NSC 408: Lipids and Inflammation

Lipids and Inflammation (NSC 408)

Essential Fatty Acids: Dietary Requirement

• Why essential? The human body cannot synthesize certain unsaturated fatty acids, making their consumption through diet critical.

• This concept is linked to Lipogenesis from an earlier lecture (Lecture 3.5).

• Key Essential Fatty Acids:

  • $\alpha$ -Linolenic acid (ALA):

    • Structure: $18:3 \Delta^{9,12,15}$ (18 carbons, 3 double bonds at carbons 9, 12, 15 from the carboxyl end).

    • Classification: Omega-3 fatty acid ($\omega-3$).

    • Sources: Nuts, seeds, flaxseed.

  • Linoleic acid:

    • Structure: $18:2 \Delta^{9,12}$ (18 carbons, 2 double bonds at carbons 9, 12 from the carboxyl end).

    • Classification: Omega-6 fatty acid ($\omega-6$).

    • Sources: Corn oil.

Eicosanoid Production

• Definition: Eicosanoids are a class of signaling molecules that are 20-carbon long.

• They are derived from essential fatty acids, specifically linoleic acid and ${\alpha}$ -linolenic acid, through complex biosynthetic pathways.

• Main Types of Eicosanoids:

  • Prostaglandins (PG): Involved in inflammation, pain, fever, and blood clotting.

  • Prostacyclins (PC): Anticoagulants and vasodilators.

  • Thromboxanes (TX): Involved in vasoconstriction and platelet aggregation.

  • Leukotrienes (LT): Potent mediators of inflammatory and allergic responses, particularly in asthma.

Omega-3 and Omega-6 Biosynthesis Pathways (Sprecher's Shunt)

• Both omega-3 and omega-6 fatty acids compete for the same desaturase and elongase enzymes in these pathways.

• Omega-6 Family Pathway (Leads to More Inflammatory Eicosanoids):

  • Linoleic acid ($18:2 \omega-6$)

    • ${\downarrow}$ $\Delta6$ desaturase

  • $\gamma$ -Linolenic acid (GLA) ($18:3 \omega-6$)

    • ${\downarrow}$ elongase

  • Dihomo-$\gamma$ -linolenic acid (DGLA) ($20:3 \omega-6$)

    • Can produce PGE1, PGF1$\alpha$, TXA1, which are considered less inflammatory.

    • Can also block leukotrienes (LTs) generated downstream.

    • ${\downarrow}$ $\Delta5$ desaturase

  • Arachidonic acid (AA) ($20:4 \omega-6$)

    • A crucial precursor for more inflammatory eicosanoids.

    • Produces: PGD2, PGE2, PGF2$\alpha$, PGI2, TXA2 (via cyclooxygenases) and LTA4 (which converts to LTB4, LTC4, LTD4, LTE4) (via 5-lipoxygenase).

    • ${\downarrow}$ elongase

  • Docosatetraenoic acid ($22:4 \omega-6$)

    • ${\downarrow}$ $\Delta4$ desaturase

  • Docosapentaenoic acid ($22:5 \omega-6$)

• Omega-3 Family Pathway (Leads to Less Inflammatory Eicosanoids):

  • $\alpha$ -Linolenic acid (ALA) ($18:3 \omega-3$)

    • ${\downarrow}$ $\Delta6$ desaturase

  • Stearidonic acid ($18:4 \omega-3$)

    • ${\downarrow}$ elongase

  • Eicosatetraenoic acid ($20:4 \omega-3$)

    • ${\downarrow}$ $\Delta5$ desaturase

  • Eicosapentaenoic acid (EPA) ($20:5 \omega-3$)

    • Produces: PGD3, PGE3, PGF3$\alpha$, PGI3, TXA3, which are generally less inflammatory than their omega-6 counterparts.

    • Also involved in the production of 17S Resolvins (via A/J-Ring Neuroprostane), which act to block prostanoids, contributing to anti-inflammatory effects.

    • ${\downarrow}$ elongase

  • Docosapentaenoic acid (DPA) ($22:5 \omega-3$)

    • ${\downarrow}$ $\Delta4$ desaturase

  • Docosahexaenoic acid (DHA) ($22:6 \omega-3$)

Benefits of Omega-3 Fatty Acids

• Production of anti-inflammatory eicosanoids.

• Promotion of more flexible cell membranes due to their unsaturated nature, leading to:

  • Improved cell signaling.

• Potential to increase High-Density Lipoprotein (HDL) levels.

• Recommended Dietary Omega 6:Omega 3 Ratio: A ratio of $4:1$ is generally recommended for optimal health benefits.

Drugs Targeting Eicosanoid Production and Inflammation

• Many medications target specific enzymes or receptors in the eicosanoid pathways to manage inflammation, pain, or allergic reactions.

• Inflammation Cascade Originating from Arachidonic Acid (AA):

  • Cyclooxygenases (COX): Enzymes that convert AA into prostaglandins.

    • COX I: Involved in maintaining normal physiological functions.

    • COX II: Primarily induced during inflammation.

    • Drugs Targeting COX:

      • Aspirin & Ibuprofen: Non-selective inhibitors, blocking both COX I and COX II, reducing inflammation, pain, and swelling.

      • COX II Inhibitors (e.g., Celebrex): Specifically target COX II to reduce inflammation, useful for conditions like arthritis, with fewer gastrointestinal side effects compared to non-selective COX inhibitors.

  • 5-Lipoxygenase (5-LO): An enzyme that converts AA into leukotrienes.

    • Drugs Targeting 5-LO:

      • 5-LO Inhibitors (e.g., Zileuton): Block the production of leukotrienes, used in asthma medication to reduce bronchoconstriction, airway obstruction, and cell infiltration.

      • CysLT Inhibitors: Block the CysLT receptors, preventing the inflammatory effects of leukotrienes (LTC4, LTD4, LTE4).

• Cytokines and Inflammation:

  • Cytokines like TNF$\alpha$ (Tumor Necrosis Factor alpha) and IL-1$\beta$ (Interleukin-1 beta) are pro-inflammatory mediators.

  • TNF Antagonists: A class of drugs that block the action of TNF$\alpha$, used in various autoimmune and inflammatory diseases to reduce overall inflammation.