Gluconeogenesis Notes

Gluconeogenesis

Overview

  • The liver maintains blood glucose levels during fasting through:
    • Glycogenolysis
    • Gluconeogenesis
  • The kidney can also perform gluconeogenesis, but to a lesser extent.
  • Regulation:
    • Promoted by glucagon and epinephrine (raise blood sugar)
    • Inhibited by insulin (lowers blood sugar)
  • During fasting:
    • Glycogen reserves decrease significantly within the first 12 hours.
    • Gluconeogenesis increases.
    • After 24 hours, gluconeogenesis becomes the primary source of glucose.

Important Substrates for Gluconeogenesis

  • Glycerol-3-phosphate:
    • From stored fats (triacylglycerols) in adipose tissue.
  • Lactate:
    • From anaerobic glycolysis.
  • Glucogenic amino acids:
    • From muscle protein.
    • Most amino acids are glucogenic EXCEPT leucine and lysine.
    • Glucogenic amino acids can be converted into intermediates that feed into gluconeogenesis.
  • Ketogenic amino acids:
    • Can be converted into ketone bodies.
    • Ketone bodies serve as an alternative fuel during prolonged starvation.
  • Dietary fructose and galactose can also be converted to glucose in the liver.

Acetyl CoA and Fatty Acids

  • In humans, glucose is converted into acetyl CoA via glycolysis and pyruvate dehydrogenase. However, acetyl CoA cannot be converted back to glucose.
  • Most fatty acids are metabolized to acetyl CoA and are thus not a major source of glucose.
  • Exception: Fatty acids with an odd number of carbon atoms (e.g., 17 carbons) yield propionyl-CoA, which is glucogenic.

Conversion of Gluconeogenic Intermediates

  • Lactate is converted to pyruvate by lactate dehydrogenase.
  • Alanine is converted to pyruvate by alanine aminotransferase.
  • Glycerol-3-phosphate is converted to dihydroxyacetone phosphate (DHAP) by glycerol-3-phosphate dehydrogenase.

Important Enzymes of Gluconeogenesis

  • Most steps are the reverse of glycolysis. The key enzymes bypass the irreversible steps of glycolysis (glucokinase, phosphofructokinase-1, and pyruvate kinase).
  • Four important enzymes to know:
    • Pyruvate carboxylase
    • Phosphoenolpyruvate carboxykinase (PEPCK)
    • Fructose-1,6-bisphosphatase
    • Glucose-6-phosphatase
Pyruvate Carboxylase
  • Location: Mitochondrial enzyme.
  • Activated by acetyl CoA from beta-oxidation.
  • Converts pyruvate to oxaloacetate (OAA).
  • OAA is a citric acid cycle intermediate that cannot leave the mitochondrion directly.
  • OAA is reduced to malate, which exits the mitochondrion via the malate-aspartate shuttle.
  • In the cytoplasm, malate is oxidized back to OAA.
  • Significance of Acetyl CoA Activation:
    • High acetyl CoA indicates the cell is energetically satisfied. It inhibits pyruvate dehydrogenase, so glucose isn't burned.
    • Pyruvate is shunted to pyruvate carboxylase for gluconeogenesis.
    • Acetyl CoA source is from fatty acids, not glycolysis in this case.
    • To reduce glucose in the liver during gluconeogenesis, fatty acids are burned to provide energy and stop the forward flow of the citric acid cycle.
    • This produces OAA, leading to glucose production.
Phosphoenolpyruvate Carboxykinase (PEPCK)
  • Location: Cytoplasm.
  • Induced by glucagon and cortisol (raise blood sugar levels).
  • Converts OAA to phosphoenolpyruvate (PEP).
  • Requires GTP.
  • PEP continues in the pathway to fructose-1,6-bisphosphate.
  • Pyruvate carboxylase and PEPCK bypass pyruvate kinase by converting pyruvate back into PEP.
Fructose-1,6-Bisphosphatase
  • Location: Cytoplasm.
  • Key control point and rate-limiting step of gluconeogenesis.
  • Reverses the action of phosphofructokinase-1 (rate-limiting step of glycolysis).
  • Removes phosphate from fructose-1,6-bisphosphate to form fructose-6-phosphate.
  • Phosphatases generally oppose kinases.
  • Regulation:
    • Activated by ATP.
    • Inhibited by AMP and fructose-2,6-bisphosphate (F26BP).
  • High ATP means the cell has enough energy to produce glucose for the body.
  • High AMP means the cell needs energy and can't afford to produce glucose for others.
  • Fructose-2,6-bisphosphate (F26BP):
    • Marker for satisfactory energy levels in liver cells.
    • Helps cells override the inhibition of phosphofructokinase-1 caused by high acetyl CoA levels.
    • F26BP (produced by PFK-2) controls both gluconeogenesis and glycolysis in the liver.
      • PFK-2 is activated by insulin and inhibited by glucagon.
      • Glucagon lowers F26BP and stimulates gluconeogenesis.
      • Insulin increases F26BP and inhibits gluconeogenesis.
Glucose-6-Phosphatase
  • Location: Lumen of the endoplasmic reticulum (ER) in liver cells only.
  • Glucose-6-phosphate is transported into the ER.
  • Free glucose is transported back into the cytoplasm (then diffuses out of the cell via GLUT transporters).
  • Absence in skeletal muscle:
    • Muscle glycogen cannot serve as a source of blood glucose.
    • Muscle glycogen is used only within the muscle.
  • Bypasses glucokinase and hexokinase (which convert glucose to glucose-6-phosphate).

Additional Notes

  • Alanine is a major glucogenic amino acid, but most amino acids are glucogenic.
  • Most glucogenic amino acids are converted to citric acid cycle intermediates, then to malate, following the same path to glucose.
  • Hepatic gluconeogenesis doesn't provide energy for the liver.
  • Gluconeogenesis requires ATP, provided by beta-oxidation of fatty acids.
  • Hepatic gluconeogenesis is dependent on beta-oxidation of fatty acids in the liver.
  • During low blood sugar, adipose tissue releases fatty acids by breaking down triacylglycerols into glycerol (converted to DHAP) and free fatty acids.
  • Acetyl CoA from fatty acids cannot be converted into glucose directly, but it can be converted into ketone bodies as an alternative fuel (including for the brain).
  • Extended periods of low blood sugar are accompanied by high levels of ketones in the blood.
  • Ketone bodies serve as a transportable form of acetyl CoA, primarily utilized during extended starvation.