Metabolism of Fatty Acids

Chapter at a Glance

The reader will be able to answer questions on the following topics:

  1. Digestion of lipids
  2. Absorption of lipids
  3. Chylomicrons
  4. Beta oxidation of fatty acids
  5. Oxidation of odd chain fatty acids
  6. Alpha oxidation
  7. Omega oxidation
  8. De novo synthesis of fatty acids
  9. Synthesis of triglycerides
  10. Metabolism of adipose tissue
  11. Fatty liver and lipotropic factors
  12. Ketogenesis and ketolysis

Digestion of Lipids

The major dietary lipids include:

  • Triacyl glycerol
  • Cholesterol
  • Phospholipids

The average normal Indian diet contains about 20-30 g of lipids per day. In contrast, the Western diet generally contains two to three times more than this amount.

Digestion in the Stomach
  • Lingual Lipase: Secreted in the mouth, active under the acidic conditions of the stomach (optimum pH of 2.5-5). It primarily acts on short chain triglycerides (SCTs) found in milk and butter, with its action noted as more significant in newborns.
  • Gastric Lipase: Acid-stable enzyme whose secretion is stimulated by gastrin, with an optimum pH around 5.4. It accounts for approximately 30% of triglyceride digestion in the stomach.
Digestion in the Intestines
  • Hormonal Regulation: The entry of chyme into the duodenum triggers the release of Cholecystokinin (CCK), which stimulates gallbladder contraction and pancreatic enzyme secretion, and Secretin, which triggers bicarbonate release to neutralize stomach acid.
  • Emulsification: Essential for lipid digestion, where the lipids are dispersed into small droplets to increase their surface area, facilitated by:
    1. Bile salts (detergent action)
    2. Peristalsis (mechanical mixing)
    3. Phospholipids
Role of Bile Salts in Digestion
  • Components such as sodium glycocholate and sodium taurocholate reduce surface tension, emulsifying fat droplets and enhancing enzyme activity, particularly pancreatic enzymes in the neutral pH environment of the duodenum.
Lipolytic Enzymes in the Intestines
  1. Pancreatic Lipase with Co-lipase: Specific for primary ester linkages (C1 and C3).
  2. Cholesterol Esterase: Hydrolyzes cholesterol esters into free cholesterol and fatty acids.
  3. Phospholipase A2: Secreted as a proenzyme activated by trypsin; it removes the fatty acid at the second position of phospholipids.

Absorption of Lipids

Long Chain Fatty Acids (LCFAs)
  • Absorbed into lymph rather than directly into the bloodstream.
Mixed Micelle Formation
  • Formation involves digestion products such as:
    • 2-monoacylglycerides
    • Long-chain fatty acids
    • Cholesterol
    • Phospholipids
    • Lysophospholipids
  • Micelles (sizes 3-10 nm) form spherical particles with hydrophilic exteriors and hydrophobic interiors, aiding in the absorption of fat-soluble vitamins (A, D, E, and K).
Re-esterification Inside Mucosal Cell
  1. Activation: LCFAs are activated to fatty acyl CoA by acyl CoA synthetase (thiokinase).
  2. Re-esterification: The Monoglyceride Pathway converts 2-MAG back to TAG using two molecules of acyl CoA.
  3. Chylomicron Formation: Nascent chylomicrons are formed by packaging TAGs, cholesterol, and fat-soluble vitamins with Apolipoprotein B-48. These enter the lacteals.

Beta Oxidation of Fatty Acids

  • Occurs in the mitochondrial matrix.
The Four Recurring Steps of Beta Oxidation

For every cycle, the following reactions occur:

  1. Oxidation: Catalyzed by Acyl CoA dehydrogenase, removing two hydrogens to form Delta^2-trans-enoyl CoA, producing 1.5 ATP via FADH_2.
  2. Hydration: Enoyl CoA hydratase adds water across the double bond to form L-3-hydroxyacyl CoA.
  3. Oxidation: 3-hydroxyacyl CoA dehydrogenase converts the hydroxyl group to a keto group (3-ketoacyl CoA), producing 2.5 ATP via NADH.
  4. Thiolytic Cleavage: Thiolase (3-ketoacyl CoA thiolase) cleaves the bond between alpha and beta carbons, releasing one Acetyl CoA and a fatty acyl CoA shortened by two carbons.
ATP Yield from Palmitate (C_{16})
  • Palmitate undergoes 7 cycles.
  • Produces 8 Acetyl CoA (8 \times 10 = 80 ATP).
  • Produces 7 FADH_2 (7 \times 1.5 = 10.5 ATP).
  • Produces 7 NADH (7 \times 2.5 = 17.5 ATP).
  • Total: 108 ATP. Net: 106 ATP (after subtracting 2 ATP for activation).

De Novo Synthesis of Fatty Acids

  • Primarily occurs in the liver, lactating mammary glands, and adipose tissue.
Fatty Acid Synthase (FAS) Complex
  • This is a multi-enzyme system existing as a homodimer.
  • Each monomer contains 7 enzyme activities and an Acyl Carrier Protein (ACP) which contains a 4'-phosphopantetheine prosthetic group.
  • The two monomers are arranged "head-to-tail," so the thiol group of the ACP of one monomer works in coordination with the thiol group of the Cys residue of the other.

Ketogenesis and Ketolysis

  • Ketogenesis: Occurs in the liver mitochondria when Acetyl CoA levels exceed the capacity of the TCA cycle (e.g., starvation, diabetes).
    • Primary Ketone Bodies: Acetoacetate, \beta-hydroxybutyrate, and Acetone.
    • Rate-limiting enzyme: HMG-CoA synthase.
  • Ketolysis: The liver cannot utilize ketone bodies because it lacks the enzyme Thiophorase (succinyl-CoA:3-oxoacid CoA-transferase). Ketone bodies are used by extrahepatic tissues (brain, heart, skeletal muscle) as fuel.

Fatty Liver and Lipotropic Factors

  • Mechanism: Occurs when the rate of TAG synthesis in the liver exceeds the rate of VLDL secretion.
  • Lipotropic Factors: These prevent fatty liver by aiding VLDL synthesis or phospholipid formation.
    • Choline and Methionine: Essential for the synthesis of Phosphatidylcholine (Lecithin), a vital component of the VLDL shell.
    • Vitamin E and Selenium: Protect against lipid peroxidation and hepatic damage.