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. 1977 Apr 15;164(1):185–191. doi: 10.1042/bj1640185

The mechanism of inhibition by acidosis of gluconeogenesis from lactate in rat liver.

R A Iles, R D Cohen, A H Rist, P G Baron
PMCID: PMC1164773  PMID: 18143

Abstract

1. Gluconeogenesis from lactate or pyruvate was studied in perfused livers from starved rats at perfusate pH7.4 or under conditions simulating uncompensated metabolic acidosis (perfusate pH6.7-6.8). 2. In 'acidotic' perfusions gluconeogenesis and uptake of lactate or pyruvate were decreased. 3. Measurement of hepatic intermediate metabolites suggested that the effect of acidosis was exerted at a stage preceding phosphoenolpyruvate. 4. Total intracellular oxaloacetate concentration was significantly decreased in the acidotic livers perfused with lactate. 5. It is suggested that decreased gluconeogenesis in acidosis is due to substrate limitation of phosphoenolypyruvate carboxykinase. 6. The possible reasons for the fall in oxaloacetate concentration in acidotic livers are discussed; two of the more likely mechanisms are inhibition of the pyruvate carboxylase system and a change in the [malate]/[oxaloacetate] ratio due to the fall in intracellular pH.

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Selected References

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  1. Addanki S., Cahill F. D., Sotos J. F. Intramitochondrial pH and intra-extramitochondrial pH gradient of beef heart mitochondria in various functional states. Nature. 1967 Apr 22;214(5086):400–402. doi: 10.1038/214400b0. [DOI] [PubMed] [Google Scholar]
  2. Alleyne G. A., Scullard G. H. Renal metabolic response to acid base changes. I. Enzymatic control of ammoniagenesis in the rat. J Clin Invest. 1969 Feb;48(2):364–370. doi: 10.1172/JCI105993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Ballard F. J. Kinetic studies with cytosol and mitochondrial phosphoenolpyruvate carboxykinases. Biochem J. 1970 Dec;120(4):809–814. doi: 10.1042/bj1200809. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Cohen R. D., Iles R. A., Barnett D., Howell M. E., Strunin J. The effect of changes in lactate uptake on the intracellular pH of the perfused rat liver. Clin Sci. 1971 Aug;41(2):159–170. doi: 10.1042/cs0410159. [DOI] [PubMed] [Google Scholar]
  5. Cohen R. D., Iles R. A. Intracellular pH: measurement, control, and metabolic interrelationships. CRC Crit Rev Clin Lab Sci. 1975 Sep;6(2):101–143. doi: 10.3109/10408367509151567. [DOI] [PubMed] [Google Scholar]
  6. Exton J. H., Park C. R. Control of gluconeogenesis in liver. I. General features of gluconeogenesis in the perfused livers of rats. J Biol Chem. 1967 Jun 10;242(11):2622–2636. [PubMed] [Google Scholar]
  7. Folbergrová J., MacMillan V., Siesjö B. K. The effect of moderate and marked hypercapnia upon the energy state and upon the cytoplasmic NADH-NAD+ ratio of the rat brain. J Neurochem. 1972 Nov;19(11):2497–2505. doi: 10.1111/j.1471-4159.1972.tb01309.x. [DOI] [PubMed] [Google Scholar]
  8. HOHORST H. J., KREUTZ F. H., BUECHER T. [On the metabolite content and the metabolite concentration in the liver of the rat]. Biochem Z. 1959;332:18–46. [PubMed] [Google Scholar]
  9. Halestrap A. P. The mitochondrial pyruvate carrier. Kinetics and specificity for substrates and inhibitors. Biochem J. 1975 Apr;148(1):85–96. doi: 10.1042/bj1480085. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hems R., Ross B. D., Berry M. N., Krebs H. A. Gluconeogenesis in the perfused rat liver. Biochem J. 1966 Nov;101(2):284–292. doi: 10.1042/bj1010284. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Kamm D. E., Cahill G. F., Jr Effect of acid-base status on renal and hepatic gluconeogenesis in diabetes and fasting. Am J Physiol. 1969 May;216(5):1207–1212. doi: 10.1152/ajplegacy.1969.216.5.1207. [DOI] [PubMed] [Google Scholar]
  12. Lloyd M. H., Iles R. A., Simpson B. R., Strunin J. M., Layton J. M., Cohen R. D. The effect of simulated metabolic acidosis on intracellular pH and lactate metabolism in the isolated perfused rat liver. Clin Sci Mol Med. 1973 Oct;45(4):543–549. doi: 10.1042/cs0450543. [DOI] [PubMed] [Google Scholar]
  13. Longshaw I. D., Alleyne G. A., Pogson C. I. The effect of steroids and ammonium chloride acidosis on phosphoenolpyruvate carboxykinase in rat kidney cortex. II. The kinetics of enzyme induction. J Clin Invest. 1972 Sep;51(9):2284–2291. doi: 10.1172/JCI107038. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Pogson C. I., Smith S. A. The activity of phosphoenolpyruvate carboxykinase in rat tissues. Assay techniques and effects of dietary and hormonal changes. Biochem J. 1975 Nov;152(2):401–408. doi: 10.1042/bj1520401. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Robson J. S., Bone J. M., Lambie A. T. Intracellular pH. Adv Clin Chem. 1968;11:213–275. doi: 10.1016/s0065-2423(08)60060-8. [DOI] [PubMed] [Google Scholar]
  16. Scrutton M. C., Utter M. F. Pyruvate carboxylase. IX. Some properties of the activation by certain acyl derivatives of coenzyme A. J Biol Chem. 1967 Apr 25;242(8):1723–1735. [PubMed] [Google Scholar]
  17. Söling H. D., Willms B., Kleineke J., Gehlhoff M. Regulation of gluconeogenesis in the guinea pig liver. Eur J Biochem. 1970 Oct;16(2):289–302. doi: 10.1111/j.1432-1033.1970.tb01084.x. [DOI] [PubMed] [Google Scholar]
  18. WADDELL W. J., BUTLER T. C. Calculation of intracellular pH from the distribution of 5,5-dimethyl-2,4-oxazolidinedione (DMO); application to skeletal muscle of the dog. J Clin Invest. 1959 May;38(5):720–729. doi: 10.1172/JCI103852. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Walsh D. A., Chen L. J. A reinvestigation of the kinetic parameters of phosphoenolypyruvate carboxykinase. Biochem Biophys Res Commun. 1971 Nov 5;45(3):669–675. doi: 10.1016/0006-291x(71)90468-2. [DOI] [PubMed] [Google Scholar]
  20. Walter P., Paetkau V., Lardy H. A. Paths of carbon in gluconeogenesis and lipogenesis. 3. The role and regulation of mitochondrial processes involved in supplying precursors of phosphoenolpyruvate. J Biol Chem. 1966 Jun 10;241(11):2523–2532. [PubMed] [Google Scholar]
  21. Williamson D. H., Lund P., Krebs H. A. The redox state of free nicotinamide-adenine dinucleotide in the cytoplasm and mitochondria of rat liver. Biochem J. 1967 May;103(2):514–527. doi: 10.1042/bj1030514. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Williamson D. H., Veloso D., Ellington E. V., Krebs H. A. Changes in the concentrations of hepatic metabolites on administration of dihydroxyacetone or glycerol to starved rats and their relationship to the control of ketogenesis. Biochem J. 1969 Sep;114(3):575–584. doi: 10.1042/bj1140575. [DOI] [PMC free article] [PubMed] [Google Scholar]

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