Lipid Metabolism: Fatty Acid Synthesis and Breakdown

Lipid Metabolism: Fatty Acid Synthesis and Breakdown

Key Concepts

• Lipids: Water-insoluble organic molecules including triacylglycerols (TAG/triglycerides), fatty acids, phospholipids, steroids, cholesterol, and glycolipids.
• Energy Source: Lipids are a significant source of energy, providing 2x more energy (kcal/g) than carbohydrates and proteins.

Functions of Lipids

• Energy Storage: Store energy for later use.
• Structural: Act as membrane constituents and anchors for membrane proteins.
• Enzymatic: Function as cofactors for enzymes.
• Signaling: Play roles in cellular signaling pathways.
• Detergents & Transporters: Assist in the transport and emulsification of lipids.
• Antioxidants: Help protect cells from oxidative damage.

Lipid Digestion

• Ingestion: 90% of dietary lipids are in the form of TAGs.
• Breakdown Enzymes: Dietary lipids are digested by lipases including lingual lipase, gastric lipase, and pancreatic lipase.
• Bile Salts: Emulsify lipids in the duodenum to form micelles, aiding in digestion.

Fatty Acid Metabolism

Fatty Acid Synthesis

• Anabolism:
  • Occurs mainly in the cytosol of animals and chloroplasts of plants.
  • Requires acetyl-CoA, malonyl-CoA, and NADPH.
• Fatty Acid Synthase (FAS): Complex enzymes (FAS I in mammals, FAS II in plants) responsible for the synthesis of fatty acids through a four-step process involving:
  1. Condensation: Acetyl and malonyl groups react, releasing CO₂ and forming a β-keto intermediate.
  2. Reduction: NADPH reduces the β-keto intermediate to an alcohol.
  3. Dehydration: -OH and -H are eliminated, forming a double bond.
  4. Reduction: NADPH reduces the double bond to form a saturated acyl-ACP.
• Palmitate Synthesis: Results in 16-carbon palmitic acid through repeated cycles.

Fatty Acid Breakdown

• Catabolism: Takes place in the mitochondria, producing acetyl-CoA and electron carriers (NADH, FADH2) via β-oxidation.
• Hormonal Regulation: Hormone-sensitive lipase (HSL) is activated under low insulin and high epinephrine, facilitating TAG breakdown into free fatty acids.
• Carnitine Shuttle: Transports fatty acids into the mitochondria for β-oxidation.

β-Oxidation Process

1. Dehydrogenation: Converts fatty acyl-CoA into trans-alkene.
2. Hydration: Adds water across the double bond to form an alcohol.
3. Oxidation: Oxidizes the alcohol to a keto group, regenerating NADH.
4. Thiolysis: Releases acetate (acetyl-CoA) and shortens the fatty acid chain by two carbons.

Ketogenesis

• Formation of Ketone Bodies: Occurs when acetyl-CoA levels are high (e.g., fasting, diabetes). Pathway involves:
  • Conversion of acetyl-CoA to acetoacetate and D-β-hydroxybutyrate.
  • Ketone bodies serve as an alternative energy source for various tissues when glucose is low.

ATP Yield from Fatty Acid Breakdown

• Breakdown of palmitic acid through β-oxidation and subsequent TCA cycle provides a substantial yield of ATP based on NADH and FADH2 produced in the reactions.

Summary

• TAG hydrolysis releases free fatty acids, transported via the carnitine shuttle into mitochondria.
• β-Oxidation produces energy in the form of acetyl-CoA, NADH, and FADH2, which enters the TCA cycle optimizing energy release.
• Under energy-deprived states, ketone bodies are synthesized and serve as crucial fuel for non-glucose-dependent tissues, getting reconverted to acetyl-CoA within those tissues.

Important Equations

• Palmitate Formation: Continuous cycles of elongation lead to the production of palmitate through the activity of Fatty Acid Synthase.
• Energy Yield Calculation: Each 16-carbon palmitoyl-CoA yields significant amounts of NADH and FADH2, contributing to high ATP production via oxidative phosphorylation.