Fatty Acid Synthesis

Overview

• Occurs primarily in the liver but can happen in other tissues.
• Triggered by high blood glucose levels or excess cellular ATP.
• Happens in the fed state (absorptive state).
• Insulin is the main hormone stimulating this process.

Process Initiation

• Glucose enters cells via transporters and converts to pyruvate.
• Pyruvate enters mitochondria and converts to acetyl CoA.
• Acetyl CoA combines with oxaloacetate to form citrate.
• Citrate can eventually lead to ATP production or return to acetyl CoA.

Citrate Shuttle

• Excess ATP inhibits isocitrate dehydrogenase, causing citrate accumulation.
• Citrate exits mitochondria and breaks down into oxaloacetate and acetyl CoA by citrate lyase.
• Oxaloacetate converts to malate, then to pyruvate by malic enzyme, generating NADPH.

Acetyl-CoA Carboxylase (ACC)

• Key enzyme in fatty acid synthesis.
• Converts acetyl CoA into malonyl CoA with biotin and CO2.
• Highly regulated: allosterically by citrate (stimulation) and fatty-acyl CoAs (inhibition).
• Hormonal regulation: insulin (stimulation) vs. glucagon/epinephrine/norepinephrine (inhibition).

Regulation Details

• Citrate and insulin activate ACC, causing polymerization (active form).
• Fatty-acyl CoAs and glucagon/epinephrine promote the inactive dimer form (phosphorylated).
• Protein kinase A (from glucagon) phosphorylates ACC to inactivate it.
• Phosphoprotein phosphatases (from insulin) dephosphorylate ACC, activating it.

Importance

• Malonyl CoA is a precursor for fatty acid synthesis.
• NADPH serves as a reducing agent, also sourced from the pentose phosphate pathway.

Conclusion

• Acetyl-CoA carboxylase plays a crucial role, with regulation ensuring fatty acids are synthesized or not, based on metabolic needs.
• Next steps in understanding full fatty acid synthesis will focus on the actual building of fatty acids.