase in lactate-to-pyruvate ratio. In addition, exogenous Mg-ATP induced rapid and reversible inhibition of both gluconeogenesis and glycolysis. The main effect on gluconeogenesis was located at the level of the fructose cycle, whereas the decrease in glycolysis was due to a strong inhibition of pyruvate kinase. Although pyruvate kinase inhibition induced by exogenous Mg-ATP was allosteric when assessed in vitro after enzyme extraction, we found a large decrease in the apparent maximal velocity when kinetics were assessed in vivo in intact perifused hepatocytes. This newly described short-term regulation of pyruvate kinase occurs only in the intact cell and may open new potentials for the pharmacological regulation of pyruvate kinase in vivo.Numerous publications have emphasized the beneficial role of Mg-ATP infusion in various models of shock or severe trauma in animals. Dysfunction of heart (1), kidney (2), muscle (3), endothelial (4), and immune cells (5, 6) are all improved by this treatment, which significantly increases the survival rate. Because such a benefit was independent of hemodynamic status (4, 7), a metabolic mechanism was proposed (8). Because the liver plays a central role in the metabolic response to such severe illnesses, it may represent a major target for Mg-ATP (9, 10).It is well known that purinergic receptor activation is responsible for a large variety of metabolic effects (11-24). ATP or adenosine or several analogues of purinergic receptors have been noted to affect liver glucose metabolism: i.e. stimulation of glycogenolysis (12, 13), increase (19,25,26) or decrease (11) of gluconeogenesis, and decrease of glycolysis (25). These effects have been related to a cAMP-dependent mechanism (12), a cAMP-independent inositol 3-phosphate/calcium-mediated signaling (13,14,16,18,21,23), a phospholipase C activation (18), or a transcriptional effect (25). It must be noted, however, that if some effects are shared among the adenine nucleotide family, others appear to be specific (12,14,18), suggesting that different signaling pathways may be involved.Because the beneficial effects were observed in vivo with Mg-ATP but not with adenosine (8, 27), we investigated the metabolic effects of exogenous Mg-ATP in rat liver cells perifused with DHA.1 Besides a significant effect on oxidative phosphorylation and on gluconeogenesis, we found that Mg-ATP was responsible for a large inhibition of pyruva...

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“…Hepatocytes were isolated by the method of Berry and Friend (16) (19,20). To study the metabolic effect of glucagon, perifused liver cells were titrated with DHA in the presence or absence of glucagon (10 Ϫ7 M).…”

Section: Methodsmentioning

confidence: 99%

Glucose 6-Phosphate Hydrolysis Is Activated by Glucagon in a Low Temperature-sensitive Manner

Ichaï

Guignot

El-Mir

et al. 2001

Journal of Biological Chemistry

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Glucagon affects liver glucose metabolism mainly by activating glycogen breakdown and by inhibiting pyruvate kinase, whereas a possible effect on glucose-6-phosphatase has also been suggested. Although such a target is of physiological importance for liver glucose production it was never proven. By using a model of liver cells, perifused with dihydroxyacetone, we show here that the acute stimulation of gluconeogenesis by glucagon (10 ؊7 M) was not related to the significant inhibition of pyruvate kinase but to a dramatic activation of the hydrolysis of glucose 6-phosphate. We failed to find an acute change in glucose-6-phosphatase activity by glucagon, but the increase in glucose 6-phosphate hydrolysis was abolished at 21°C; conversely the effect on pyruvate kinase was not affected by temperature. The activation of glucose 6-phosphate hydrolysis by glucagon was confirmed in vivo, in postabsorptive rats receiving a constant infusion of glucagon, by the combination of a 2-fold increase in hepatic glucose production and a 60% decrease in liver glucose 6-phosphate concentration. Besides the description of a novel effect of glucagon on glucose 6-phosphate hydrolysis by a temperature-sensitive mechanism, this finding could represent an important breakthrough in the understanding of type II diabetes, because glucose 6-phosphate is proposed to be a key molecule in the transcriptional effect of glucose.The metabolic effects of glucagon on liver glucose metabolism have long been described, mediated by both cAMP-and calciumdependent signalings (1-3). Besides a powerful and well documented effect on glycogen breakdown, glucagon also increases liver gluconeogenesis mainly by the allosteric inhibition of pyruvate kinase by its phosphorylation (4, 5). In addition, some effects of glucagon on the fructose phosphate cycle have been described, i.e. inhibition of 6-phosphofructo-1-kinase and activation of fructose-1,6-bisphosphatase (6, 7). Apart from these indisputable effects, a stimulation of glucose-6-phosphatase, a key enzyme in glucose production, has been proposed but never proven (8 -10). In view of a potential key role of glucose 6-phosphate as a cellular intermediate in the transcriptional effects of glucose (11,12), an effect of glucagon on glucose-6-phosphatase could be of major importance. Indeed, despite a prominent effect on liver glucose metabolism, the role of glucagon in the pathogenesis of type II diabetes is still unclear and a matter of debate (13).By studying glucose production under steady state conditions in a model of rat hepatocytes perifused with dihydroxyacetone (DHA) 1 as an exogenous source of carbohydrate, we show in the present work that despite a clear inhibitory effect of glucagon on pyruvate kinase, this effect was not responsible for the enhanced glucose production, indicating that this step is actually not controlling this pathway. Actually, the dramatic increase in the glucose production after glucagon addition was related to a substantial activation of glucose 6-phosphate hydrolysis in glucos...

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Uncoupling effect of polyunsaturated fatty acid deficiency in isolated rat hepatocytes:effect on glycerol metabolism

Cited by 24 publications

References 34 publications

Acute in vivo administration of a fish oil-containing emulsion improves post-ischemic cardiac function in n-3-depleted rats

Acute in vivo administration of a fish oil-containing emulsion improves post-ischemic cardiac function in n-3-depleted rats

Exogenous Mg-ATP Induces a Large Inhibition of Pyruvate Kinase in Intact Rat Hepatocytes

Glucose 6-Phosphate Hydrolysis Is Activated by Glucagon in a Low Temperature-sensitive Manner

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