Ketone Body Metabolism

Ketone bodies are an important source of energy and their metabolism is a tightly regulated process. Ketone bodies are molecules used by the liver to synthesize acetyl-CoA, which, in turn, is made available to other tissues for energy production. When glucose reserves in the body run low, more fatty acids are made available to the liver for oxidation, leading to the consequent production of energy-rich molecules, most notably acetyl-CoA. Acetyl-CoA can either enter the citric acid cycle in the liver or be used for the synthesis of ketone bodies.

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Ketone Bodies and Their Function

  • 3 major types of ketones are produced in the liver:
    • Acetoacetate
    • Acetone: a product of the spontaneous decarboxylation of acetoacetate or the action of acetoacetate decarboxylase
    • β-Hydroxybutyrate: the most abundant ketone body derived from acetoacetate by D-β-hydroxybutyrate dehydrogenase
  • Other ketones are synthesized from the metabolism of triglycerides (i.e., β-ketopentanoate, β-hydroxypentanoate).
  • Ketone bodies are produced during periods of caloric restriction.
  • Released by the liver after glycogen consumption
  • Ketones have a characteristic fruity smell.
  • Functions:
    • Source of energy for the heart, brain, and muscle:
      • Cannot be used as a source of energy by the liver because of the lack of thiophorase
      • Acetoacetate produces 2 GTP and 22 ATP
    • Brain is dependent on ketone bodies as its sole energy resource during periods of fasting because the blood-brain barrier is not permeable to fatty acids.

Ketogenesis

  • Location: mitochondria of liver cells 
  • Timing: Ketogenesis occurs in a state of caloric restriction during hypoglycemia.
  • Regulation:
    • Insulin (primary regulation) inhibits ketogenesis.
    • Activation of adenosine monophosphate-activated protein kinase promotes ketogenesis.
    • Inhibition by ethanol
    • During starvation, acetyl-coenzyme A (CoA) is used in ketogenesis because intermediates in the citric acid cycle are not readily available.
  • Synthesis:
    • Thiolase catalyzes the combination of 2 acetyl-CoA molecules → acetoacetyl-CoA
    • Rate-determining enzyme: HMG-CoA synthase converts acetoacetyl-CoA → β-hydroxy-β-methylglutaryl-CoA (HMG-CoA)
    • HMG-CoA lyase breaks HMG-CoA → 1st ketone body: acetoacetate
    • Acetoacetate can form other ketone bodies:
      • D-β-hydroxybutyrate (β-hydroxybutyric acid) via the action of β-hydroxybutyrate dehydrogenase
      • Acetone via nonenzymatic decarboxylation
Ketone body metabolism diagram

Steps required for the synthesis of ketone bodies

Image by Lecturio. License: CC BY-NC-SA 4.0

Transport and Utilization

  • Ketone bodies are delivered to cells as an energy source during fasting states.
  • Acetoacetate and β-hydroxybutyrate are water-soluble ketone bodies that can travel freely through blood:
    • Acetoacetate may spontaneously decarboxylate into acetone.
    • Acetoacetate may be converted into 3-hydroxybutyrate by the action of β-hydroxybutyrate dehydrogenase.
  • Acetone is not a productive molecule and is expelled through the lungs.
  • Other ketone bodies may be excreted in the urine before they reach target tissues to become energetically useful.
  • Acetoacetyl-CoA is hydrolyzed by thiolase into 2 acetyl-CoA molecules, which are taken up in the citric acid cycle.
Utilization of ketone bodies

Citric acid cycle

FFA: free fatty acid
Image by Lecturio. License: CC BY-NC-SA 4.0

Clinical Relevance

  • Diabetes mellitus: the absence of insulin can increase the β-oxidation of fatty acids due to the influence of glucagon. This phenomenon drastically increases the production of ketone bodies, producing a state of ketosis. Diabetic ketoacidosis (DKA) occurs when there is a prolonged accumulation of ketoacids and other endogenously produced acids in the bloodstream, further leading to anion-gap metabolic acidosis. Diabetic ketoacidosis may lead to confusion, Kussmaul respirations, and cerebral edema. 
  • Ketosis: a condition seen in cases of prolonged fasting, starvation, and malnutrition (extremely low-carbohydrate diets), wherein glucose reserves are used up and ketogenesis increases dramatically. 
  • HMG-CoA: an intermediate in cholesterol synthesis. The enzyme HMG-CoA synthase forms HMG-CoA from acetyl-CoA and acetoacetyl-CoA and is also an intermediate in ketogenesis. The enzyme HMG-CoA lyase hydrolyzes HMG-CoA into acetyl CoA and acetoacetate. Statins are a group of drugs that block the enzyme HMG-CoA reductase, which catalyzes cholesterol synthesis in the liver. Statins are most commonly used in the management of cardiovascular diseases.

References

  1. Botham, K.M., Mayes, P.A. (2018). Oxidation of fatty acids: Ketogenesis. In V.W. Rodwell, D.A. Bender, K.M. Botham, P.J. Kennelly, P.A. Weil (Eds.), Harper’s Illustrated Biochemistry, 31e. New York, NY: McGraw-Hill Education. accessmedicine.mhmedical.com/content.aspx?aid=1160192486
  2. Elliott, B., Mina, M., Ferrier, C. (2016). Complete and voluntary starvation of 50 days. Clinical Medicine Insights. Case Reports, 9, 67–70. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4982520/
  3. Paoli, A., Bosco, G., Camporesi, E.M., Mangar, D. (2015). Ketosis, ketogenic diet and food intake control: A complex relationship. Frontiers in Psychology, 6, 27. https://doi.org/10.3389/fpsyg.2015.00027

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