Fatty Acid Metabolism Lecture

Key Topics to Master: You should be able to demonstrate comprehension of the following without notes or references:
- Describe the general structure of fatty acids.
- Explain the mobilization of triacylglycerols.
- Describe the processes involved in β-oxidation and the chemical reactions that occur.
- Detail the palmitate synthesis pathway.
- Discuss the regulation of fatty acid metabolism.

Functional Network of Enzymes:
- Enzymes do not operate in isolation; they work in complex networks where substrates are transferred between different enzymes.
- Example Pathway: A → B → C → D
- Each enzyme modifies a substrate and transfers the product to the next enzyme in the sequence.

Definition and Characteristics:
- Lipids are primarily hydrophobic molecules that exhibit a variety of important biological functions including:
- Formation of biological membranes
- Signaling molecules
- Providing solvent properties in biochemical reactions
- Supporting lung maintenance.
- The flux of fatty acids is regulated by the metabolic state of the organism, categorized into:
- Fasted state
- Fed state

Saturated and Unsaturated Fatty Acids:
- Saturated fatty acids contain no double bonds (e.g., Palmitic Acid).
- Unsaturated fatty acids contain one or more double bonds (e.g., Cis-palmitoleic).
Carbon Chain Length:
- Most fatty acids are typically composed of 16 to 20 carbon atoms, whereas C14 molecules may be linked to proteins and very long chains are often found in complex lipids, particularly within the nervous system (e.g., Docosahexaenoic acid, C22).

Key Examples:
- Propionic acid: C3, involved in the metabolism of odd-chain fatty acids and gluconeogenesis.
- Palmitic acid: C16, a primary product of fatty acid synthase.
- Palmitoleic acid: C16:1, major constituent in triglycerides.
- Linoleic and Linolenic acids: C18:2 and C18:3, known as essential fatty acids as they must be obtained from the diet.

Benefits of Hydrophobic Nature:
- Facilitates the formation of cellular membranes.
- Allows for efficient storage of fatty acids, requiring less water compared to glycogen.
- Offers virtually unlimited storage capacity as fatty acids can generate 2.5 times more energy per gram than glycogen.
- Plays a role in thermal regulation of the body.

Catalysis of Acyl-CoA:
- Breakdown of fatty acids occurs through the catabolism of acyl-CoA, an important metabolic pathway.
- Three primary processes involved:
1. Mobilization: Release of fatty acids from storage.
2. Transport: Movement of fatty acids into the mitochondria.
3. Oxidation: Conversion to Acetyl-CoA.

Primary Storage Form:
- Triacylglycerides are the storage form of fatty acids located in adipose tissues, including subcutaneous and visceral fat.
- Breakdown involves three steps facilitated by lipases that hydrolyze triacylglycerides into free fatty acids and glycerol.

Hormonal Regulation:
- Hormones such as glucagon and epinephrine initiate the mobilization of stored fats by activating hormone-sensitive lipase, while insulin inhibits this process.
- Perilipin is a key protein that, when phosphorylated by protein kinase A, allows lipase to access stored triacylglycerides.
Free Fatty Acids and Glycerol:
- Free fatty acids are released and transported by serum albumin to tissues that require energy, while glycerol travels to the liver.

Glycerol Metabolism:
- Glycerol in the liver is phosphorylated by glycerol kinase and eventually enters glycolysis or gluconeogenesis pathways.

Mechanism of Entry:
- Fatty acids are transported into cells via specific transporters.
- Inside the cell, fatty acids combine with CoA to form acyl-CoA, a process occurring on the outer mitochondrial membrane, initiated by acyl-CoA synthetase.
- This reaction is near-equilibrium and is driven forward by the hydrolysis of inorganic pyrophosphate by pyrophosphatase.

Carnitine Transfer:
- Acyl-CoA is transferred to carnitine through the activity of carnitine acyltransferases (type I on the cytoplasmic side and type II within the mitochondrial matrix) to facilitate its transport into mitochondria as acylcarnitine.

End Goals of β-Oxidation:
- The principal objective of β-oxidation is to generate:
- Acetyl-CoA
- NADH
- FADH2
Four Enzymatic Steps:
1. Acyl-CoA dehydrogenase for oxidation.
2. Enoyl-CoA hydratase for hydration.
3. L-3-hydroxyacyl-CoA dehydrogenase for oxidation.
4. β-ketothiolase for thiolysis, resulting in the release of acetyl-CoA and shortening the fatty acid chain by two carbon atoms.

Overview:
- The primary goal of fatty acid synthesis is to produce palmitic acid (C16).
Three Stages of Biosynthesis:
- Preparation: Acetyl-CoA is transported from the mitochondria to the cytosol as citrate, later cleaved to yield Acetyl-CoA and oxaloacetate.
- Activation: Acetyl-CoA is activated to malonyl-CoA.
- Elongation: The addition of two carbons at a time occurs through a five-step elongation cycle.

Requirements:
- 8 Acetyl-CoA, 14 NADPH, and ATP.
- Key reactions involving malate and pyruvate generate NADPH used by fatty acid synthase in the synthesis of palmitate.

Hormonal Control:
- Fed state is characterized by insulin promoting storage and synthesis of fatty acids and triacylglycerols.
- Fasting state leads to increased glucagon, activation of lipases, and release of free fatty acids and glycerol, with liver fatty acid synthesis decreasing and ketone body production increasing.

Key Facts:
- Lipids are vital hydrophobic molecules important for membrane structure, signaling, and energy reserves.
- Fatty acids comprise a long alkyl chain and carboxylic acid group.
- Insulin and glucagon play crucial roles in regulating lipid metabolism based on the body's fed and fasting states.
- Fatty acid synthesis integrates several metabolic pathways including TCA, glycolysis, and pentose phosphate pathways, with triacylglycerols as the primary form of stored fatty acids governed by hormonal regulation.