Lipid Signaling Compounds

Lipids as Signaling Compounds

• Lipids have multiple roles in the body:
  • Storage form as triglycerides.
  • Structural component of cell membranes (5-10% of cell mass).
  • Signaling compounds (active role).

Lipid Signaling Mechanisms

• Signaling lipids can act as:
  • Potent hormones (steroid hormones like estrogen and testosterone).
  • Intracellular messengers (PIP2 signaling pathway).
  • Cofactors for enzymes.
• Signaling can be extracellular or intracellular.

Extracellular Lipid Signals: Steroid Hormones

• Steroid hormones:
  • Oxidized versions of cholesterol.
  • Travel through the blood to target tissues.
  • Enter cells via receptors with high affinity, requiring only tiny concentrations to elicit a response.
  • Bind to receptors in the nucleus, causing changes in gene expression.
• Steroid drugs (e.g., prednisone) are anti-inflammatory.
  • They block phospholipase A2, preventing the release of arachidonic acid from membrane phospholipids.
  • This reduces the production of inflammatory compounds from arachidonic acid.
  • NSAIDs block phospholipase A2.

Intracellular Lipid Signals

• Phosphatidylinositols (e.g., PIP2, PIP3).
• Ceramides regulate cell division, differentiation, and apoptosis.
• Ceramide production in muscles is associated with insulin resistance.
  • Immobilization of muscle increases ceramide concentration, leading to insulin resistance.
  • Exercise decreases ceramide concentration, improving insulin sensitivity.

Eicosanoids: Paracrine Signaling Molecules

• Eicosanoids:
  • Paracrine signals (act on nearby cells).
  • Short half-life.
  • Derived from 20-carbon fatty acids (arachidonic acid and EPA).
  • Functions include inflammation, blood pressure regulation, and uterine muscle contraction.

Two Phases of Eicosanoid Production

• Initial inflammatory phase:
  • Stimulated by infection, trauma, or viral triggers.
  • Produces prostaglandins (PG), thromboxanes (TX), and leukotrienes (LT).
• Resolution phase (cleanup mechanism):
  • Resolves and cleans up excessive inflammation.
  • Produces resolvins, lipoxins, and protectins.

Naming Eicosanoids

• Two-letter abbreviation indicates the type of eicosanoid (PG, TX, LT).
• Third letter indicates where it was originally found or the order of discovery.
• Subscript number (series number) indicates the number of double bonds.

Prostaglandins (PG)

• First discovered in the prostate gland.
• Involved in various functions:
  • Uterine contractions (delivery).
  • Menstruation.
  • Sleep-wake cycle regulation.
  • Fever (prostaglandins can induce fever).

Thromboxanes (TX)

• Produced by platelets (thrombocytes).
• Mainly involved in clotting:
  • Stimulate platelet aggregation; they make platelets sticky.
  • Restrict blood flow to the clot site.
• NSAIDs (ibuprofen, aspirin) inhibit thromboxane synthesis, thinning the blood.

Leukotrienes (LT)

• Produced by white blood cells (leukocytes).
• Potent signaling compounds:
  • Cause anaphylactic shock and allergic reactions.
  • Stimulate asthmatic reactions.
  • Induce generalized inflammation (the worst inflammation offenders).

Eicosanoid Synthesis Pathways

• Requires release of arachidonic acid and EPA from membrane phospholipids via phospholipase A2 activation.
• Two main pathways:
  • Cyclooxygenase (COX) pathway (cyclic pathway).
  • Lipoxygenase (LOX) pathway (linear pathway).

Cyclooxygenase (COX) Pathway

• Also known as the cyclic pathway because it puts a ring in the structure.
• Removes two double bonds during the process.
• Highly dependent on the starting fatty acid.

Lipoxygenase (LOX) Pathway

• Also known as the linear pathway because it does not put a ring into the structure.
• Does not change the number of double bonds.
• Rearranges the structure, but the total number of double bonds remains the same.

Eicosanoid Synthesis from Arachidonic Acid (ARA)

• Arachidonic acid (ARA): 20 carbons, 4 double bonds (omega-6).
• COX pathway:
  • Removes two double bonds (4 - 2 = 2).
  • Produces two-series prostaglandins (e.g., PGE2).
  • Two-series prostaglandins are converted to two-series thromboxanes (e.g., TXA2).
• LOX pathway:
  • Does not change the number of double bonds.
  • Produces four-series leukotrienes (e.g., LTB4).

Eicosanoid Synthesis from Eicosapentaenoic Acid (EPA)

• EPA: 20 carbons, 5 double bonds (omega-3).
• COX pathway:
  • Removes two double bonds (5 - 2 = 3).
  • Produces three-series prostaglandins (e.g., PGE3).
  • Three-series prostaglandins are converted to three-series thromboxanes (e.g., TXA3).
• LOX pathway:
  • Does not change the number of double bonds.
  • Produces five-series leukotrienes (e.g., LTB5).

Bioactivity of Eicosanoids

• Eicosanoids derived from arachidonic acid are more bioactive (more potent).
• Eicosanoids derived from EPA are weaker (three-series prostaglandins/thromboxanes and five-series leukotrienes).

Functions of Eicosanoids

• Vasodilation and Vascular Tone
• Uterine contractions
• Labor Induction
• Gastric mucus production
• Smooth muscle contraction
• Vascular adhesion

Enzyme Specificity and Eicosanoid Production

• Cells selectively activate enzymes to produce specific eicosanoids.
• Quantities produced are altered by the physiologic conditions of the cell.
• Eicosanoids do not travel far; they are paracrine signals, not hormones.
• The COX enzyme has a lower K_m for arachidonic acid (prefers arachidonic acid).
• The LOX enzyme prefers EPA (lower K_m for EPA).

COX and LOX Isoforms

• COX1, COX2, and COX3 (in the brain) isoforms involved in gastric secretions, pain, and fever.
• Different isoforms make different types of prostaglandins and thromboxanes.
• Generalized NSAIDs (ibuprofen) bind both COX1 and COX2, decreasing the mucosal barrier in the stomach and leading to gastric irritation.

Inflammatory Lipids and Proteins

• Leukotrienes are highly inflammatory.
• Inflammatory proteins:
  • Histamine (from histidine).
  • Cytokines (acute phase proteins like interleukin-6, tumor necrosis factor alpha, and interferons).
• Chronic inflammation contributes to approximately 20% of all cancers.

EPA and Anti-Inflammatory Effects

• Eicosanoids made from EPA are weak and less stimulatory than the ones made by arachidonic acid.
• More EPA leads to less production of two-series prostaglandins and thromboxanes.
• More EPA leads to more production of five-series leukotrienes and less of the inflammatory four-series leukotrienes.
• Anti-inflammatory action from fish and fish oils is due to what WE ARE making LESS of AND what the body produces from EPA.

Specialized Pro-resolving Mediators (SPMs)

• SPMs: resolvins, protectins, and lipoxins (anti-inflammatory compounds).
• Made primarily from EPA and DHA (omega-3s).

Anti-Inflammatory Effects of Exercise

• Exercise increases inflammatory compounds like interleukin-6, but also increases anti-inflammatory interleukin-10.
• Overall, chronic exercise leads to a greater anti-inflammatory response.

Fish Consumption and Omega-3 Intake

• Limit consumption of shark, swordfish, tilefish, and king mackerel (high in mercury, from the Gulf of Mexico).
• Pregnant women should eat fish (8-12 ounces of low-mercury fish per week): about two to three servings overall.
• Salmon, catfish, and tuna are good choices.
• Avoid tilefish from the Gulf of Mexico, shark, swordfish, and king mackerel during pregnancy.
• Limit albacore tuna to 6 ounces per week during pregnancy (higher in mercury).
• Methylmercury in fish is neurotoxic, but protective mechanisms (glutathione, antioxidants) help decrease oxidative stress.