Fatty acid oxidation and synthesis are crucial processes in lipid metabolism. Oxidation breaks down fatty acids for energy, while synthesis builds them for storage. These opposing pathways are tightly regulated to maintain energy balance in cells.

The location and enzymes involved in these processes differ. Oxidation occurs in mitochondria, using enzymes like CPT I. Synthesis happens in the cytosol, relying on the fatty acid synthase complex. Understanding these differences is key to grasping lipid metabolism.

Fatty Acid Oxidation: Steps and Regulation

Activation and Transport of Fatty Acids

• Fatty acid oxidation (β-oxidation) occurs primarily in the mitochondrial matrix
  • Involves sequential removal of two-carbon units from fatty acids
• Activation of fatty acids in the cytosol by acyl-CoA synthetase forms fatty acyl-CoA
• Carnitine palmitoyltransferase I (CPT I) facilitates fatty acyl group transfer from CoA to carnitine
  • Allows crossing of outer mitochondrial membrane
• Carnitine-acylcarnitine translocase shuttles acylcarnitine across inner mitochondrial membrane
• CPT II regenerates fatty acyl-CoA inside mitochondria

β-Oxidation Cycle and Regulation

• β-oxidation cycle involves four main steps catalyzed by specific enzymes:
  1. Dehydrogenation
  2. Hydration
  3. Oxidation
  4. Thiolysis
• Regulation primarily occurs through control of CPT I activity
  • Inhibited by malonyl-CoA (key intermediate in fatty acid synthesis)
• Hormonal regulation influences fatty acid oxidation rate
  • Glucagon increases oxidation
  • Insulin decreases oxidation
  • Changes enzyme activities and substrate availability

Fatty Acid Synthesis: Process and Enzymes

Fatty Acid Synthase Complex

• Fatty acid synthesis occurs in cytosol catalyzed by multi-enzyme complex fatty acid synthase (FAS)
  • Contains seven distinct enzymatic activities
• FAS utilizes acetyl-CoA as primer and malonyl-CoA as two-carbon donor
  • Series of condensation reactions build fatty acid chain
• Growing fatty acid chain attaches to acyl carrier protein (ACP) domain of FAS during synthesis
• Key enzymes within FAS complex:
  • β-ketoacyl-ACP synthase
  • β-ketoacyl-ACP reductase
  • β-hydroxyacyl-ACP dehydratase
  • Enoyl-ACP reductase
• Final product typically palmitate (16:0)
  • Further modified by elongases and desaturases to produce other fatty acids (oleic acid, linoleic acid)

Synthesis Process and Cofactors

• Process begins with carboxylation of acetyl-CoA to malonyl-CoA
  • Catalyzed by acetyl-CoA carboxylase (ACC), rate-limiting enzyme of fatty acid synthesis
• NADPH serves as primary reducing agent throughout fatty acid synthesis
  • Provides necessary electrons for reduction reactions
• Synthesis requires energy input in form of ATP and NADPH
  • Contrasts with energy-producing fatty acid oxidation

Acetyl-CoA Carboxylase in Fatty Acid Synthesis

ACC Isoforms and Function

• Acetyl-CoA carboxylase (ACC) catalyzes first committed step in fatty acid synthesis
  • Converts acetyl-CoA to malonyl-CoA
• Two ACC isoforms exist:
  1. ACC1: primarily involved in fatty acid synthesis
  2. ACC2: regulates fatty acid oxidation through malonyl-CoA production
• ACC activity regulated by allosteric effectors and covalent modifications
  • Allows rapid responses to cellular energy status

Regulation of ACC Activity

• Allosteric regulation:
  • Citrate promotes ACC polymerization and increases activity
  • Long-chain fatty acyl-CoAs act as allosteric inhibitors
• Covalent modification:
  • Phosphorylation by AMP-activated protein kinase (AMPK) inhibits ACC activity
    • Reduces malonyl-CoA production and fatty acid synthesis during energy-depleted states
  • Insulin promotes ACC dephosphorylation and activation
    • Stimulates fatty acid synthesis in response to high glucose levels
• ACC regulation provides coordinated control mechanism
  • Balances fatty acid synthesis and oxidation in response to cellular energy demands

Fatty Acid Oxidation vs Synthesis: Energy Balance

Metabolic Pathways and Cellular Localization

• Fatty acid oxidation generates energy (ATP, NADH, FADH2)
  • Catabolic process
• Fatty acid synthesis requires energy input
  • Anabolic process
• Oxidation occurs primarily in mitochondria
• Synthesis takes place in cytosol
  • Separate localization allows independent regulation of opposing processes
• Carbon flow direction reversed between processes:
  • Oxidation breaks down fatty acids into acetyl-CoA
  • Synthesis builds fatty acids from acetyl-CoA units

Cofactors and Regulation

• Oxidation utilizes NAD+ and FAD as electron acceptors
  • Produces NADH and FADH2
• Synthesis requires NADPH as reducing agent
• Distinct enzymes involved in oxidation and synthesis
  • Different cofactor requirements and regulatory mechanisms
• Energy balance maintained through reciprocal regulation:
  • High energy states promote fatty acid synthesis and storage
  • Low energy states stimulate oxidation for ATP production
• Malonyl-CoA serves as key regulatory molecule:
  • Inhibits fatty acid oxidation via CPT I inhibition
  • Required for fatty acid synthesis