Gluconeogenesis

Overview

  •  Function
    • de novo glucose synthesis
    • effectively glycolysis in reverse
    • can maintain blood glucose when glycogen stores are exhausted
    • must supply brain and RBCs which utilize glucose for energy
    • is NOT a source of energy for the liver
    • hepatocytes use β-oxidation to supply the energy needed for gluconeogenesis
    • potential substrates
    • all amino acids
    • except for leucine and lysine 
    • lactate
    • produced in anaerobic glycolysis
    • glycerol-3-phosphate
    • produced in fat catabolism
    • propionyl-CoA
    • produced in odd-carbon fatty acid catabolism
  • Pathway
    • location 
      • hepatocytes (primary)
      • kidney
      • enterocytes
      • NOT muscle
        • no glucose-6-phosphatase
          • cannot release free glucose
    • enzymes   
      • involves both mitochondrial and cytosolic enzymes
      • several steps of glycolysis are reversible
      • the non-reversible steps must be bypassed with special gluconeogenic enzymes
        • pyruvate carboxylase
          • pyruvate → oxaloacetate
          • requires biotin and ATP
          • activated by acetyl-CoA 
            • oxaloacetate must be converted to malate to exit the mitochondria via the malate-aspartate shuttle
          • in mitochondria
        • PEP carboxykinase (PEPCK) 
          • oxaloacetate → phosphoenolpyruvate (PEP)
          • requires GTP
          • activated by glucagon and cortisol
          • in both cytosol and mitochondria
        • fructose-1,6-bisphosphatase 
          • fructose-1,6-bisphosphate → fructose-6-P
          • important control point of gluconeogenesis
          • activated by ATP, inhibited by AMP and fructose-2,6-bisphosphate
          • in cytosol
        • glucose-6-phosphatase (G6P)
          • glucose-6-P → glucose
          • in ER of hepatocytes
          • clinical relevance
            • von Gierke disease = G6P deficiency
              • see Glycogen metabolism 
      • other enzymes
        • lactate dehydrogenase
          • lactate → pyruvate
          • requires free NAD+
    • regulation 
      • stimulation
        • glucagon
        • acetyl CoA
        • citrate
      • inhibition
        • high NADH/NAD+ ratio
  • alcohol may cause elevated NADH/NAD+ ratio leading to hypoglycemia