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• The dietary carbohydrates and amino acids, when consumed in excess, can be converted to fatty acids and stored as triacylglycerols
• De novo synthesis of fatty acids

  Occurs predominantly in liver, kidney, adipose tissue, and lactating mammary glands
• Enzyme machinery for fatty acid production

  Located in the cytosomal fraction of the cell
• Acetyl CoA


  Source of carbon atoms for fatty acid synthesis
• NADPH


  Provides the reducing equivalents for fatty acid formation
• ATP


  Supplies energy for fatty acid formation
• Fatty acid synthesis stages

  1. Production of acetyl CoA and NADPH

  2. Conversion of acetyl CoA to malonyl CoA

  3. Reactions of fatty acid synthase complex
• Production of acetyl CoA and NADPH

  1. Acetyl CoA produced in mitochondria

  2. Oxidation of pyruvate and fatty acids

  3. Degradation of carbon skeleton of certain amino acids

  4. Transfer of acetyl CoA to cytosol
• Acetyl CoA condenses with oxaloacetate in mitochondria to form citrate
• Citrate is freely transported to cytosol where it is cleaved by citratelyase to liberate acetyl CoA and oxaloacetate
• Oxaloacetate in the cytosol is converted to malate
• Malic enzyme converts malate to pyruvate
• NADPH and CO2 are generated in the conversion of malate to pyruvate
• Transport of acetyl CoA from mitochondria to cytosol is coupled with the cytosomal production of NADPH and CO2
• Formation of malonyl CoA

  Acetyl CoA is carboxylated to malonyl CoA by acetyl CoA carboxylase
• Formation of malonyl CoA is an ATP-dependent reaction and requires biotin for CO2 fixation
• Fatty Acid Synthase Complex


  Sequentially adds two-carbon units from malonyl CoA to the growing fatty acyl chain to form palmitate
• Fatty acid synthase is more appropriately called palmitate synthase because palmitate is the only fatty acid that humans can synthesize de novo
• Fatty acid synthase is in the cytoplasm and is rapidly induced in the liver after a meal by high carbohydrate and rising insulin levels
• NADPH is required to reduce the acetyl groups added to the fatty acid
• Eight acetyl CoA groups are required to produce palmitate (16:0)
• Fatty acyl CoA may be elongated and desaturated using enzymes associated with the smooth endoplasmic reticulum (SER)
• Cytochrome b5 is involved in the desaturation reactions
• These enzymes cannot introduce double bonds past position 9 in the fatty acid
• Of the 16 carbons present in palmitate, only two come from acetyl CoA directly
• The remaining 14 carbons in palmitate are from malonyl CoA
• Overall reaction of palmitate synthesis


  8 Acetyl CoA + 7 ATP + 14 NADPH + 14 H+ → Palmitate + 8 CoA + 7 ADP + 7 Pi + 6 H2O
• Regulation of fatty acid synthesis

  Controlled by enzymes, metabolites, end products, hormones, and dietary manipulations
• Acetyl CoA carboxylase


  Controls a committed step in fatty acid synthesis
• Acetyl CoA carboxylase exists as an inactive protomer or an active polymer
• Citrate promotes polymer formation, hence increases fatty acid synthesis
• Palmitoyl CoA and malonyl CoA cause depolymerization of the enzyme and inhibit fatty acid synthesis
• Hormonal influence


  Regulates acetyl CoA carboxylase by phosphorylation (inactive form) and dephosphorylation (active form)
• Glucagon, epinephrine, and norepinephrine inactivate the enzyme by cAMP dependent phosphorylation
• Insulin dephosphorylates and activates the enzyme
• Insulin promotes fatty acid synthesis while glucagon inhibits
• Insulin stimulates tissue uptake of glucose and conversion of pyruvate to acetyl CoA
• Consumption of high carbohydrate or fat-free diet increases the synthesis of acetyl CoA carboxylase and fatty acid synthase
• Fasting or high fat diet decreases fatty acid production by reducing the synthesis of these two enzymes
• NADPH is provided by citrate transport or hexose monophosphate shunt