2. Free fatty acids -> three fatty acids

Hormone-sensitive lipase is activated in response to stress hormones (eg, catecholamines, glucagon, ACTH), whereas it is inhibited by the release of insulin.

Regulation by fructose-2,6-bisphosphate

Main idea: Insulin & glucagon control PFK-2 & FBPase-2 → control amount of F-2,6-BP → direction towards gluconeogenesis or glycosis.
Fructose bisphosphatase-2 (FBPase-2) and phosphofructokinase-2 (PFK-2) are the same bifunctional enzyme whose function is reversed by phosphorylation by protein kinase A.

• Fasting state: ↑ glucagon → ↑ cAMP → ↑ protein kinase A → ↑ FBPase-2, ↓ PFK-2, less glycolysis, more gluconeogenesis.
• Fed state: ↑ insulin → ↓ cAMP → ↓ protein kinase A → ↓ FBPase-2, ↑ PFK-2, more glycolysis, less gluconeogenesis.

Enzymes Increased in Fed State (High Insulin:Glucagon Ratio)

The fed state focuses on using and storing incoming fuel (anabolism). Insulin is the dominant hormone.

• Glycolysis & Glucose Uptake (Energy Production & Storage Precursors):

  • Glucokinase (Liver) / Hexokinase (Most Tissues): Traps glucose in the cell by phosphorylating it to glucose-6-phosphate. Glucokinase in the liver is induced by insulin.
  • Phosphofructokinase-1 (PFK-1): The rate-limiting enzyme of glycolysis. Activated by fructose-2,6-bisphosphate (F-2,6-BP).
  • Phosphofructokinase-2 (PFK-2): Activated by insulin. PFK-2 produces F-2,6-BP, which strongly activates PFK-1, pushing glycolysis forward.
  • Pyruvate Kinase: Catalyzes the final, irreversible step of glycolysis.

• Glycogen Synthesis (Glucose Storage):

  • Glycogen Synthase: The rate-limiting enzyme for glycogenesis. Activated by insulin-mediated dephosphorylation.

• Fatty Acid & Triglyceride Synthesis (Fat Storage):

  • Acetyl-CoA Carboxylase (ACC): The rate-limiting enzyme for fatty acid synthesis. Activated by insulin and citrate.
  • Fatty Acid Synthase: Synthesizes fatty acids from acetyl-CoA and malonyl-CoA.
  • Lipoprotein Lipase (LPL): Found on endothelial cells; breaks down triglycerides from chylomicrons and VLDL for uptake into adipose tissue and muscle. Activated by insulin.

Enzymes Increased in Fasting State (Low Insulin:Glucagon Ratio)

The fasting state focuses on mobilizing stored fuel to maintain blood glucose for the brain and RBCs (catabolism). Glucagon and epinephrine are the dominant hormones.

• Glycogenolysis (Glucose Release from Storage):

  • Glycogen Phosphorylase: The rate-limiting enzyme of glycogenolysis. Activated by glucagon and epinephrine via a cAMP-mediated cascade.

• Gluconeogenesis (New Glucose Synthesis):

  • Pyruvate Carboxylase: Converts pyruvate to oxaloacetate. Activated by acetyl-CoA.
  • Phosphoenolpyruvate Carboxykinase (PEPCK): Converts oxaloacetate to PEP. Upregulated by glucagon and cortisol.
  • Fructose-1,6-bisphosphatase: Bypasses PFK-1 in glycolysis. Inhibited by F-2,6-BP.
  • Glucose-6-phosphatase: Found only in the liver; dephosphorylates G6P to release free glucose into the blood.

• Lipolysis & Fatty Acid Oxidation (Fat Breakdown for Energy):

  • Hormone-Sensitive Lipase (HSL): Breaks down stored triglycerides in adipocytes into free fatty acids and glycerol. Activated by glucagon and epinephrine; inhibited by insulin.
  • Carnitine Palmitoyltransferase I (CPT-I): Rate-limiting enzyme for β-oxidation; transports fatty acids into the mitochondria.

• Ketogenesis (Alternate Fuel Production):

  • HMG-CoA Synthase: Rate-limiting enzyme for ketone body synthesis in the liver mitochondria.
  • HMG-CoA Lyase: Produces acetoacetate from HMG-CoA.