Chapter 21: Lipid Metabolism

Introduction to Lipids

• Definition: Lipids represent an efficient way of storing chemical energy.

• Metabolic Function: The metabolic oxidation of lipids releases large quantities of energy through the production of acetyl-CoA, NADH, and FADH2.

Catabolism of Lipids

• The oxidation of fatty acids is the chief source of energy for most organisms.

• Triacylglycerol:
    - Main storage form of chemical energy in most organisms.
    - Carbon chains in triacylglycerols are in a highly reduced form.
    - Energy yield per gram of fatty acid oxidized is greater than that per gram of carbohydrate oxidized.

• Phosphoacylglycerol:
    - A key component of biological membranes.
    - May have multiple sites of action.

Breakdown of Lipids

• Lipids:
    - Triacylglycerols and phosphoacylglycerols contain fatty acids as part of their covalently bonded structures.
    - The bond between the fatty acid and the rest of the molecule can be hydrolyzed.
    - Lipases hydrolyze lipids, while phospholipases hydrolyze phospholipids.

Hormone-Dependent Liberation of Fatty Acids in Adipose Tissue

• Hormonal regulation involves the following steps:
    - Activation of adenylate cyclase which converts ATP to cAMP.
    - cAMP activates protein kinase, which subsequently activates triacylglycerol lipase.
    - The result is the hydrolysis of triacylglycerols into diacylglycerol (DAG) and monoacylglycerol (MAG), leading to the liberation of fatty acids and glycerol.

Fatty Acid Activation

• Fatty acid oxidation begins with the activation of the fatty acid molecule.

• Activation Process:
    - A thioester bond is formed between the carboxyl group of the fatty acids and the thiol group of CoA-SH.
    - Catalysis: Acyl-CoA synthetase catalyzes the formation of the ester bond and requires ATP for activation.
    - This esterification takes place in the cytosol, while the subsequent reactions of fatty acid oxidation occur in the mitochondrial matrix.
    - Transport Mechanism: Acyl-CoA is capable of crossing the outer mitochondrial membrane but not the inner membrane.

Formation of an Acyl-CoA

• Steps involved in forming Acyl-CoA:
    1. Reaction between RCOO and ATP forms an acyl adenylate intermediate.
    2. CoA-SH combines with the acyl adenylate to produce Acyl-CoA and AMP.

• Overall Reaction:
    $ext{RCOO} + ext{ATP} + ext{CoA-SH} <br>ightarrow ext{RC-S-CoA} + ext{AMP} + ext{PP}$

Transport of Acyl Groups

• The acyl group is transferred to carnitine, allowing it to cross the inner mitochondrial membrane.

• Carnitine's Role:
    - It is a molecule used in fatty acid metabolism to shuttle acyl groups across the mitochondrial membranes.
    - Enzymes:
      - Carnitine acyltransferase (CPT-I) transfers the fatty acyl group to carnitine.
      - Carnitine palmitoyltransferase (CPT-II) is located in the mitochondrial matrix.

Beta-Oxidation

• Definition: Beta-oxidation involves a series of reactions that cleave two-carbon units from the carboxyl end of a fatty acid.

• Reactions: This process requires four reactions in total:
    1. Oxidation of acyl-CoA to form α,β-unsaturated acyl-CoA, catalyzed by FAD-dependent acyl-CoA dehydrogenase.
    2. Hydration of unsaturated acyl-CoA to produce β-hydroxyacyl-CoA, catalyzed by enoyl-CoA hydratase.
    3. Oxidation reaction of β-hydroxyacyl-CoA, catalyzed by NAD+-dependent β-hydroxyacyl-CoA dehydrogenase.
    4. Cleavage of β-ketoacyl-CoA, catalyzed by thiolase.

B-Oxidation of Saturated Fatty Acids

• Cycle of Reactions:
    - Each cycle of four enzyme-catalyzed reactions results in the shortening of a fatty acyl-CoA by two carbon units.
    - Eight cycles of β-oxidation are required to completely oxidize one mole of stearic acid (18 carbons) into nine moles of acetyl-CoA.

Energy Yield from Oxidation of Fatty Acids

• Energy released from the oxidation of acetyl-CoA formed in β-oxidation can be used to produce ATP.

• Nine moles of acetyl-CoA produced from each mole of stearic acid subsequently enter the citric acid cycle.

• Electrons from FADH2 and NADH produced during β-oxidation and the citric acid cycle are transferred into the electron transport chain, producing ATP via oxidative phosphorylation.

Overall Reaction for the Oxidation of Stearic Acid

• The overall equation for the oxidation of stearic acid is derived from adding up the equations for β-oxidation, the citric acid cycle, and oxidative phosphorylation.

Balance Sheet for Oxidation of Stearic Acid

• Components of Reactions:
    1. Stearic acid → Stearyl-CoA (activation step) - Reagents: +8 NADH, +8 FADH2, -2 ATP.
    2. Stearyl-CoA → 9 Acetyl-CoA (8 cycles of β-oxidation) - Products: +27 NADH, +9 FADH2.
    3. 9 Acetyl-CoA → 18 CO2 (citric acid cycle) - Other Reagents: GDP to GTP (9 molecules).
    4. Reoxidation contributions from β-oxidation: +9 NADH, -8 FADH2.
    5. Reoxidation contributions from citric acid cycle: -27 NADH, +67.5 ATP (not net change in NADH or FADH2).

• Net Production:
    - NADH: 0
    - FADH2: 0
    - ATP: +120.

Ketone Bodies

• Definition: Ketone bodies are formed when there is an excess of acetyl-CoA compared to oxaloacetate.

• Conditions for Formation:
    - In starvation, an organism relies on fat breakdown for energy leading to acetyl-CoA production.
    - In diabetic patients, ketone bodies result from inadequate carbohydrate intake.

• Types of Ketone Bodies: Acetone, β-hydroxybutyrate, and acetoacetate.

• Utilization of Ketone Bodies: Acetoacetate can be used as fuel by most tissues and organs.

Formation of Ketone Bodies in the Liver

• Biochemical Pathway:
    1. Acetyl-CoA + Acetyl-CoA (via thiolase) → Acetoacetyl-CoA.
    2. Acetoacetyl-CoA can transform into HMG-CoA through HMG-CoA synthase.
    3. HMG-CoA is then cleaved by HMG-CoA lyase to form acetoacetate and acetyl-CoA.
    4. Acetoacetate can be reduced to β-hydroxybutyrate by β-hydroxybutyrate dehydrogenase while utilizing NADH as a reducing agent.