Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1975 Jun;55(6):1237–1244. doi: 10.1172/JCI108042

Hepatic mitochondrial function in ketogenic states. Diabetes, starvation, and after growth hormone administration.

J P DiMarco, C Hoppel
PMCID: PMC301878  PMID: 124319

Abstract

The study was designed to evaluate hepatic mitochondrial function during ketotic states. The ketogenic models studied were streptozotocin-induced diabetic ketoacidosis, 48 h of starvation, and after growth hormone administration. In the last-mentioned model we observed increased free fatty acids but not ketonemia. Oxidative phosphorylation was measured using the citric acid cycle substrates pyruvate and succinate, the amino acid glutamate, a ketone body beta-hydroxybutyrate, and a long-chain fatty acid palmitoyl-l-carnitine. State 3 (ADP stimulated) and state 4 (ADP limited) respiration, respiratory control ratio (state 3/state 4), and the ADP/O ratios were normal in the controls and the experimental groups. Uncoupled respiration produced by dinitrophenol with a variety of substrates was unchanged in the experimental groups compared to the controls. Fatty acid oxidation was studied in detail. The rate of utilization of palmitoyl-l-carnitine by controls or experimental groups did not depend on the product formed (citrate, acetoacetate). No significant changes were observed in the oxidation of palmitoyl-CoA (+ carnitine) or with an intermediate-chain fatty acid hexanoate. The specific activity of hepatic mitochondria carnitine palmitoyltransferase did not change in any of the three experimental groups. It is concluded that during diabetic ketoacidosis, starvation, and growth hormone administration, there is (a) no alteration in hepatic mitochondrial function; (b) no change in the intrinsic capacity of hepatic mitochondria to oxidize fatty acids; and (c) no change in the specific activity of mitochondrial carnitine palmitoyltransferase. The mechanism by which the body restrains flux through the mitochondrial oxidative machinery remains to be fully determined.

Full text

PDF
1237

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aas M., Daae L. N. Fatty acid activation and acyl transfer in organs from rats in different nutritional states. Biochim Biophys Acta. 1971 Jul 13;239(2):208–216. doi: 10.1016/0005-2760(71)90166-4. [DOI] [PubMed] [Google Scholar]
  2. Bieber L. L., Abraham T., Helmrath T. A rapid spectrophotometric assay for carnitine palmitoyltransferase. Anal Biochem. 1972 Dec;50(2):509–518. doi: 10.1016/0003-2697(72)90061-9. [DOI] [PubMed] [Google Scholar]
  3. Bremer J., Davis E. J. Phosphorylation coupled to acyl-coenzyme A dehydrogenase-linked oxidation of fatty acids by liver and heart mitochondria. Biochim Biophys Acta. 1972 Sep 20;275(3):298–301. doi: 10.1016/0005-2728(72)90210-1. [DOI] [PubMed] [Google Scholar]
  4. Brendel K., Bressler R. The resolution of (plus or minus)-carnitine and the synthesis of acylcarnitines. Biochim Biophys Acta. 1967 Feb 14;137(1):98–106. doi: 10.1016/0005-2760(67)90012-4. [DOI] [PubMed] [Google Scholar]
  5. Bunyan P. J., Greenbaum A. L. The effect of treatment of rats with pituitary growth hormone on the activities of some enzymes involved in fatty acid degradation and synthesis. Biochem J. 1965 Aug;96(2):432–438. doi: 10.1042/bj0960432. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. CHANCE B., WILLIAMS G. R. Respiratory enzymes in oxidative phosphorylation. III. The steady state. J Biol Chem. 1955 Nov;217(1):409–427. [PubMed] [Google Scholar]
  7. Chappell J. B. The oxidation of citrate, isocitrate and cis-aconitate by isolated mitochondria. Biochem J. 1964 Feb;90(2):225–237. doi: 10.1042/bj0900225. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chen R. F. Removal of fatty acids from serum albumin by charcoal treatment. J Biol Chem. 1967 Jan 25;242(2):173–181. [PubMed] [Google Scholar]
  9. DUNCOMBE W. G. THE COLORIMETRIC MICRO-DETERMINATION OF NON-ESTERIFIED FATTY ACIDS IN PLASMA. Clin Chim Acta. 1964 Feb;9:122–125. doi: 10.1016/0009-8981(64)90004-x. [DOI] [PubMed] [Google Scholar]
  10. Fletcher M. J. A colorimetric method for estimating serum triglycerides. Clin Chim Acta. 1968 Nov;22(3):393–397. doi: 10.1016/0009-8981(68)90041-7. [DOI] [PubMed] [Google Scholar]
  11. Goldman J. K., Bressler R. Growth hormone stimulation of fatty acid utilization by adipose tissue. Endocrinology. 1967 Dec;81(6):1306–1310. doi: 10.1210/endo-81-6-1306. [DOI] [PubMed] [Google Scholar]
  12. Gross M. D., Harris S., Beyer R. E. The effect of streptozotocin-induced diabetes on oxidative phosphorylation and related reactions in skeletal muscle mitochondria. Horm Metab Res. 1972 Jan;4(1):1–7. doi: 10.1055/s-0028-1094106. [DOI] [PubMed] [Google Scholar]
  13. HALL J. C., SORDAHL L. A., STEFKO P. L. The effect of insulin on oxidative phosphorylation in normal and diabetic mitochondria. J Biol Chem. 1960 May;235:1536–1539. [PubMed] [Google Scholar]
  14. Hanson R. W., Ballard F. J. Citrate, pyruvate, and lactate contaminants of commercial serum albumin. J Lipid Res. 1968 Sep;9(5):667–668. [PubMed] [Google Scholar]
  15. Harano Y., DePalma R. G., Lavine L., Miller M. Fatty acid oxidation, oxidative phosphorylation and ultrastructure of mitochondria in the diabetic rat liver. Hepatic factors in diabetic ketosis. Diabetes. 1972 May;21(5):257–270. doi: 10.2337/diab.21.5.257. [DOI] [PubMed] [Google Scholar]
  16. Harano Y., Kowal J., Yamazaki R., Lavine L., Miller M. Carnitine palmitoyltransferase activities (1 and 2) and the rate of palmitate oxidation in liver mitochondria from diabetic rats. Arch Biochem Biophys. 1972 Dec;153(2):426–437. doi: 10.1016/0003-9861(72)90360-8. [DOI] [PubMed] [Google Scholar]
  17. Herrera E., Freinkel N. Interrelationships between liver composition, plasma glucose and ketones, and hepatic acetyl-CoA and citric acid during prolonged starvation in the male rat. Biochim Biophys Acta. 1968 Dec 23;170(2):244–253. doi: 10.1016/0304-4165(68)90004-4. [DOI] [PubMed] [Google Scholar]
  18. Hoppel C. L., Tomec R. J. Carnitine palmityltransferase. Location of two enzymatic activities in rat liver mitochondria. J Biol Chem. 1972 Feb 10;247(3):832–841. [PubMed] [Google Scholar]
  19. Krebs H. A., Wallace P. G., Hems R., Freedland R. A. Rates of ketone-body formation in the perfused rat liver. Biochem J. 1969 May;112(5):595–600. doi: 10.1042/bj1120595. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Mackerer C. R., Paquet R. J., Mehlman M. A., Tobin R. B. Oxidation and phosphorylation in live mitochondria from alloxan and steptozotocin diabetic rats. Proc Soc Exp Biol Med. 1971 Jul;137(3):992–995. doi: 10.3181/00379727-137-35712. [DOI] [PubMed] [Google Scholar]
  21. Matsubara T., Tochino Y. Depression of respiratory activities in the liver mitochondria of diabetic rats and the restorative action of insulin. J Biochem. 1969 Sep;66(3):397–404. doi: 10.1093/oxfordjournals.jbchem.a129158. [DOI] [PubMed] [Google Scholar]
  22. McGarry J. D., Foster D. W. Acute reversal of experimental diabetic ketoacidosis in the rat with (+)-decanoylcarnitine. J Clin Invest. 1973 Apr;52(4):877–884. doi: 10.1172/JCI107252. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. McGarry J. D., Foster D. W. Regulation of ketogenesis and clinical aspects of the ketotic state. Metabolism. 1972 May;21(5):471–489. doi: 10.1016/0026-0495(72)90059-5. [DOI] [PubMed] [Google Scholar]
  24. McGarry J. D., Foster D. W. The regulation of ketogenesis from oleic acid and the influence of antiketogenic agents. J Biol Chem. 1971 Oct 25;246(20):6247–6253. [PubMed] [Google Scholar]
  25. McGarry J. D., Meier J. M., Foster D. W. The effects of starvation and refeeding on carbohydrate and lipid metabolism in vivo and in the perfused rat liver. The relationship between fatty acid oxidation and esterification in the regulation of ketogenesis. J Biol Chem. 1973 Jan 10;248(1):270–278. [PubMed] [Google Scholar]
  26. Meier J. M., McGarry J. D., Faloona G. R., Unger R. H., Foster D. W. Studies of the development of diabetic ketosis in the rat. J Lipid Res. 1972 Mar;13(2):228–233. [PubMed] [Google Scholar]
  27. Norum K. R. Activation of palmityl-coA: carnitine palmityltransferase in livers from fasted, fat-fed, or diabetic rats. Biochim Biophys Acta. 1965 Jun 1;98(3):652–654. doi: 10.1016/0005-2760(65)90166-9. [DOI] [PubMed] [Google Scholar]
  28. Olsen C. An enzymatic fluorimetric micromethod for the determination of acetoacetate, -hydroxybutyrate, pyruvate and lactate. Clin Chim Acta. 1971 Jul;33(2):293–300. doi: 10.1016/0009-8981(71)90486-4. [DOI] [PubMed] [Google Scholar]
  29. Van Harken D. R., Dixon C. W., Heimberg M. Hepatic lipid metabolism in experimental diabetes. V. The effect of concentration of oleate on metabolism of triglycerides and on ketogenesis. J Biol Chem. 1969 May 10;244(9):2278–2285. [PubMed] [Google Scholar]
  30. Ziegler H. J., Bruckner P., Binon F. O-acylation of dl-carnitine chloride. J Org Chem. 1967 Dec;32(12):3989–3991. doi: 10.1021/jo01287a057. [DOI] [PubMed] [Google Scholar]
  31. van Tol A. The effect of fasting on the acylation of carnitine and glycerophosphate in rat liver subcellular fractions. Biochim Biophys Acta. 1974 Jul 25;357(1):14–23. doi: 10.1016/0005-2728(74)90107-8. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES