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Gluconeogenesis in the kidney cortex. Effects of D-malate and amino-oxyacetate.

ABSTRACT: 1. Rat kidney-cortex slices incubated with d-malate alone formed very little glucose. d-Malate, however, augmented gluconeogenesis from l-lactate and inhibited gluconeogenesis from pyruvate and l-malate. 2. d-Malate had little effect on the rate of the tricarboxylic acid cycle with or without other substrates added. 3. d-Malate inhibited the activity of the l-malate dehydrogenase in a high-speed-supernatant fraction from kidney cortex. 4. It was concluded that d-malate inhibited either the operation of the cytoplasmic l-malate dehydrogenase or malate outflow from the mitochondria in the intact kidney-cortex cell. This supports the hypothesis of Lardy, Paetkau & Walter (1965) and Krebs, Gascoyne & Notton (1967) on the role of malate as carrier for carbon and reducing equivalents in gluconeogenesis. 5. Gluconeogenesis from l-lactate in kidney-cortex slices was strongly inhibited by a low concentration (0.1mm) of amino-oxyacetate, whereas glucose formation from pyruvate, malate, aspartate and several other compounds was only slightly affected. 6. High concentrations of l-aspartate largely reversed the inhibition of gluconeogenesis from l-lactate caused by amino-oxyacetate. 7. Amino-oxyacetate inhibited strongly the glutamate-oxaloacetate transaminase in the 30000g supernatant fraction of a kidney-cortex homogenate. The presence of l-aspartate decreased the inhibition of the transaminase by amino-oxyacetate. 8. Detritiation of l-[2-(3)H]aspartate was inhibited by 90% during an incubation of kidney-cortex slices with l-lactate and amino-oxyacetate. 9. Low concentrations (10mum) of artificial electron acceptors such as Methylene Blue and phenazine methosulphate abolished most of the inhibition of gluconeogenesis from l-lactate by amino-oxyacetate. This is interpreted as an activation of net malate outflow from the mitochondria by-passing the inhibited transfer of oxaloacetate. 10. These findings support the concept that transamination to aspartate is involved in the transfer of oxaloacetate from mitochondria to cytosol required in gluconeogenesis from l-lactate.

SUBMITTER: Rognstad R

PROVIDER: S-EPMC1185386 | biostudies-other | 1970 Feb

REPOSITORIES: biostudies-other

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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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Gluconeogenesis in the kidney cortex. Effects of D-malate and amino-oxyacetate.

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