Fatty Acid Synthesis and Oxidation

• Study notes on fatty acid synthesis and oxidation

Biosynthesis of Fatty Acids: Precursors

• Excess calories are stored as liver and muscle glycogen, fat is synthesized when glycogen stores are full

Nonruminants

• Glucose serves as the primary substance for fat synthesis, it enters the glycolytic cycle and becomes pyruvate
• Sufficient food intake leads to ample availability of oxaloacetate
• Pyruvate gets diverted to acetyl CoA which is then used for fat synthesis
• Acetyl CoA can't directly cross the mitochondrial wall, citrate can
• Acetyl CoA and oxaloacetate condense into citrate, which moves into the cytosol
• ATP citrate lyase removes oxaloacetate in the cytosol, which makes 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 as acetate and butyrate
• Propionate is preferentially diverted to glucose
• Ruminants can't convert glucose to fat because of 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 occurs in the liver, kidney, brain, lungs, mammary gland, and adipose tissue
• NADPH, ATP, Mn+2, and CO2 are required as cofactors
• Acetyl CoA and malonyl CoA react with acyl carrier protein to form acetoacetyl-ACP
• Acetoacetyl-ACP is reduced to butyryl-ACP
• 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
• A mitochondrial system exists for elongation of fatty acid chains but is active only under anaerobic conditions
• Elongation of fatty acid chains happens by two-carbon addition, using malonyl CoA as a donor
• Saturated acids with 18, 20, 22, and 24 carbon atoms are produced
• Chain elongation occurs mainly in the endoplasmic reticulum
• Desaturation of preformed fatty acids happens in the endoplasmic reticulum of the microsomes
• Stearic acid is converted to oleic acid
• Synthesis of linoleic and alpha linolenic acid is 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 happens in the intestinal mucosa of higher animals
• Fat 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, which is not possible in ruminants

β-Oxidation of Fatty Acids

• Fatty acids combine with albumin and circulate as an albumin-fatty acid complex
• Fatty acid oxidation starts outside the mitochondria in the cytoplasm w/ the formation of fatty acyl CoA
• Fatty acid + coenzyme A → fatty acyl CoA
• Fatty acyl CoA needs a carnitine carrier to enter 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
• Process continues stepwise, a fatty acid shorter by two carbons remains
• Each sequence producing a molecule of acetyl CoA
• Acetyl CoA enters the TCA cycle and gets 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 happens 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) influences hepatic and peripheral nutrient metabolism
• L-Carnitine abomasal infusion decreases liver lipid accumulation during feed restriction and increases capacity for hepatic fatty acid oxidation