Hepatic Concentrations Of Citrate Research Articles

Model-Based Assessment of Plasma Citrate Flux Into the Liver: Implications for NaCT as a Therapeutic Target.

Cytoplasmic citrate serves as an important regulator of gluconeogenesis and carbon source for de novo lipogenesis in the liver. For this reason, the sodium‐coupled citrate transporter (NaCT), a plasma membrane transporter that governs hepatic influx of plasma citrate in human, is being explored as a potential therapeutic target for metabolic disorders. As cytoplasmic citrate also originates from intracellular mitochondria, the relative contribution of these two pathways represents critical information necessary to underwrite confidence in this target. In this work, hepatic influx of plasma citrate was quantified via pharmacokinetic modeling of published clinical data. The influx was then compared to independent literature estimates of intracellular citrate flux in human liver. The results indicate that, under normal conditions, <10% of hepatic citrate originates from plasma. Similar estimates were determined experimentally in mice and rats. This suggests that NaCT inhibition will have a limited impact on hepatic citrate concentrations across species.

Inhibition of hepatic ketogenesis by tumor necrosis factor-alpha in rats.

Tumor necrosis factor-alpha (TNF-alpha) stimulates hepatic lipogenesis. Therefore, it could play a role in the control of ketogenesis. To test this hypothesis, we measured simultaneously free fatty acids (FFA; [1-13C]palmitate) and ketone body (KB; [3,4-13C2]acetoacetate) kinetics, before and after intraperitoneal injection of saline or TNF-alpha, in postabsorptive rats or rats starved for 24 h. In both groups of rats, TNF-alpha injection did not modify insulinemia and induced a moderate increase of FFA concentrations and appearance rates (P < 0.05). Despite increased FFA availability, ketogenesis was impaired after TNF-alpha injection, as shown by lower KB concentrations and appearance rates; this effect was more important in postabsorptive than in starved rats. The percentage of FFA flux used for ketogenesis was decreased by TNF-alpha in the postabsorptive group (P < 0.05) and starved (P < 0.05) rats. In both groups, maximal liver acetyl-coenzyme A carboxylase activity and estimated phosphorylation state were not modified by TNF-alpha injection, but hepatic concentrations of citrate were increased (P < 0.05). This increased citrate level could be related to a mobilization of glucose stored as glycogen since liver glycogen was decreased by TNF-alpha injection (P < 0.05). In conclusion, TNF-alpha injection in rats decreased hepatic ketogenesis. This action could be related to an increased mobilization and utilization of carbohydrate stores.

Tumor Necrosis Factor–Increased Hepatic Very-Low-Density Lipoprotein Production and Increased Serum Triglyceride Levels in Diabetic Rats

Previous studies demonstrated that administration of tumor necrosis factor (TNF) to diabetic rats rapidly increases serum triglyceride levels and stimulates hepatic lipogenesis without affecting the activity of adipose tissue lipoprotein lipase or serum insulin levels. The purpose of this study was to determine the mechanism by which TNF increases serum triglyceride levels and stimulates hepatic fatty acid synthesis in diabetic animals. The maximal increase (approximately 2-fold) in serum triglyceride levels in diabetic rats is seen with a dose of 10 micrograms TNF/200 g body wt, and the half-maximal effect is observed with 5 micrograms TNF/200 g body wt. The clearance of labeled triglyceride-rich lipoproteins from the circulation is not affected by TNF administration (triglyceride t 1/2; diabetic vs. TNF-administered diabetic, 3.5 +/- 0.7 vs. 4.0 +/- 0.6 min, respectively; NS). The production of triglyceride, measured by the Triton WR-1339 technique, is increased twofold in diabetic animals after TNF administration. These results indicate that the rapid increase in serum triglyceride levels after TNF treatment is accounted for by increased hepatic lipoprotein secretion. TNF administration did not alter either the amount or activation state of hepatic acetyl-CoA carboxylase, a key regulatory enzyme in fatty acid synthesis. There was also no change in the hepatic levels of fatty acyl-CoA, an allosteric inhibitor of acetyl-CoA carboxylase. However, there was a 71% increase in hepatic citrate concentrations. Citrate is an allosteric activator of acetyl-CoA carboxylase, and changes in hepatic citrate concentrations have been shown to mediate changes in the rates of fatty acid synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of fasting on the concentrations of intermediate metabolites in the blood and hepatic tissues of pregnant and non-pregnant ewes

SummaryBlood and liver samples were taken from four fasted pregnant and five fasted non-pregnant Finnish Landrace × Dorset Horn ewes. The following metabolites were measured: adenine monophosphate (AMP), adenine diphosphate (ADP), adenine triphosphate (ATP), citrate, 2-oxoglutarate, phosphoenolpyruvate, pyruvate, lactate, 2-phosphoglycerate, 3-phosphoglycerate, α-glycerophosphate, malate, β-hydroxybutyrate, acetoacetate, glutamate, alanine and NAD+.The effects of a 6-day fast on non-pregnant ewes were shown as significant reductions in the hepatic concentrations of 2-phosphoglycerate, alanine, NAD+ and ADP, together with significant increases in the hepatic concentrations of 3-hydroxybutyrate, malate and the ratio of 3-hydroxybutyrate:acetoacetate. In the blood there were significant reductions in the concentrations of urea, citrate and in the ratio of 3-hydroxybutyrate: acetoacetate.Similar but more marked changes occurred in the late pregnant ewes, with additional significant reductions in the hepatic concentrations of citrate, ATP and the level of cell energy, and additional increases in the blood of the ratio of lactate: pyruvate and the concentrations of 3-hydroxybutyrate and 2-oxoglutarate. However, unlike the non-pregnant ewes no significant changes in either the plasma concentration of urea or the hepatic concentration of ADP were observed in the late pregnant ewes.

Anti-ketogenic effect of glucose in the lactating cow deprived of food.

1. The aim of this study was to determine the effect of a constant infusion of glucose on the ketosis that is observed when dairy cows are deprived of food in early lactation. 2. Cows in early lactation were first deprived of food for 4 days (96h) to induce a 'fasting ketosis'. Glucose was then infused intravenously at a constant rate of 0.75 g/min for 48h while deprivation of food was maintained. At the end of this 48 h period, blood and liver ketone-body concentrations had decreased to values well below those found in healthy fed cows. 3. On the assumption that the anti-ketogenic effect of glucose was mainly due to suppression of hepatic ketogenesis, it was concluded that two anti-ketogenic mechanisms had been identified. These were (a) a decrease in the availability of free fatty acids for hepatic oxidation, and (b) anti-ketogenic changes within the liver itself. 4. These latter anti-ketogenic changes were twofold. The first was a major increase in the hepatic concentrations of citrate and 2-oxoglutarate. The second was an increase in the degree of oxidation of the hepatic cytosol. It was proposed that both these intrahepatic changes might indicate an augmentation of the quantity of oxaloacetate available for condensation with acetyl-CoA derived from fat oxidation. 5. Hepatic glycerol 1-phosphate concentration fell substantially after glucose infusion. 6. Glucose infusion into fed cows produced qualitatively similar effects to those observed in the unfed cows. However, blood and liver ketone-body concentrations were not decreased to the same extent in the fed cows as in the unfed cows.

The Antiketogenic Action of an Anabolic Steroid Administered to Ketotic Cows

The effects of an anabolic steroid, trienbolone acetate, in healthy early lactatiug cows and cows suffering from primary ketosis or an experimental ketosis are described. Four out of four cows with primary ketosis were restored to normal health following a single injection of 120 mg of anabolic steroid, and 2/3 cows responded to a single dose of 60 mg steroid, a third cow requiring a further injection of 60 mg steroid. Three out of three cows with a severe experimentally induced ketosis responded to a single injection of 60 mg steroid. In the ketotic cows treated with 120 mg steroid, significant decreases were observed in the blood concentrations of 3-hydroxybutyrate and acetoacetate 24 h and 48 h after treatment. However, no hyperglycemic effect was observed in ketotic cows after the steroid therapy. The changes in hepatic metabolites following anabolic steroid administration were greater in healthy cows than ketotic COWS. In healthy cows there were significant increases in hepatic concentrations of citrate, 2-ketoglutarate, and some glucogenic amino-acids. In the ketotic liver, there was a tendency for some improvement towards normal values for intermediates of both the citric acid cycle and the Embden-Meyerhof pathway. An interesting effect of the steroid in ketotic cows was the immediate improvement of appetite. Trienbolone acetate has no significant effect on milk yield of healthy cows over a 1-week period. Although complicated by the effects of a liver biopsy, the administration of an anabolic steroid improved the milk yield of ketotic cows.

Regulation of Fatty Acid Synthesis in the Liver of Prenatal and Early Postnatal Chicks: HEPATIC CONCENTRATIONS OF INDIVIDUAL FREE FATTY ACIDS AND OTHER METABOLITES

Abstract A normal mash diet or a single glucose injection stimulates fatty acid synthesis and increases the total activities of acetyl coenzyme A carboxylase, fatty acid synthetase, and malic enzyme in the livers of neonatal chicks. Feeding and glucose injection caused a decrease in the concentration of free fatty acids and fatty acyl-CoA and an increase in α-glycerophosphate and free CoA. These concentration changes are appropriate for intermediates which may regulate both the rate of fatty acid synthesis and the concentration of the lipogenic enzymes. The hepatic concentrations of citrate and acetyl-CoA were unaffected by feeding or glucose injection. During the hatching process, total activities of acetyl-CoA carboxylase and fatty acid synthetase in the liver increased but the rate of fatty acid synthesis did not. Concomitantly, free stearate in the liver decreased, but none of the other metabolites indicated above were affected. Fatty acid synthetase increased and hepatic free stearate decreased when embryos were incubated in 100% oxygen. Stearate or a metabolite derived from stearate is a potential negative regulator of the concentration of fatty acid synthetase in chick liver. Injection of glucose into 18-day-old embryos markedly increased the α-glycerophosphate content of the liver but had no effect on the total activities of the lipogenic enzymes. Hence, α-glycerophosphate is not a direct regulator of the total activities of acetyl-CoA carboxylase or fatty acid synthetase in embryonic chicks.

Gluconeogenesis in the cow. The effects of a glucocorticoid on hepatic intermediary metabolism.

1. The hepatic concentrations of the ketone bodies and of metabolites and activities of enzymes involved in gluconeogenesis were measured in healthy lactating and non-lactating cows 48h after administration of Voren, an ester of dexamethasone, and compared with those found in control animals given saline. Parallel measurements were also made of the blood concentrations of several of the metabolites. 2. Blood glucose concentrations were raised in the Voren-treated animals, whereas blood ketone body and free fatty acid concentrations were unaltered. Similarly there was no change in the hepatic concentrations of the ketone bodies. 3. Significant increases were found in the hepatic concentrations of citrate, 2-oxo-glutarate and malate in both groups of animals given Voren. 4. The hepatic concentrations of those glycolytic intermediates that were measured either decreased or did not change after Voren treatment. 5. The enzymes aspartate transaminase and fructose 1,6-diphosphatase were unchanged in activity after Voren administration, whereas phosphopyruvate carboxylase (EC 4.1.1.32) activity was depressed in the lactating group. However, glucose 6-phosphatase, tryptophan oxygenase and tyrosine aminotransferase increased in activity. 6. In several cases those hepatic metabolites that increased in concentration after Voren administration were present in lower concentration in normal lactating cows than in normal non-lactating cows. The same applied mutatis mutandis to those metabolites that were decreased by Voren. 7. These findings are discussed in relation to the use of glucocorticoids in the treatment of bovine ketosis.