Phospholipids and Eicosanoids

Membrane Dynamics and Fatty Acid Transport

• Red Stimulation and Membrane Interaction

  • Fatty acids require a chaperone when in cells.

  • Upon membrane interaction, fatty acids may lack a chaperone, transforming them into signaling molecules.

Phosphatidylinositol Signaling Pathway

• Phosphatidylinositol Phosphorylation

  • Converts phosphatidylinositol into phosphatidylinositol four, five bisphosphate (PIP2).

  • PIP2 is further converted to triphosphate (IP3) and diacylglycerol (DAG).

• Diacylglycerol and Insulin Resistance

  • Elevated diacylglycerol (DAG) concentrations correlate with lower insulin sensitivity.

  • Pathophysiological implications of DAG include damaging insulin signaling pathways.

Protein Kinase C Activation

• Role of Diacylglycerol

  • DAG acts as a signaling molecule that activates protein kinase C (PKC).

  • PKC amplifies signaling, triggering multiple downstream actions and enzyme activations.

Calcium Release and Cellular Metabolism

• IP3 Functionality

  • IP3 initiates calcium release from intracellular stores (mitochondria and endoplasmic reticulum).

  • Calcium serves as a second messenger amplifying signals, increasing cellular metabolism.

  • Analogous to starting a fire with lighter fluid; it accelerates metabolic activities.

Inflammation and Fatty Acid Context

• Calcium Signaling in Inflammation

  • Calcium activates enzymes like calmodulin, enhancing inflammation signaling pathways.

  • Fatty acids influence inflammation based on whether they are saturated (pro-inflammatory) or unsaturated (anti-inflammatory).

Hormone Sensitive Lipase and Fat Mobilization

• Hormone Activation Mechanisms

  • Hormone sensitive lipase is activated by glucagon under fasting conditions.

  • Adipose cells produce glycerides, which are acted on by the enzyme ATGL (adipose triglyceride lipase).

Chronic Low-Grade Inflammation

• Adiposity and Inflammation

  • Increased adiposity leads to higher oxidative stress and ATP demands.

  • Chronic low-grade inflammation corresponds to expanding adipose tissue, especially visceral fat.

Pre-adipocyte Differentiation and Expansion

• Pre-adipocyte Role

  • Pre-adipocytes serve as precursors ready to develop into mature adipocytes.

  • They require specific signals to differentiate into functional fat cells as nutrient availability increases.

• Consequences of Adipocyte Overexpansion

  • Overexpansion leads to limited elasticity, occlusion of blood supply, and apoptosis of enlarged adipocytes leading to inflammation.

Visceral vs Subcutaneous Fat Expansion

• Impact of Fat Location

  • Visceral adiposity is damaging as it expands into organs and can lead to systemic inflammation.

  • Subcutaneous fat can expand more flexibly but still poses risks if excessive.

  • Chronic inflammation is particularly dangerous due to proximity to critical organs and tissue.

Immune Response and Tissue Repair

• Role of Eicosanoids in Inflammation

  • Prostaglandins and thromboxanes derived from adipose tissue orchestrate repair and immune responses.

  • These mediators help manage blood clotting and recruit immune cells to damaged tissues.

Eicosanoid Production Pathways

• Sources of Eicosanoids

  • Linoleic acid (omega-6) and alpha-linolenic acid (omega-3) are essential for eicosanoid synthesis.

  • Different diets lead to varying eicosanoid profiles, influencing inflammation severity.

• Diverse Eicosanoid Families

  • Distinct groups include mild (group 1) and overreactive (group 2) eicosanoids, based on omega-6 or omega-3 fatty acid prevalence in the diet.

  • Group 2 eicosanoids often lead to excessive inflammatory responses.

Dietary Influences on Eicosanoid Formation

• Dietary Fat Impact

  • Diet high in vegetable oils increases omega-6-derived eicosanoids, leading to pro-inflammatory effects.

  • Conversely, a diet rich in omega-3 oils promotes anti-inflammatory eicosanoids.

Epidemiological Evidence

• Correlation of Omega Fatty Acids with Health

  • Diets rich in omega-3 fatty acids diminish the risk of chronic diseases, including cardiovascular disorders, autoimmune diseases, and inflammation-related conditions.

Therapeutic Implications of Fatty Acids

• Medication Mechanisms

  • Glucocorticoids and NSAIDs (such as aspirin) inhibit eicosanoid synthesis by targeting enzymes like phospholipase and COX, thereby reducing inflammation.

• Cautions with Inhibition

  • Long-term use may lead to complications such as mucosal damage due to loss of protective prostaglandins in the gastrointestinal tract.

Omega-6 vs Omega-3 Fatty Acids

• Comparison of Effects

  • Omega-6 fatty acids primarily yield pro-inflammatory eicosanoids (group 2).

  • Omega-3 fatty acids produce anti-inflammatory and precise responding eicosanoids (groups 1 and 3).

Key Recommendations

• Increased Omega-3 Consumption

  • Regular intake of fish or omega-3 supplements is advocated for reducing inflammation and supporting general health.

  • Monitor dietary ratios of omega-6 to omega-3 to maintain appropriate inflammatory responses.