Fatty Acid Catabolism Study Notes

Fatty Acid Catabolism

Chapter 17 Overview

  • Focus on the process of fatty acid catabolism and the role of Acyl CoA.

  • Terms:

    • Acyl CoA

    • Dehydrogenase

    • FAD, FADH2

    • Enoyl CoA

    • Hydroxy acyl CoA

    • NAD, NADH

    • Thiolase

Energy Storage and Lipids

  • Energy Storage Lipids - Triacylglycerols (TAGs)

    • Fatty acids are commonly incorporated into Triacylglycerols (also known as triglycerides).

    • Definition: TAGs are fatty acid esters of glycerol, consisting of three fatty acids each in ester linkage to one glycerol.

    • TAGs contain approximately twice the energy of carbohydrates (2X carbohydrates).

    • TAGs act as emulsifiers, stabilizing mixtures of fats and water (emulsification).

Fatty Acid Catabolism Outline

  • Key Steps in Fatty Acid Catabolism:

    1. Digestion and Transport of Dietary Fats.

    2. Mobilization and Transport of Stored Fats.

    3. Fatty Acid Activation.

    4. Fatty Acid Transport into the Mitochondria.

    5. β-oxidation of fatty acids to Acetyl-CoA:

    • Fully saturated FA with even number of carbons.

    • Unsaturated FA (double bonds) and odd number of carbons.

    • Formation of ketone bodies.

    1. Acetyl-CoA oxidized to CO₂ in the citric acid cycle (CAC).

    2. Electrons released in the CAC contribute to the electron transport chain producing ATP.

Dietary Lipids and Their Digestion

  • Digestion involves:

    • Bile: Emulsifies fats.

    • Micelle formation: Facilitates absorption in the intestinal tract.

    • Lipase enzymes: Break down TAGs into fatty acids before incorporation into cells.

    • Chylomicrons: Transport dietary lipids through the lymphatic then the blood system, allowing for the conversion of TAGs into fatty acids via lipoprotein lipase (LPL).

Mobilization of Stored Fats from Adipose Tissue

  • Lipolysis in adipose tissue is activated by hormones such as glucagon and epinephrine:

    1. Phosphorylation of perilipin activates lipase (ATGL).

    2. ATGL converts TAGs to DAGs.

    3. Hormone-sensitive lipase (HSL) converts DAGs to MAGs.

    4. Monoacylglycerol lipase (MGL) converts MAGs to free fatty acids, which can exit adipose tissue, travel to cells, and be broken down for energy.

Fatty Acid Activation

  • Fatty acid catabolism occurs in the mitochondrial matrix, but the fatty acid must first undergo activation:

    • Activation involves adenylation, converting fatty acid to fatty acyl-AMP, consuming ATP and producing AMP and inorganic pyrophosphate (PPi).

    • The high-energy thioester bond in fatty acyl-CoA is formed, enabling the fatty acid to enter the mitochondria.

Carnitine Shuttle for Mitochondrial Transport

  • Fatty acyl-CoA cannot cross mitochondrial membranes directly:

    1. In the outer membrane, combine fatty acyl-CoA with carnitine to form fatty acyl-carnitine.

    2. In the inner membrane, fatty acyl-carnitine is converted back to fatty acyl-CoA, recapturing carnitine for reuse.

β-Oxidation of Fatty Acids in Mitochondria

  • The oxidation of the fatty acyl-CoA occurs in a cyclic, multi-step process:

    1. Oxidation (dehydrogenation), yields FADH2.

    2. Hydration, adding H₂O.

    3. Further oxidation, yielding NADH.

    4. Thiolysis, where Acetyl-CoA is removed and CoA is added back, resulting in a two-carbon shorter fatty acid.

    • Note: The fatty acid is reduced in length by two carbons with each cycle.

Energy Yield from β-Oxidation

  • Each pair of carbons yields 10 ATP equivalents:

    • 4 ATP from FADH2 and 7 ATP from NADH, minus the activation cost of 2 ATP, results in a net yield of 106 ATP

  • Formula for total yield:
    extNetATP=7imesC−6ext{Net ATP} = 7 imes C - 6
    where C is the number of carbons in the fatty acid chain.

Special Cases in Fatty Acid Oxidation

  • Unsaturated Fatty Acids (FAs): Oxidation requires additional steps to handle double bonds:

    • Conversion from cis to trans configuration using isomerase, skipping the first oxidation step in the process.

  • Polyunsaturated FAs: Require additional processing to manage multiple double bonds, losing additional NADH.

  • Odd Chain FAs: End with propionyl-CoA rather than acetyl-CoA:

    1. Conversion of propionyl-CoA to succinyl-CoA enables entry into the CAC.

    2. Enzymes involved include a biotin-requiring enzyme that adds CO₂, an epimerase, and a vitamin B12-dependent mutase.

Regulation of Fatty Acid Catabolism

  • Prevention of unnecessary degradation of fatty acids is critical:

    • Activated through signaling by low energy states (AMP, glucagon, epinephrine).

    • Inhibited by high energy states (NADH, ATP, insulin).

  • Fasting and Fed States:

    • In fasting, adipose tissue actively releases fatty acids for ATP production.

    • In the fed state, excess glucose is converted to fatty acids, stored as TAGs, and inhibits entry of fatty acids into mitochondria through malonyl-CoA.

Genetic Defects Affecting Fatty Acid Catabolism

  • Medium-Chain Acyl-CoA Dehydrogenase (MCAD) deficiency leads to the inability to oxidize medium-chain fatty acids, causing fat accumulation and hypoglycemia – a serious health challenge with significant mortality rates.

Ketone Body Formation

  • In conditions of inadequate glucose availability (like uncontrolled diabetes or starvation), acetyl-CoA is converted into ketone bodies when intermediates for the CAC are low.

    • Ketone bodies serve as an alternative energy source for various tissues, including the heart and brain, but high levels can lead to ketoacidosis.

Summary of Ketone Body Metabolism

  • Fatty acids are converted into acetyl-CoA, which can either enter the CAC or be converted to ketone bodies (acetoacetate and D-β-hydroxybutyrate).

    • Excessive formation can lead to increased acidosis, causing significant health risks, including coma or death.