Ketone Bodies

• Metabolism of ketone bodies:

  • Ketone compounds (bodies) include acetoacetate (AcAc), b-hydroxibutyrate (3HB), and acetone
  • Ketone bodies are synthesized mainly in mitochondria of hepatocytes
  • Hydroxybutyrate dehydrogenase is a mitochondrial enzyme in hepatocytes and peripheral tissues, able to utilize ketone bodies in heart, skeletal muscle, certain cells of the kidney, and brain
  • Acetone is formed via spontaneous decarboxylation of acetoacetate and is exhaled

  
• Ketogenesis occurs in mitochondria of hepatocytes using Acetyl-CoA and/or Acetoacetyl-CoA obtained in b-oxidation of fatty acids
• Ketolysis involves the utilization of ketone bodies as fuel for extrahepatic tissues like the heart, skeletal muscle, kidney cells, intestinal mucosa, and brain
• Regulation of ketogenesis is indirect and occurs at three main phases: control of lipolysis/lipogenesis in adipose tissues, metabolic fate of active fatty acids in the liver, and metabolic fate of Acetyl-CoA obtained in b-oxidation
• Ketogenesis is enhanced when there is an increase in circulating free fatty acids that arise from lipolysis of triacylglycerol in adipose tissue
• Factors regulating mobilization of TAG to FFA from adipose tissue are important in controlling ketogenesis
• Main factors affecting ketogenesis: glucagon and insulin
• In normal conditions, when the ratio of glucagon/insulin is low, insulin suppresses lipolysis by inhibiting hormone-sensitive lipase, leading to minor ketogenesis in the liver
• Regulation phase 2 in normal conditions involves esterification of FFA to acylglycerols and phospholipids, then transport into the mitochondrial matrix via the carnitine shuttle for beta-oxidation
• In normal conditions, when the ratio of glucagon/insulin is low, insulin stimulates esterification and inhibits beta-oxidation indirectly via the synthesis of malonyl-CoA
• Regulation phase 3 in normal conditions involves the full oxidation of Acetyl-CoA to CO2 and H2O in the Citric Acid Cycle for energy and citrate in the cytoplasm for fatty acid synthesis
• Ketosis and ketoacidosis:

  • In a balanced diet, concentration of ketone bodies (KB) is < 2 mmol/l, excretion with urine <1 mg/day
  • Increased KB in blood leads to ketonemia and in urine to ketouria, causing ketosis
  • Ketosis results from increased generation of KB in the liver and relatively lower consumption in peripheral tissues
• Ketoacidosis criteria are based on the concentration of KB in blood, not urine
• Diabetic ketoacidosis is a severe condition with very high KB and FFA levels, requiring insulin administration as a therapeutic approach