Fatty Acid Synthesis

• Fatty acid synthesis can occur in various tissues, but we will focus on the liver
• Occurs in the fed state when blood glucose levels are high
• Insulin is the main hormone that stimulates fatty acid synthesis
• High cellular ATP levels can also trigger fatty acid synthesis
• Glucose is converted into pyruvate, which is then converted into acetyl CoA in the mitochondria
• Acetyl CoA combines with oxaloacetate to form citrate
• Citrate is converted into isocitrate by the enzyme aconitase
• Isocitrate is converted into alpha-ketoglutarate, which can enter the Krebs cycle to produce ATP
• High ATP levels inhibit the enzyme isocitrate dehydrogenase, leading to citrate accumulation
• Citrate is broken down into oxaloacetate and acetyl CoA by the enzyme citrate lyase
• Acetyl CoA carboxylase converts acetyl CoA into malonyl-CoA by adding a carbon from CO2 or bicarbonate
• Malonyl-CoA is a three-carbon molecule crucial for fatty acid synthesis
• Acetyl CoA carboxylase is regulated allosterically by citrate and long-chain fatty acids with CoA
• Acetyl CoA carboxylase can exist in two forms: active form and inactive form
• In the inactive form, acetyl CoA carboxylase exists as dimers
• Stimulants for acetyl CoA carboxylase include citrate and insulin
• Long-chain fatty acids with coenzyme A inhibit acetyl CoA carboxylase
• Insulin stimulates acetyl CoA carboxylase, while cortisol, glucagon, epinephrine, and norepinephrine inhibit it
• Citrate and insulin activate acetyl CoA carboxylase, causing dimers to polymerize into the active form
• Long-chain fatty acids with coenzyme A stimulate the conversion of the active form back to the inactive dimeric form
• Phospho protein phosphatases remove phosphates from the inactive form, converting it back to the active form
• NADPH is important for fatty acid synthesis and can be obtained from the pentose phosphate pathway
• Malonyl CoA is a precursor for fatty acids and requires NADPH for its synthesis
• Fatty acids are biological molecules consisting of a long hydrocarbon chain and a terminal carboxylate group
• The terminal carboxylate group gives the molecule hydrophilic polar properties
• The long hydrocarbon chain gives the fatty acids hydrophobic nonpolar properties
• Functions of fatty acids in cells:

  • Fuel molecules that can be broken down to generate high-energy ATP molecules
  • Used to build molecules in cell membranes like lipids and phospholipids
  • Modify proteins by attaching fatty acids to increase functionality
  • Building blocks for molecules such as hormones and intracellular messenger molecules
• Breakdown of fatty acids consists of four steps:

  • Oxidation
  • Hydration
  • Another oxidation
  • Cleavage
  • This is an oxidative process that shortens the fatty acid chain by two carbons
• Synthesis of fatty acids:

  • Begins with activated acyl units and malonyl units
  • Mirror image of the breakdown process
  • Consists of steps in reverse order compared to breakdown
  • Reductive process that builds up the hydrocarbon chain of fatty acids
• In fatty acid synthesis, glucose is converted into pyruvate via the glycolytic pathway, then pyruvate is taken up into the mitochondria in the presence of oxygen to be converted into acetyl CoA
• Acetyl CoA combines with oxaloacetate to form citrate, which goes through the Krebs cycle to produce NADHs and FADH2s for the electron transport chain, generating ATP
• High ATP levels inhibit the conversion of citrate into isocitrate, leading to citrate buildup, which is then transported out of the mitochondria into the cytoplasm
• In the cytoplasm, citrate is converted back into acetyl CoA and oxaloacetate by citrate lyase, with the addition of a CoA group
• Oxaloacetate is converted into malate, which is then converted back into pyruvate by the malic enzyme, generating NADPH, a crucial molecule for fatty acid synthesis
• NADPH is also produced in the pentose phosphate pathway, providing another source of this important molecule for fatty acid synthesis
• Acetyl CoA is carboxylated by acetyl-CoA carboxylase to form malonyl CoA, a three-carbon structure that serves as a building block for fatty acid synthesis
• Malonyl CoA not only acts as a building block but also regulates the activity of specific proteins on the mitochondria
• Insulin stimulates acetyl-CoA carboxylase, glucagon, norepinephrine, and epinephrine inhibit it, and long-chain fatty acids act as regulators based on the need for fatty acid production
• NADPH and malonyl CoA are two crucial substrates needed to start building the fatty acid chain in the synthesis process
• Understanding the regulation and production of these substrates is essential for comprehending the intricacies of fatty acid synthesis