The biochemistry of ketogenesis and its role in weight management, neurological disease and oxidative stress

Abstract

Ketogenesis is the branch of mammalian metabolism concerned with the synthesis of ketone bodies. In this process, the small, water-soluble compounds acetoacetate, D-3-β-hydroxybutyrate and propanone are produced by the liver in response to reduced glucose availability. Although ketone bodies are always present at a low level in healthy individuals, dietary manipulation and certain pathological conditions can increase the levels of these compounds in vivo. In some instances, such as in refractory epilepsy, high levels of ketone bodies can be beneficial—in this instance, by exerting an anticonvulsant effect. Conversely, if the levels of ketones rise to supraphysiological levels, as can occur in diabetes mellitus, a state of ketoacidosis can occur, which has serious consequences for cellular function. More recently, research has identified a possible link between ketogenesis and free radical-mediated pathologies, highlighting the potential application of ketogenic diets to the treatment of conditions such as Alzheimer's disease. Overall, an understanding of ketone body metabolism and its links to human disease may prove to be vital in developing new regimens for the treatment of human disease.

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Notes

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    Decarboxylation is also possible via. the cytosolic enzyme acetoacetate decarboxylase.

  2. 2.

    Glutathione (γ-glutamylcysteinylglycine) has the largest negative reduction potential found in vivo (E°′ = −1.5 V) making it the most potent naturally occuring antioxidant in biological systems. See Ref. [4] for an excellent treatment of the thermodynamics of reduction by glutathione.

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Acknowledgements

This work was partially supported by the Northern Ireland R&D Office (Extension to RRG 5.42). The authors would like to thank Dr DJ Timson, School of Biological Sciences, Queen's University Belfast, for useful discussions of mammalian metabolism.

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Correspondence to Peter Andrew C. McPherson.

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McPherson, P.A.C., McEneny, J. The biochemistry of ketogenesis and its role in weight management, neurological disease and oxidative stress. J Physiol Biochem 68, 141–151 (2012). https://doi.org/10.1007/s13105-011-0112-4

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Keywords

  • Alzheimer's disease
  • Atkin's diet
  • Epilepsy
  • Diabetes
  • Free radicals
  • Ketogenic diets
  • Ketone bodies
  • Oxidative stress