Dawson 3 - Fatty Acid Oxidation

Biological Roles of Fats

  • Fats (lipids) have multiple biological roles in living organisms.

  • Fats are generally hydrophobic but can have their properties modified by various chemical groups.

Fat as a Fuel

  • Triacylglycerol (TAG):

    • Most important form of fat storage in mammals, accounting for approximately 85% of stored energy.

    • TAG stores significantly more energy than glycogen:

    • TAG: ~38 kJ/g

    • Glycogen: ~17 kJ/g (lower energy density due to water binding and hydrous, so weight increases without energy increase)

Metabolic States and Fat Utilization

  • Fasting:

    • Increased use of fats by most tissues, preserving glucose for other tissues.

    • Fats can be used to create ketone bodies, an alternative fuel for the brain.

  • Exercise:

    • Mobilization of metabolic fuels (both glucose and fat) for muscle activity.

Sources of Fat

  • Liver:

    • Can synthesize fat and release it into the bloodstream.

  • Adipose Tissue:

    • Main site of fat storage.

    • Circulates in plasma as free fatty acids (FFAs) bound to albumin or as TAG in lipoproteins.

  • Types of Muscle Fibres:

    • Some contain fat droplets for energy.

Lipase Enzymes and Fatty Acid Release

  • Lipases release fatty acids from TAG:

    • Intracellular lipases: Stimulated by adrenaline (exercise), noradrenaline (cold), and low insulin (during fasting).

    • Lipoprotein lipase:

    • Secreted by tissues like muscle and adipose tissue to act on TAG in lipoproteins.

    • Plays roles during fasting, exercise, and the late fed state.

Mechanism of Fatty Acid Entry into Mitochondria

  • Fatty acids enter mitochondria through diffusion.

  • Coenzyme A (CoA) is attached to acyl group of the fatty acid via thioester linkage by acyl-CoA synthetase.

    • Acyl-CoA synthase are enzymes that "activate" fatty acids by thioesterification to coenzyme A. It represents the initial step of fatty acid metabolism.

    • The reaction requires the hydrolysis of ATP to AMP. Pyrophosphate is also produced with AMP.

Process of Fatty Acid Oxidation (Beta-Oxidation)

  • Produces no ATP directly but generates:

    • Acetyl-CoA goes to the TCA cycle.

    • NADH and FADH₂ go to the electron transport chain (ETC).

  • Enzymes involved: Acyl-CoA dehydrogenase, enoyl-CoA hydratase, Hydroxy-acyl-CoA dehydrogenase, Thiolase.

  • These products then feed into the Electron Transport Chain (ETC) for ATP production:

    • FADH2 and NADH contribute to the ETC as long as O2 is available.

Beta-oxidation

Flavoprotein (FADH2) P:O ratio

  • Notice one FADH2 is produced by Fatty acyl-CoA dehydrogenase.

  • 2 electrons of FADH2 are transferred to the ETC, pumping 6 H+ out.

  • So P:O ratio is 6/3.67=1.6 (3.67 is the efficiency of our mitochondria)

Regulation of Fatty Acid Oxidation

  • Fatty acid oxidation can be limited by:

    • Insufficient mitochondria.

    • Lack of blood supply (low oxygen levels).

      • In the ETC, electrons from NADH and FADH₂ are passed through complexes and eventually transferred to oxygen, which becomes water.

        • This regenerates NAD⁺ and FAD, which are absolutely required for fatty acid oxidation to continue.

        • No oxygen → ETC backs up → NADH and FADH₂ accumulate → NAD⁺ and FAD run out → β-oxidation grinds to a halt.

        So, fatty acid oxidation is indirectly oxygen-dependent because it depends on the ETC, which directly requires oxygen.

  • Certain tissues, like neurons in the brain, do not oxidize fatty acids.

  • Fatty acid oxidation and glycolysis generally do not occur simultaneously at high rates, except in exercising muscle.

  • During fasting or prolonged exercise, acetyl CoA from fatty acid oxidation can be converted in the liver into ketone bodies for energy.

Metabolic States and Fatty Acid Oxidation

  • Fed State:

    • Fatty acid oxidation is inhibited due to increased glycolysis.

  • Fasting State:

    • Glycolysis is inhibited, and fat utilization increases as adipose tissue releases fatty acids into circulation.

  • Starvation:

    • Body uses both glucose and ketone bodies. Fats are oxidized, and acetyl CoA is utilized to create ketone bodies.

  • Exercise:

    • Fatty acid oxidation increases as the supply of fatty acids is enhanced.

Key Questions for Review

  • Describe the structure and importance of triacylglycerol.

  • Explain how fatty acid availability is controlled in different metabolic states.

  • Discuss how fatty acid oxidation is regulated in various tissues and metabolic states, including its relation to other pathways.

  • Describe the fatty acid oxidation process and calculate its net yield for a given fatty acid.

  • Explain the fate of oxidation products in different tissues and metabolic states.