Acceleration of gluconeogenesis from lactate by lysine (Short Communication).
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ABSTRACT:
SUBMITTER: Cornell NW
PROVIDER: S-EPMC1177859 | biostudies-other | 1973 Jun
REPOSITORIES: biostudies-other
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Project description:1. In freshly prepared isolated rat liver cells there is a lag in gluconeogenesis from lactate. The magnitude of the lag increases with increasing lactate concentration. 2. The lag is virtually abolished by lysine. 3. A few other amino acids (tyrosine, arginine, asparagine, ornithine) and NH(4)Cl had effects similar to, but less pronounced than, lysine during the early stage of incubation. Lysine was unique in accelerating gluconeogenesis beyond the lag period. 4. The effects of the accelerators are not additive. 5. Glycine, serine, threonine, cysteine, tryptophan and histidine at 2mm markedly inhibit (>20%) gluconeogenesis from lactate. 6. Oleate, which promotes gluconeogenesis from lactate by supplying acetyl-CoA required for the pyruvate carboxylase reaction, had no effect on the lag, yet oleate oxidation showed no lag. 7. Preincubation of cells decreased the lag and decreased the magnitude of the lysine effect. 8. Pyruvate (added at 1mm to give an initial [lactate]/[pyruvate] ratio of 10) also abolished the lag and decreased the lysine effect by about 50%. 9. Lysine reversed the inhibition by ethanol of gluconeogenesis from lactate. 10. All accelerators increased the rate of re-oxidation of cytosolic NADH as shown by a rapid re-adjustment of the [lactate]/[pyruvate] ratio on addition of 10mm-lactate. 11. The accelerated rates of gluconeogenesis are associated with an increased formation of aspartate and glutamate and especially alanine. 12. The existence of the lag period can be explained on the basis of the fact that the accumulation of pyruvate during the lag diverts oxaloacetate from gluconeogenesis to malate formation, i.e. that the re-oxidation of cytosolic NADH takes precedence over gluconeogenesis. This means that much oxaloacetate formed by the pyruvate carboxylase reaction has to be transferred twice from the mitochondria to the cytosol by the aspartate shuttle. Under these conditions the operation of the shuttle limits the rate of gluconeogenesis from lactate. Lysine and other accelerators may increase the effectiveness of the shuttle by providing components of the aspartate aminotransferases involved. The question of why lysine specifically accelerates gluconeogenesis beyond the lag period is discussed.
| S-EPMC1168283 | biostudies-other
Project description:ObjectiveFasting results in major metabolic changes including a switch from glycogenolysis to gluconeogenesis to maintain glucose homeostasis. However, the relationship between the length of fasting and the relative contribution of gluconeogenic substrates remains unclear. We investigated the relative contribution of glycogen, lactate, and glycerol in glucose production of male C57BL/6 J-albino mice after 6, 12, and 18 h of fasting.MethodsWe used non-perturbative infusions of 13C3 lactate, 13C3 glycerol, and 13C6 glucose combined with liquid chromatography mass spectrometry and metabolic flux analysis to study the contribution of substrates in gluconeogenesis (GNG).ResultsDuring infusion studies, both lactate and glycerol significantly label about 60% and 30-50% glucose carbon, respectively, but glucose labels much more lactate (∼90%) than glycerol carbon (∼10%). Our analyses indicate that lactate, but not glycerol is largely recycled during all fasting periods such that lactate is the largest direct contributor to GNG via the Cori cycle but a minor source of new glucose carbon (overall contribution). In contrast, glycerol is not only a significant direct contributor to GNG but also the largest overall contributor to GNG regardless of fasting length. Prolonged fasting decreases both the whole body turnover rate of glucose and lactate but increases that of glycerol, indicating that the usage of glycerol in GNG become more significant with longer fasting.ConclusionCollectively, these findings suggest that glycerol is the dominant overall contributor of net glucose carbon in GNG during both short and prolonged fasting.
| S-EPMC6881678 | biostudies-literature
Project description:1. Acetoacetate or short-chain fatty acids (acetate, butyrate, propionate, n-hexanoate, n-octanoate) accelerate the rate of glucose formation from lactate, fumarate and other precursors in slices of kidney cortex (rat, rabbit, sheep). The cause of this acceleration has been investigated. 2. There are two different mechanisms of acceleration. At low concentrations of glucogenic precursors the acceleration is mainly due to a ;sparing' action. The substances which accelerate are oxidizable and serve as fuel of respiration in place of the glucogenic precursor. This is indicated by the fact that the ratio lactate used/glucose formed falls in the presence of the accelerators and approaches the value 2. 3. At high concentrations of lactate the acceleration appears to be mainly due to the activation of pyruvate carboxylase by acetyl-coenzyme A. The evidence in support of this is summarized. The results indicate that the activation of pyruvate carboxylase by acyl-coenzyme A discovered by Utter & Keech (1963) in purified enzyme preparations also occurs in crude tissue homogenates and can play a part in the control of oxaloacetate synthesis and gluconeogenesis.
| S-EPMC1206607 | biostudies-other
Project description:The timing of reproduction is a critical determinant of fitness, especially in organisms inhabiting seasonal environments. Increasing evidence suggests that inter-plant communication plays important roles in plant functioning. Here, we tested the hypothesis that flowering coordination can involve communication between neighboring plants. We show that soil leachates from Brassica rapa plants growing under long-day conditions accelerated flowering and decreased allocation to vegetative organs in target plants growing under non-inductive short-day conditions. The results suggest that besides endogenous signaling and external abiotic cues, flowering timing may involve inter-plant communication, mediated by root exudates. The study of flowering communication is expected to illuminate neglected aspects of plant reproductive interactions and to provide novel opportunities for controlling the timing of plant reproduction in agricultural settings.
| S-EPMC4091325 | biostudies-literature
Project description:As an evolutionarily conserved posttranslational modification, protein lysine acetylation plays important roles in many physiological and metabolic processes. However, there are few reports about the applications of lysine acetylation in metabolic regulations. Lactate is a main byproduct in microbial fermentation, and itself also an important bulk chemical with considerable commercial values in many fields. Lactate dehydrogenase (LdhA) is the key enzyme catalyzing lactate synthesis from pyruvate. Here, we reported that Escherichia coli LdhA can be acetylated and the acetylated lysine sites were identified by mass spectrometry. The effects and regulatory mechanisms of acetylated sites on LdhA activity were characterized. Finally, lysine acetylation was successfully used to regulate the lactate synthesis. LdhA (K9R) mutant overexpressed strain improved the lactate titer and glucose conversion efficiency by 1.74 folds than that of wild-type LdhA overexpressed strain. LdhA (K154Q-K248Q) mutant can inhibit lactate accumulation and improve 3HP production. Our study established a paradigm for lysine acetylation in lactate synthesis regulation and suggested that lysine acetylation may be a promising strategy to improve the target production and conversion efficiency in microbial synthesis. The application of lysine acetylation in regulating lactate synthesis also provides a reference for the treatment of lactate-related diseases.
| S-EPMC9424733 | biostudies-literature
Project description:Reprogramming energy metabolism, such as enhanced glycolysis, is an Achilles' heel in cancer treatment. Most studies have been performed on isolated cancer cells. Here, we studied the energy-transfer mechanism in inflammatory tumor microenvironment. We found that human THP-1 monocytes took up lactate secreted from tumor cells through monocarboxylate transporter 1. In THP-1 monocytes, the oxidation product of lactate, pyruvate competed with the substrate of proline hydroxylase and inhibited its activity, resulting in the stabilization of HIF-1α under normoxia. Mechanistically, activated hypoxia-inducible factor 1-α in THP-1 monocytes promoted the transcriptions of prostaglandin-endoperoxide synthase 2 and phosphoenolpyruvate carboxykinase, which were the key enzyme of prostaglandin E2 synthesis and gluconeogenesis, respectively, and promote the growth of human colon cancer HCT116 cells. Interestingly, lactate could not accelerate the growth of colon cancer directly in vivo. Instead, the human monocytic cells affected by lactate would play critical roles to 'feed' the colon cancer cells. Thus, recycling of lactate for glucose regeneration was reported in cancer metabolism. The anabolic metabolism of monocytes in inflammatory tumor microenvironment may be a critical event during tumor development, allowing accelerated tumor growth.
| S-EPMC4594635 | biostudies-literature
Project description:1. The rate of gluconeogenesis from propionate in rat kidney-cortex slices was stimulated up to 3.5-fold by dl-carnitine and by bicarbonate, and was inhibited by inorganic phosphate or high concentrations of propionate (above 3mm). 2. The stimulatory effect of carnitine was dependent on the bicarbonate concentration and could be replaced at low propionate concentration by addition of 25mm-bicarbonate-carbon dioxide buffer. At low bicarbonate concentration the carnitine concentration can be rate-limiting. 3. All observations are in accordance with the view that the action of carnitine is in principle the same as that established for other fatty acids in other tissues, namely that carnitine promotes the appearance of propionyl-CoA within the mitochondrion by acting as a carrier. 4. The accelerating effects of carnitine and bicarbonate and the inhibitory effect of phosphate can be explained on the basis of the known properties of key enzymes of propionate metabolism, i.e. the reversibility of the reactions leading to the formation of methylmalonyl-CoA from propionyl-CoA. 5. 5mm-Propionate caused a five- to ten-fold fall in the free CoA content of the tissue. This fall can account for the inhibition of respiration and gluconeogenesis caused by high propionate concentration. 6. Relatively large quantities of propionyl-l-carnitine (15% of the propionate removed) were formed when dl-carnitine was present; thus the ;activation' of propionate proceeded at a faster rate than the carboxylation of propionyl-CoA. The metabolism of added propionyl-l-carnitine was accompanied by glucose synthesis. 7. The appearance of radioactivity from [2-(14)C]propionate in both glucose and carbon dioxide was as expected on account of the randomization of C-2 and C-3 of propionate, i.e. the formation of succinate as an intermediate. 8. The maximum rate of glucose synthesis from propionate (93.3+/-3.3mumoles/g. dry wt./hr.) was not affected by dietary changes aimed at varying the rate of caecal volatile fatty acid formation in the rat. 9. Inhibition of gluconeogenesis by high propionate concentration was not found in those species where the rate of caecal or ruminal propionate production is high under normal conditions (rabbit, sheep and cow).
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Project description:1. The specific radioactivity of plasma l-lactate and the incorporation of (14)C into plasma d-glucose, liver glycogen and skeletal-muscle glycogen were measured as a function of time after the intraperitoneal injection of l-[U-(14)C]lactate into 2-, 10- and 30-day-old rats. 2. Between 15 and 60min after the injection of the l-[U-(14)C]lactate, the specific radioactivity of plasma lactate decreased with a half-life of 20-33min in animals at all three ages. 3. At all times after injection examined, the specific radioactivity of plasma glucose of the 2- and 10-day-old rats was at least fourfold greater than that of the 30-day-old rats. 4. Although (14)C was incorporated into liver glycogen the amount incorporated was always less than 5% of that present in plasma glucose. 5. The results are discussed with reference to the factors that may influence the rate of incorporation of (14)C into plasma glucose, and it is concluded that the rate of gluconeogenesis in the 2- and 10-day-old suckling rat is at least twice that of the weaned 30-day-old animal.
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Project description:When mice are subjected to 7-day calorie restriction (40% of normal food intake), body fat disappears, but blood glucose is maintained as long as the animals produce ghrelin, an octanoylated peptide that stimulates growth hormone secretion. Mice can be rendered ghrelin-deficient by knock-out of the gene encoding either ghrelin O-acyltransferase, which attaches the required octanoate, or ghrelin itself. Calorie-restricted, fat-depleted ghrelin O-acyltransferase or ghrelin knock-out mice fail to show the normal increase in growth hormone and become profoundly hypoglycemic when fasted for 18-23 h. Glucose production in Goat(-/-) mice was reduced by 60% when compared with similarly treated WT mice. Plasma lactate and pyruvate were also low. Injection of lactate, pyruvate, alanine, or a fatty acid restored blood glucose in Goat(-/-) mice. Thus, when body fat is reduced by calorie restriction, ghrelin stimulates growth hormone secretion, which allows maintenance of glucose production, even when food intake is eliminated. In humans with anorexia nervosa or kwashiorkor, ghrelin and growth hormone are known to be elevated, just as they are in fat-depleted mice. We suggest that these two hormones prolong survival in starved humans as they do in mice.
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Project description:Tumor cells commonly have increased glucose uptake and lactate accumulation. Lactate is produced from pyruvate by lactate dehydrogenase A (LDH-A), which is frequently overexpressed in tumor cells and is important for cell growth. Elevated transcription by c-Myc or HIF1? may contribute to increased LDH-A in some cancer types. Here, we show that LDH-A is acetylated at lysine 5 (K5) and that this acetylation inhibits LDH-A activity. Furthermore, the K5-acetylated LDH-A is recognized by the HSC70 chaperone and delivered to lysosomes for degradation. Replacement of endogenous LDH-A with an acetylation mimetic mutant decreases cell proliferation and migration. Importantly, K5 acetylation of LDH-A is reduced in human pancreatic cancers. Our study reveals a mechanism of LDH-A upregulation in pancreatic cancers.
| S-EPMC3885615 | biostudies-literature