Fatty Acid Metabolism Overview

Focus on triglycerides, fatty acids, and their degradation and biosynthesis.

Storage of Fatty Acids

• Adipose Tissue: Specialized tissue designed for storing fatty acids primarily as triglycerides (triacylglycerides). This tissue is composed of adipocytes, which can expand to accommodate increased lipid storage.

• Triacylglycerides: Formed by the esterification of three fatty acids with glycerol, these molecules serve as long-term, high-energy stores due to their lipophilic (fat-loving) characteristics. They are stored in an anhydrous state, meaning they do not require water for storage, which makes them energy-dense.

• Energy Production: The oxidation of fatty acids leads to the production of significant levels of electron carriers NADH and FADH2, which are crucial for ATP generation in the electron transport chain following the tricarboxylic acid (TCA) cycle.

Mobilization of Triacylglycerides

• Hydrolysis: The mobilization of stored triglycerides begins with hydrolysis, a process facilitated by the enzyme lipase. This results in the release of three fatty acids and glycerol from the triglyceride molecule.

• Glycerol Metabolism: The released glycerol undergoes phosphorylation to form glycerol phosphate, which can then be converted to glucose through gluconeogenesis or enter glycolysis as three-phosphoglycerate, contributing to glucose homeostasis.

Fatty Acid Beta-Oxidation

Process Overview:

• Fatty acids are broken down through a process called beta oxidation, which shortens the fatty acid chain by two carbon atoms per cycle. This process predominantly occurs in the mitochondria, with the initial steps occurring in the cytosol where fatty acids are first produced or obtained.

Formation of Acyl CoA:

• The conversion of free fatty acids into acyl CoA is critical for mitochondrial transport; this conversion is energy-dependent and happens only in the first round of beta oxidation.

Steps of Beta-Oxidation:

1. Formation of Acyl CoA Ester: This step requires ATP and involves the hydrolysis of pyrophosphate (PPi) to achieve an irreversible reaction.

2. Oxidation Steps: The process involves two oxidation reactions using FAD and NAD+:

   • First Oxidation: Acyl CoA is oxidized to form a trans-double bond, converting FAD to FADH2.

   • Hydration Step: Water is added to the double bond, facilitating a subsequent reaction.

   • Second Oxidation: The alcohol formed during hydration is oxidized to a ketone, with NAD+ being reduced to NADH.

3. Cleavage: In the final step, the acyl CoA bond is cleaved to produce one acetyl CoA and a shorter acyl CoA, which can re-enter the beta-oxidation cycle.

ATP Yield from Beta-Oxidation:

• Each round of beta-oxidation yields approximately 14 ATP (factoring in acetyl CoA oxidation in the TCA cycle). For example, a C16 fatty acid like palmitic acid can yield a total of 106 ATP, minus 2 ATP for acyl CoA formation, demonstrating a more efficacious energy yield compared to glucose oxidation (approximately 3.5 times greater).

Fatty Acid Biosynthesis

Biosynthesis Overview:

• The process of fatty acid biosynthesis mirrors beta oxidation but runs in reverse, utilizing acetyl CoA and requiring carbon dioxide and reducing agents.

Key Enzyme:

• Acetyl CoA Carboxylase: This crucial enzyme catalyzes the conversion of acetyl CoA into malonyl CoA, an essential step that requires energy in the form of ATP and the vitamin biotin as a cofactor. This enzyme is localized within the endoplasmic reticulum, underscoring the importance of transport mechanisms for metabolites in biosynthesis.

Steps in Fatty Acid Biosynthesis:

1. Activation: Energy from ATP is used for the carboxylation of acetyl CoA to form malonyl CoA.

2. Condensation: Involves the combination of malonyl ACP and acyl ACP producing a dicarbonyl compound while releasing carbon dioxide. This reaction is driven to completion, making it an irreversible step.

3. Reduction: The intermediate goes through reduction with NADPH, forming a hydroxy ACP derivative.

4. Dehydration: Removal of water leads to the formation of a double bond in the fatty acid chain.

5. Second Reduction: Another round of reduction by NADPH converts the double bond into a saturated acyl ACP.

6. Cycle Continuation: This cycle iteratively adds two carbon units until the desired fatty acid chain length is achieved, with the end product being a long-chain fatty acid.

Conclusion of Fatty Acid Metabolism

• Fatty acid metabolism encompasses a complex series of biochemical processes for energy storage, mobilization, and biosynthesis, with crucial intersections with other metabolic pathways that maintain overall metabolic function and health.