10-+Fatty+Acid+Synthesis+and+Lipoproteins+-+MBS602+-+2025

De novo Synthesis of Fatty Acids

  • Objective: Understand the synthesis of fatty acids, key enzymes, and regulatory mechanisms.

  • Key Steps in Fatty Acid Synthesis: Four main steps:

    1. Citrate Transport:

      • Citrate moves from the mitochondrion to the cytoplasm, usually during the postprandial state (after eating).

      • Metabolic conditions that enable this: High insulin, low glucagon, activity of PFK1 (phosphofructokinase), excess glucose converted to pyruvate.

    2. Cytoplasmic Acetyl-CoA Production:

      • Conversion of citrate back to acetyl-CoA and oxaloacetate via citrate lyase.

    3. Malonyl-CoA Formation:

      • Acetyl-CoA is converted to malonyl-CoA by acetyl-CoA carboxylase (ACC); this is a key regulatory step of fatty acid synthesis.

    4. Fatty Acid Synthesis:

      • Enzymatic assembly into fatty acids through fatty acid synthase (FAS) complex which catalyzes a series of reactions that add two-carbon units.

  • Enzymatic Costs: Each cycle requires 2 NADPH and 1 ATP for two-carbon elongation.

  • Sources of NADPH: Two key sources in the liver include:

    • Pentose phosphate pathway (generating 2 NADPH per glucose).

    • Malic enzyme from malate also produces NADPH.

Elongation and Desaturation of Fatty Acids

  • Learning Objectives: Understand the processes of elongation and desaturation, reactants, products, and limitations in humans.

  • Elongation Process:

    • Fatty acids longer than 16 carbons are generated through elongation.

    • Mechanism includes:

      • Activation of fatty acids via acyl-CoA synthase.

      • Malonyl-CoA adds 2-carbon units leading to very-long-chain fatty acids (C ≥ 20).

  • Desaturation Process:

    • Introduction of double bonds to fatty acids (e.g., stearic acid to oleic acid) utilizing desaturase enzymes.

  • Limitations:

    • Humans can only introduce double bonds between carbons 1 and 9; thus, polyunsaturated fatty acids with double bonds beyond the 9th must come from dietary sources.

Trans Fatty Acids

  • Contrast between Cis and Trans Fatty Acids:

    • Cis: Naturally occurring in fats, beneficial.

    • Trans: Formed during hydrogenation or high-temperature processing, linked to adverse health effects.

  • Sources of Trans Fatty Acids:

    • Found in ruminant meat; created when heating cis fats (e.g. frying).

    • Industrial hydrogenation of unsaturated fats (e.g., margarine production).

Essential Fatty Acids

  • Definition: Compounds that must be obtained from diet as the body cannot synthesize them.

  • Key Essential Fatty Acids:

    • Linoleate (omega-6)

    • Linolenate (omega-3)

  • Derivatives formed from Essential Fatty Acids:

    • From Linoleate: Arachidonate (20:4, omega-6)

    • From Linolenate: EPA (20:5, omega-3), DHA (22:6, omega-3)

Synthesis of Eicosanoids

  • Purpose: Mediators derived from polyunsaturated fatty acids which regulate various physiological processes.

  • Eicosanoid Synthesis:

    • Primarily derived from arachidonic acid (C20:4) through cyclooxygenase (COX) pathways leading to prostaglandins and thromboxanes.

    • Influenced by NSAIDs which inhibit COX activity, affecting pain, inflammation, and clotting.

Lipoproteins and Apolipoproteins

  • Lipoprotein Classes: Five major groups categorized based on density and function:

    1. Chylomicrons

    2. VLDL (very low-density lipoproteins)

    3. IDL (intermediate-density lipoproteins)

    4. LDL (low-density lipoproteins)

    5. HDL (high-density lipoproteins)

  • Composition: Each lipoprotein consists of lipids (e.g., triglycerides, cholesterol) and proteins (apolipoproteins).

  • Functions of Apolipoproteins:

    • Structural, enzymatic, and ligands for receptors. For example, ApoB-100 is key in LDL metabolism and cholesterol transport.

    • Elevated levels of ApoB-100 are linked to cardiovascular risk.