Energy Release from Fat

Energy Release from Fat

Biological Functions of Lipids

• Components of Cell Membranes:
  • Phospholipids
  • Cholesterol
• Precursors of Hormones:
  • Cholesterol → Steroid hormones
  • Arachidonic acid → Prostaglandins
• Long Term Fuels:
  • Triglycerides

Efficiency of Triglycerides as Fuel

• Compact Storage: Triglycerides are stored as large fat droplets in the fat cells of adipose tissue.
• Large Body Stores (for a 70 kg adult):
  • 11 kg fat (as triglycerides)
  • 120 g glycogen in the liver
  • 10 g glucose
• Efficiency on Weight Basis:
  • 1 g fat yields 38 kJ
  • 1 g protein yields 21 kJ
  • 1 g carbohydrate yields 17 kJ

Structure of Triglyceride Fat (Triacylglycerols)

• Triacylglycerol is formed by three fatty acids linked to a glycerol backbone via ester bonds.

Breakdown of Stored Triglyceride Fat in Adipose Tissue

• Triglycerides are broken down into fatty acids and glycerol.
• Lipase Activation: Adrenaline & glucagon activate lipase.
• Fate of Glycerol: Diffuses into the bloodstream to all tissues.
• Fate of Fatty Acids: Travel in plasma bound to albumin.

Metabolism of Glycerol

• Glycerol is water-soluble and taken up by all tissues.
• Most Tissues: Enters the glycolysis pathway and is converted to pyruvate, then into the TCA cycle for oxidation to CO_2.
• Liver (in starvation): Enters the glycolysis pathway and is converted to glucose by gluconeogenesis.

Fatty Acid Metabolism by β-Oxidation Pathway

• All reactions occur in the mitochondrial matrix.
• Intermediates are present as CoA thioesters.
• Biological energy of the fatty acid molecule is conserved via the transfer of 2 H atoms to the cofactors NAD^+ and FAD to form NADH & FADH_2. (no direct ATP synthesis).
• A series of four enzyme reactions results in the removal of a two-carbon unit as acetyl-CoA.

Activation of Long Chain Fatty Acids

• Long chain fatty acids are activated in the cytosol by the addition of CoA.
• Reaction:
  CH3 – (CH2)n – CH2 – CH2 – C – O – H + CoASH + ATP \rightarrow CH3 – (CH2)n – Cβ – Cα – C – S-CoA + AMP + PPi

Coenzyme A

• Coenzyme A (CoA) forms thioester bonds with carboxylic acids.
• Reaction: RCH2-C-O-H + CoA-SH \rightarrow RCH2-C-S-CoA + H_2O

Energetically, Activation of Fatty Acids Requires 2 ATP

• Activation of fatty acids results in the production of AMP from ATP, i.e., 1 ATP molecule is used.
• Recreating ATP from AMP requires the hydrolysis of 2 ATP molecules to ADP:
  • ATP \rightarrow ADP + Pi
  • ATP \rightarrow ADP + Pi
  • AMP + Pi + Pi \rightarrow ATP
• So energetically, the activation of fatty acids requires 2 ATP. Note: The recreation of ATP is not part of the β-oxidation pathway.

Transport of Fatty Acyl-CoA into Mitochondria: Carnitine Shuttle

1. Fatty acyl-CoA freely diffuses across the outer mitochondrial membrane.
2. Fatty acid group transferred to carnitine by carnitine acyltransferase I, creating fatty acyl-carnitine.
3. Fatty acyl-carnitine crosses the inner mitochondrial membrane via a translocase.
4. Carnitine is switched back for CoA by carnitine acyltransferase II, recreating fatty acyl-CoA.
5. Carnitine is transported back into the intermembrane space.

• The process is energetically neutral.

Overview of β-Oxidation Pathway

• One round of β-oxidation produces acetyl-CoA and a fatty acyl-CoA that is 2 carbons shorter.
• The 2 carbons are carried by acetyl-CoA.
• It's called β-oxidation because the β-carbon undergoes oxidation to produce a carbonyl group (carbon double-bonded to oxygen).

β-Oxidation Pathway: Reactions in More Detail

1. Reaction 1 - Removal of 2 H atoms
   • Fatty acyl-CoA → Enoyl-CoA
2. Reaction 2 – Addition of Water
   • Enoyl-CoA + H_2O → Hydroxyacyl-CoA
3. Reaction 3 – Removal of 2 H atoms
   • Hydroxyacyl-CoA → β-Ketoacyl-CoA
4. Reaction 4 - Removal of 2 C units
   • β-Ketoacyl-CoA + CoA-SH → Fatty acyl-CoA (2 C atoms shorter) + Acetyl-CoA

Summary of β-Oxidation Pathway

• Activation stage occurs in the cytosol.
• ẞ-oxidation occurs in the mitochondrial matrix
• Fatty acid with 16 C atoms will pass through repeats of β-oxidation pathway producing NADH & FADH_2
• Fatty acid with 16 C atoms will give rise to acetyl CoA which enter the TCA cycle.

Energy Yield from Fatty Acid Oxidation

• Complete oxidation of palmitic acid (16:0) produces ATP.
• Recall: oxidation of NADH + H^+ produces 2.5 ATP, oxidation of FADH_2 produces 1.5 ATP.

Regulation of Fat Metabolism

• Release of fatty acids from adipose tissue: Adrenaline & glucagon activate lipase enzyme.
• Rate of entry into mitochondria: Via carnitine shuttle.
• Rate of reoxidation of cofactors NADH & FADH_2: By Electron Transport Chain.

Metabolism of Odd Numbered Fatty Acids

• β-oxidation will result in the following:
  C15 → C13 → C11 → C9 → C7 → C5 → C3

Metabolism of Odd Numbered Fatty Acids – Dealing with the Last 3 Carbons

• Propionyl-CoA is converted to Succinyl-CoA in a series of reactions.

Ketone Body Formation

• ‘Ketogenesis’ occurs when fat metabolism is the main source of energy:
  • In starvation
  • In Type I diabetes
• Fatty acid oxidation in hepatocytes leads to high concentrations of Acetyl CoA - exceeds capacity of the TCA cycle.
• Excess Acetyl CoA is converted into ‘ketone bodies’ in the liver.
• Acetoacetate and β hydroxybutyrate are released into the bloodstream

Ketone Bodies Can Be Utilised for Energy by Most (but not all) Tissues

• Acetoacetate and β hydroxybutyrate are released into the bloodstream.
• In most cell types, they can be converted back into TCA cycle intermediates (acetyl CoA and succinate).
• Most tissues oxidise a mixture of fatty acids and ketone bodies.
• Liver cannot utilise ketone bodies.
• Brain cannot utilise fatty acids – uses glucose and a small amount of ketone bodies (‘emergency fuel’).
• Red blood cells cannot utilise fatty acids or ketone bodies, use glucose only.