🧬

Xu R, Molenaar AJ, Chen Z, Yuan Y. 2025 Mode and mechanism of action of omega-3 and omega-6 unsaturated fatty acids in chronic diseases.

Jun 15, 2025

Overview

This lecture reviews the structural properties, sources, metabolic pathways, and roles of omega-3 and omega-6 unsaturated fatty acids in various chronic diseases, highlighting their mechanisms and dietary strategies for health optimization.

Introduction to Unsaturated Fatty Acids

  • Omega-3 and omega-6 PUFAs are essential fats with distinct roles in chronic disease pathogenesis.
  • The ratio of omega-6 to omega-3 intake is critical for modulating chronic disease risk.
  • Omega-3s are mostly sourced from fatty fish; omega-6s from vegetable oils.
  • Both types regulate inflammation, metabolic function, neurodevelopment, and more.

Structural Properties, Metabolism, and Sources

  • The first double bond of omega-3 is on the third carbon; omega-6's is on the sixth.
  • Key omega-3s: ALA, EPA, DPA, DHA; key omega-6s: LA, AA.
  • Conversion from ALA to EPA/DHA is inefficient, making dietary intake important.
  • Omega-3s are abundant in marine fish and algae; omega-6s are in seed oils and some seafood.
  • Genetic variations affect PUFA metabolism, especially in FADS genes.

Mechanisms and Disease Roles

Cardiovascular Disease

  • Omega-3s lower triglycerides, support endothelial function, and reduce inflammation.
  • High omega-6 intake may increase pro-inflammatory eicosanoids but evidence on harm is mixed.
  • Disease risk relates more to the omega-6/omega-3 ratio than absolute amounts.

Diabetes

  • Omega-3s improve insulin sensitivity and reduce triglycerides via PPAR activation.
  • High LA (omega-6) intake is linked to lower type 2 diabetes risk, possibly by enhancing cell membrane fluidity and insulin sensitivity.

Cancer

  • Omega-3s (EPA, DHA) suppress inflammation, induce cancer cell apoptosis, and inhibit metastasis.
  • Omega-6s have dual roles: high levels may promote cancer, but AA derivatives can induce cancer cell death via ROS.

Skin Diseases

  • LA (omega-6) maintains skin barrier; deficiency causes scaly dermatitis.
  • Omega-3s reduce acne inflammation by inhibiting TLR signaling and inflammasome activation.

Neurodegenerative Diseases

  • DHA (omega-3) supports cognition, synaptic plasticity, and neuron protection.
  • Some AA metabolites are neuroprotective, but effects are complex and dose-dependent.

Depression

  • Omega-3s, especially EPA and DHA, improve neurotransmitter balance and reduce depression risk.
  • Elevated omega-6/omega-3 ratios may worsen depressive symptoms.

Dietary Sources and Practical Considerations

  • Marine fish are the main dietary sources of beneficial omega-3s; conversion from plant ALA is limited.
  • Commercially farmed fish may have lower EPA/DHA if fed omega-6-rich diets.
  • Conjugated linoleic acid (CLA), mainly from ruminant products, may offer metabolic and immune benefits but has some risks.

Key Terms & Definitions

  • PUFA — Polyunsaturated fatty acid, including omega-3 and omega-6 varieties.
  • ALA (Alpha-linolenic acid) — A plant-based omega-3 precursor.
  • EPA (Eicosapentaenoic acid) — Marine omega-3 with anti-inflammatory effects.
  • DHA (Docosahexaenoic acid) — Marine omega-3 important for brain health.
  • LA (Linoleic acid) — Main dietary omega-6 fatty acid.
  • AA (Arachidonic acid) — Omega-6 fatty acid with roles in inflammation.
  • PPAR — Nuclear receptor regulating metabolism and inflammation.

Action Items / Next Steps

  • Review current dietary intake of omega-3 and omega-6 fatty acids and aim for a balanced ratio.
  • Prioritize fish and algal oils for omega-3s; limit excessive intake of omega-6-rich vegetable oils.
  • Consider further reading on PUFA metabolism, genetics (FADS genes), and disease-specific dietary guidelines.