What is the omega-6 fatty acid (FA) pathway?

From the Guidelines

The omega-6 fatty acid pathway should be balanced with adequate omega-3 consumption to maintain optimal health and reduce the risk of inflammatory conditions, as evidenced by the most recent guidelines on healthy diet characteristics 1. The omega-6 fatty acid pathway begins with linoleic acid (LA), an essential fatty acid that must be obtained from the diet. Once consumed, LA is converted to gamma-linolenic acid (GLA) by the enzyme delta-6-desaturase. GLA is then elongated to form dihomo-gamma-linolenic acid (DGLA), which can be converted to arachidonic acid (AA) by delta-5-desaturase. Arachidonic acid serves as the precursor for eicosanoids, including prostaglandins, thromboxanes, and leukotrienes, which are important inflammatory mediators.

Key Points to Consider

• When cell membranes are damaged, phospholipase A2 releases AA, which is then metabolized by cyclooxygenase (COX) enzymes to produce prostaglandins and thromboxanes, or by lipoxygenase enzymes to produce leukotrienes.
• These eicosanoids regulate inflammation, immune function, blood clotting, and other physiological processes.
• The modern Western diet often contains an excessive ratio of omega-6 to omega-3 fatty acids, which may promote inflammatory conditions, as highlighted in the 2018 American Family Physician study 1.
• Increasing consumption of foods high in omega-3 fatty acids, such as fish, nuts, and green vegetables, while limiting the use of corn and vegetable oils, can help balance the ratio of omega-3 to omega-6 fatty acids and reduce inflammation, as recommended by the European Heart Journal in 2016 1.

Recommendations for a Healthy Diet

• Saturated fatty acids should account for less than 10% of total energy intake, replaced by polyunsaturated fatty acids 1.
• Trans unsaturated fatty acids should be limited to as little as possible, preferably no intake from processed food, and less than 1% of total energy intake from natural origin 1.
• A daily intake of 30-45g of fiber, 200g of fruit, and 200g of vegetables is recommended, along with 30g of unsalted nuts and 1-2 servings of fish per week 1. In summary, a balanced diet that includes a variety of whole foods, such as fruits, vegetables, whole grains, and lean proteins, and limits processed and saturated foods, can help maintain optimal health and reduce the risk of chronic diseases, as supported by the evidence from 1 and 1.

From the Research

Omega-6 Fatty Acid Pathway

• The omega-6 fatty acid pathway involves the metabolism of linoleic acid (LA) to arachidonic acid (ARA), which is a precursor to pro-inflammatory mediators such as prostaglandins and leukotrienes 2.
• ARA is a significant contributor to the fatty acids present in the membrane phospholipids of cells involved in inflammation, and its metabolism is targeted by anti-inflammatory pharmaceuticals 2.
• However, studies have found that increased intake of ARA or LA does not necessarily increase inflammatory markers in healthy human adults, and epidemiological studies have suggested that ARA and LA may be linked to reduced inflammation 2.
• The interaction between omega-3 and omega-6 fatty acids and their lipid mediators in the context of inflammation is complex and not fully understood, with evidence suggesting that a high omega-6 fatty acid diet may inhibit the anti-inflammatory effects of omega-3 fatty acids 2, 3.

Inflammation and Omega-6 Fatty Acids

• Omega-6 fatty acids, particularly gamma-linolenic acid (GLA), have been shown to have anti-inflammatory effects, with GLA metabolites producing anti-inflammatory eicosanoids 4.
• The balance between omega-6 and omega-3 fatty acids is important, with a high omega-6/omega-3 ratio predisposing to supraphysiologic inflammatory responses and chronic low-grade inflammation 5.
• Reducing the omega-6/3 ratio, particularly through reductions in refined omega-6 seed oil intake and increasing marine omega-3 intake, may be an effective strategy for reducing inflammation, allergies, and autoimmune reactions 5.

Therapeutic Applications

• Omega-6 fatty acids, particularly GLA, may have therapeutic applications in the management of inflammatory skin diseases, such as atopic dermatitis, psoriasis, and acne, although individual results may vary due to genetic variations in PUFA metabolism 6.
• Combined supplementation with omega-6 and omega-3 fatty acids may exhibit the highest potential in diminishing inflammatory processes, although well-balanced nutrition and targeted supplementation strategies are recommended 6.