Fatty Acid Oxidation Notes

Fatty Acid Oxidation

• Beta Oxidation Steps: Oxidation of fatty acids starts from the beta carbon atom.

• Energy Calculation: Calculate the energy produced by beta oxidation.

• Regulation: Understand the regulation of beta oxidation.

• Other Types: List other types of fatty acid oxidation.

• Clinical Aspects: Understand the clinical aspects of fatty acid oxidation.

What is Beta Oxidation of Fatty Acids?

• Process in which free fatty acids are oxidized as fuel.

• Oxidation starts from the beta carbon atom of fatty acids.

Different Types of Fatty Acids

• Even chain

• Odd chain

• Unsaturated

• Saturated

• Short chain / Medium chain

• Long chain (14-20 C)

• Very Long Chain (> 20 C)

Fat Storage

• Stored in adipose tissue as triacylglycerides (TAG).

• TAG is hydrolyzed to release free fatty acids (mainly long chain).

• Free fatty acids are transported from adipose tissues in blood bound to albumin because they are not soluble in blood.

When Does the Body Access Stored Fatty Acids?

• When energy from glucose is not enough.

• In stress, exercise.
  *Glucagon from pancreas in response to low glucose.
  *Epinephrine from adrenal medulla in response to sympathetic stimulation in stress.

Hormonal Influence on Fatty Acid Release

• Glucagon and epinephrine facilitate the release of fatty acids from triacylglycerols.

  • Glucagon: Released from the pancreas in response to low glucose levels.

  • Epinephrine: Released from the adrenal medulla in response to sympathetic stimulation during stress.

How are Fatty Acids Released from TAG?

• Enzymes involved:

  • Hormone-sensitive lipase

  • Adipocyte triglyceride lipase

• These enzymes release fatty acids and glycerol in response to glucagon and epinephrine.

  • Glycerol: Taken to the liver and converted to glucose (gluconeogenesis).

  • Fatty Acids: Transported to various tissues like skeletal muscles, cardiac muscles, liver, kidney, etc., when glycogen and gluconeogenic precursors become scarce.

  • Not utilized by RBCs (lack mitochondria).

  • Not utilized by the brain (fatty acids bound to albumin cannot cross the blood-brain barrier).

How is Energy in Fatty Acids Accessed?

1. Activation:

   • Long-chain fatty acids are converted to fatty acyl CoA in the cytosol.

2. Transport:

   • Activated long-chain fatty acids enter the mitochondria.

   • The inner mitochondrial membrane is impermeable to activated fatty acyl CoA.

   • Carnitine shuttle helps transport activated fatty acids into the mitochondria.

   • Medium & short-chain fatty acids do not need carnitine shuttle as they are activated inside the mitochondria.

Carnitine Shuttle

• Acyl CoA + Carnitine

• Carnitine acyl transferase 1 converts Acyl CoA + Carnitine to Acyl carnitine + CoASH

• Acyl carnitine is transported across the membrane

• Carnitine acyl transferase 2 converts Acyl carnitine back to ACYL Co A + Carnitine

• TRANSPORTER moves carnitine back across the membrane

Beta Oxidation Cycle

• Each cycle comprises 4 steps.

• Fatty acid length is shortened by 2 carbon atoms with the removal of acetyl CoA at the end of each cycle.

• Example: Palmitic acid (C16) undergoes 7 cycles of beta oxidation to be completely broken down into 8 acetyl CoA molecules.

• Each cycle involves:

  1. FAD

  2. FAD H

  3. Lessened by 2 carbon atoms

ATP Production in Beta-Oxidation of Palmitoyl CoA (C16)

• Palmitic acid (C16) requires 7 cycles of β-oxidation to be completely broken down, producing:

  • 7 FADH2

  • 7 NADH

  • 8 molecules of Acetyl CoA

• Energy Calculation:

  • 7 FADH2 yields $7 \times 1.5 = 10.5$ ATP

  • 7 NADH yields $7 \times 3 = 17.5$ ATP

  • 8 Acetyl CoA yields $8 \times 12 = 80$ ATP

• Total energy from one mole of palmitoyl CoA:

  • $10.5 + 17.5 + 96 = 108$ ATP

• Energy utilized for activation: -2 ATP

• Net ATP yield of β-oxidation of one molecule of palmitate:

  • $108 - 2 = 106$ ATP

Regulation of Beta Oxidation

• Controlling carnitine acyl transferase 1 (rate-limiting enzyme).

• Malonyl CoA inhibits carnitine acyltransferase 1.

Oxidation of Odd Chain Fatty Acids

• Produces Acetyl CoA & Propionyl CoA.

• Propionyl CoA gives rise to Succinyl CoA, which enters gluconeogenesis (glucose synthesis).

Alpha Oxidation

• Occurs on phytanic acid - branched-chain fatty acid present in chlorophyll, dairy products.

• Requires alpha oxidase.

• It is a minor pathway.

Refsum’s Disease

• Caused by a defect in alpha-oxidase enzyme.

• Leads to the accumulation of phytanic acid in the brain.

• Characterized by progressive neurological signs such as tremors, unsteady gait, and poor night vision.

Omega-Oxidation

• Minor pathway.

• Substrates: Medium-chain and long-chain fatty acids.

• Site: Microsomes.

Peroxisomal Beta-Oxidation

• Substrates: Very long chain fatty acids.

• Site: Peroxisomes.

Zellweger Syndrome

• Defect in Peroxisomal Oxidation.

• Genetic defects in peroxisomal biogenesis lead to the accumulation of VLCFAs in the blood and tissues.

• Results in impaired brain development and reduction in central nervous system myelin, referred to as hypomyelination.

Primary Carnitine Deficiency

• Caused by a defect in the protein that brings carnitine into the cell.

• Long-chain fatty acids cannot be transported into the mitochondrial matrix.

• Symptoms include cardiomyopathy.

• Treatment involves carnitine supplementation.

Acquired Secondary Carnitine Deficiency

• Can be seen in patients with liver disease, kidney disease (decreased carnitine synthesis), or due to malnutrition.

Medium-Chain Fatty Acyl CoA Dehydrogenase Deficiency (MCAD)

• An autosomal-recessive disorder, one of the most common inborn errors of metabolism.

• Fasting hypoglycemia is a common symptom.

Jamaican Vomiting Sickness

• Caused by hypoglycin in ackee fruit.

• Symptoms: Vomiting, abdominal discomfort, low blood glucose.

• The chemical interferes with the transport of long-chain fatty acids to mitochondria and inhibits acyl CoA dehydrogenases.

Carnitine Acylcarnitine Translocase (Transporter) Deficiency

• Causes accumulation of fatty acids in cardiac cells, which can affect electrical properties, leading to arrhythmia.

• Other symptoms: Hypotonia, etc.