Fatty Acid Biosynthesis: Precursors

• Biosynthesis of Fatty Acids: Precursors

Nonruminants

• Excess calories are stored as liver and muscle glycogen, and when full, fat is synthesized
• Glucose is the primary substance for fat synthesis, entering the glycolytic cycle and becoming pyruvate
• Ample oxaloacetate is available when there is sufficient food
• Pyruvate is diverted to acetyl CoA, which is used for fat synthesis
• Acetyl CoA cannot penetrate the mitochondrial wall, but citrate can
• Acetyl CoA and oxaloacetate condense to form citrate, which passes into the cytosol
• Oxaloacetate is removed in the cytosol by ATP citrate lyase, making acetyl CoA available for fatty acid synthesis
• Oxaloacetate is converted to malate by NADP malate dehydrogenase
• Malate is converted to pyruvate and returns to the citric acid cycle

Ruminants

• Excess energy from the rumen exists primarily as acetate and butyrate
• Propionate is preferentially diverted to glucose
• Ruminants cannot convert glucose to fat due to low activity of ATP citrate lyase and NADP malate dehydrogenase (malic enzyme)

Three Systems of Fatty Acid Synthesis

• Cytosolic synthesis of palmitate from acetyl coenzyme A, active in liver, kidney, brain, lungs, mammary gland and adipose tissue
• Requires NADPH, ATP, Mn+2 and CO2 as cofactors
  • Acetyl CoA and malonyl CoA react with acyl carrier protein to form acetoacetyl-ACP
  • Acetoacetyl-ACP is reduced to butyryl-ACP
  • It chain is elongated with malonyl-ACP to a length of 16 carbon Palmityl-ACP
  • 1 mole acetyl CoA + 7 moles malonyl CoA + 14 NADPH + 14H+ → Palmitate + 7 CO₂ + 14 NADP+ + 6 H2O + 8 coenzyme A
• Mitochondrial system for elongation of fatty acid chains exists but is active only under anaerobic conditions
• Involves elongation of fatty acid chains by two-carbon addition, with malonyl CoA as donor
• Saturated acids with 18, 20, 22 and 24 carbon atoms are produced
• Chain elongation occurs chiefly in the endoplasmic reticulum
• Desaturation of preformed fatty acids occurs in the endoplasmic reticulum of the microsomes
• Stearic acid is converted to oleic acid
• Synthesis of linoleic and alpha linolenic acid are not possible because mammals lack enzymes to introduce a double bond beyond A9
• Double bonds may be introduced into ingested fatty acid chains by fatty acyl-CoA desaturases in the microsomes

Fat Synthesis

• Direct synthesis of triacylglycerols (triglycerides) from monoacylglycerols occurs in the intestinal mucosa of higher animals.
• Fat in animals synthesized from carbohydrates contains two-thirds unsaturated fatty acids
• Fat deposited in adipose tissue comes from carbohydrates and dietary fat
• Composition of depot fat in nonruminants can be altered by dietary fat, while not in ruminants

β-Oxidation of Fatty Acids

• Fatty acids are combined with albumin and circulate as albumin-fatty acid complex

• Fatty acid oxidation starts in extramitochondrial cytoplasm with the formation of fatty acyl CoA

• Fatty acid + coenzyme A → fatty acyl CoA

• Fatty acyl CoA needs a carnitine carrier to pass into the mitochondrion

• Knoop proposed that fatty acids were oxidized physiologically by β-oxidation

• In the mitochondria, fatty acyl CoA is dehydrogenated, hydrated, dehydrogenated, and cleaved to acetyl CoA

  • A fatty acid shorter by two carbons remains
  • This process continues stepwise, each sequence producing a molecule of acetyl CoA
  • Acetyl CoA enters the TCA cycle, is oxidized to CO₂ + H₂O
  • Steps for Palmitic acid result in 129 ATP/mole

• Acetyl CoA can condense to form acetoacetate and ketone bodies, be converted to malonyl CoA, or react with acetoacetyl units in sterol synthesis

• Fatty acids containing odd numbers of carbon atoms are metabolized to two carbon units, until the terminal three carbon unit is reached

• Resulting propionate can form malonyl CoA or succinyl CoA

Importance of Carnitine in Fatty Acid Oxidation

• Dairy ruminants are susceptible to metabolic disorders and infectious diseases during the periparturient period
• Understanding lipid metabolism may allow development of nutritional and management approaches to prevent metabolic disorders in dairy cows
• Hepatic oxidation of long-chain fatty acids occurs in mitochondria and peroxisomes
• L-Carnitine is required for mitochondrial fatty acid oxidation
• Mitochondrial fatty acid oxidation involves 4 key steps
  • Uptake and activation of fatty acids to fatty acyl-CoA
  • Translocation of fatty acyl-CoA into the mitochondria
  • Beta-oxidation of fatty acyl-CoA
  • Ketogenesis
• Carnitine palmitoyltransferase (CPT) system allows fatty acids to be translocated into the mitochondria
• Carnitine abomasal infusion (20 g/d) influenced hepatic and peripheral nutrient metabolism
• L-Carnitine abomasal infusion decreased liver lipid accumulation during feed restriction, which increased capacity for hepatic fatty acid oxidation