KETONE BODIES

KETONE BODIES

1. Organic chemical compounds derived from lipids

   • Acetone
   • Acetoacetic acid
     • Necessary for the synthesis of Cholesterol
   • β-Hydroxybutyric acid
   • Water-soluble molecules with a ketone functional group
     • METABOLISM
       • Biosynthesis
         • Acetyl CoA Recycling
           • Free fatty acids are broken down into Acetyl CoA molecules
             • Condensation of two acetyl CoA molecules
               • Acetoacetyl-CoA formation
                 • Mediated by Acetoacetyl-CoA thiolase (ACAT1)
                 • Synthesis of HMG CoA from the union of a third molecule of Acetyl CoA
                   • Mediated by HMG-CoA synthetase (HMGSC2)
                   • Acetoacetate formation
                     • Mediated by HMG-CoA lyase (HMGSCL)
                     • Acetone formation
                     • β-hydroxybutyrate formation
             • β-oxidation
       • Regulation
         • Endocrine
           • Inhibited by insulin
             • Blocking of lipolysis in adipocytes
             • High levels of Succinyl CoA and malonyl-CoA levels
           • Stimulated by Glucagon and Cortisol
             • Increase fatty acid transport and β-oxidation
             • Inhibited by high levels of insulin
           • Stimulated by epinephrine and norepinephrine
         • Trasncriptional
           • PPARα transcription factor
             • Stimulation of MCT1 expression
             • HMG CoA synthase expression regulation
         • Post transcriptional
           • HMG CoA synthase
             • Activation
               • Palmitoylation, mediated by palmitoyl-CoA concentration
             • Inactivation
               • Acetylation, mediated by mitochondrial acetyltransferases
               • Succinylation, mediated by succinyl-CoA concentration
     • Transported to brain, heart, and skeletal muscle through bloodstream
     • Produced under conditions of long-lasting fasting state or prolonged intense exercise
       • Low levels of oxaloacetate and malate in liver mitochondria

2. Physiological effects

   • Anti-inflammatory
     • Decrease neuroinflammation in brain
       • Activation of the receptor hydroxy-carboxylic acid receptor 2 (HCA2)
         • Inhibition of NF-kB
   • Antioxidant
     • Stimulates transcriptional machinery of antioxidant genes
       • Manganese superoxide dismutase (MnSOD)
       • Forkhead transcription factors 3 (FoxO3)
     • Neuroprotective effects
       • β-Hydroxybutyrate reduces the production of reactive oxygen species
   • Energy source
     • Absorbed by peripheral tissues by monocarboxylate transporter 1 (MCT1)
       • Ketolysis
         • Via oxidation in mitochondria
           • Conversion of Hydroxybutyrate to Acetoacetate
             • Mediated by β-hydroxybutyrate dehydrogenase
             • Acetoacetyl CoA formation
               • Mediated by succinyl-CoA:3-ketoacid-CoA transferase (SCOT)
               • Synthesis of two acetyl-CoA molecules
                 • Mediated by ACAT1
                 • Krebs cycle oxidation

3. Pathologies

   • Diabetic ketoacidosis
     • Excessive gluconeogenesis, not controlled by insulin
       • Acetyl CoA accumulation
     • Decrease in SCOT activity
       • Accumulation of ketone bodies
         • Decrease in plasma pH
   • Alcoholic ketoacidosis
     • Prolonged intake of ethanol
       • Oxidation by hepatic alcohol dehydrogenase
         • Increase of NADH and ketogenesis

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