Inflammation: Friend and Foe

The acute inflammatory response defends against invading microorganisms and damaged cells, and is essential for wound healing & tissue repair. Chronic inflammation, however, damages tissues and can lead to or worsen chronic diseases such as arthritis, heart disease & dry eye syndrome.

GLA as an Anti-Inflammatory Nutrient

A recent review underscores the role of the fatty acid gamma linolenic acid (GLA) in modulating the inflammatory response (1). GLA has gained recognition over the last few decades for its anti-inflammatory and anti-cancer actions. Some key findings from controlled clinical trials include:

• In arthritics, several trials report that GLA reduced inflammation, symptoms, and the requirement for NSAIDs
• In inflammatory dry eye, GLA improved symptoms and reduced inflammation; in PRK patients, GLA relieved symptoms, and increased tear production and clearance; in Sjögren's patients, GLA eased ocular discomfort by reducing inflammation and increasing tear content of PGE1
• In diabetics, GLA improved nerve conduction velocity leading to improved blood flow and reduced tingling of extremities
• In patients with acute lung injury, GLA along with EPA improved gaseous exchange
• In breast cancer patients, GLA improved the effectiveness of tamoxifen, reduced side-effects, and hastened therapeutic response
• In uremic pruiritis, a common problem in hemodialysis patients, topically applied GLA relieved symptoms

Sources & Rationale for Supplementation

Dietary intake of GLA is typically negligible as GLA is present only in trace amounts in some green leafy vegetables and nuts. Supplemental sources include the oils of: borage (Borage officinalis), 20-26% GLA; black currant (Ribes nigrum), 15-18%; and evening primrose (Oenoethera biennis), 8-12%. According to Tufts researchers, black currant seed oil is a preferred source because it contains 13-16% of the omega-3 fatty acid alpha-linolenic as well as GLA. Examining the effects of black currant seed oil (vs. placebo) in healthy elderly subjects, researchers from Tufts found that GLA reduced levels of PGE2 and improved immune function (2).

GLA is produced in the body as an intermediate in the metabolism of linoleic acid (LA). However this reaction is very slow and further restricted by alcohol use, stress, smoking, saturated and trans-fatty acid intake, and deficiencies of magnesium, vitamin B6 and zinc. These factors - as well as hypertension, arthritis, psoriasis and diabetes - impair the activity of delta-6-desaturase, the enzyme that converts linoleic acid to GLA. Administering oral GLA is a means to bypass this often inefficient and rate-limiting step in the metabolism of LA to GLA.

Anti-Inflammatory Mechanism of Action

GLA is rapidly converted to dihomo GLA (DGLA) which is incorporated into cell membrane phospholipids. When released by the action of the enzyme phospholipase A2, DGLA competes with arachidonic acid for the enzymes COX and LOX. Arachidonic acid is the omega-6 found abundantly in meat and dairy, and the precursor to pro-inflammatory eicosinoids like PGE2.

The COX products of DGLA include prostaglandins of series 1 (PGE1) and thromboxane A1. These products exert anti-inflammatory, anti-aggregation and vaso-dilatory actions.

A key LOX product of DGLA, 15-HETrE, inhibits production of leukotriene B4 from inflammatory cells including neutrophils. Some research suggests that DGLA may act directly on T-cells to modulate immune response in diseases such as rheumatoid arthritis.

Anti-Cancer Mechanisms of Action

Pre-clinical research indicates that the anti-cancer properties of GLA include: direct cytotoxic action on cancer cells, anti-angiogenic action in tumor cells, stimulation of apoptosis, gene activation, and the effects of DGLA eicosinoids. Preliminary clinical studies suggest that GLA may have benefit in some cancers. GLA injected directly into tumor cells of patients with advanced glioma significantly reduced tumor mass.

Safety of Supplemental GLA

Supplemental GLA has been safely administered in clinical trials at oral doses of 2.8 grams per day or less, for up to a year (3-5). GLA-rich oils have also been commonly used in the U.S. for over 20 years, with no reports of serious adverse events or effects (6).

Americans, who generally obtain an excess of omega-6 fats through over-consumption of meat, dairy, vegetable cooking oils and shortenings, are advised to consume more omega-3s from fatty fish and nuts. The amount of omega-6 fatty acids present in common doses of GLA-rich oil do not make a significant contribution to overall fat intake - typically about 67 grams daily for a 2000 kcal diet with 30% of calories from fats. Further, black currant seed oil contains a recommended ratio of omega-6 to omega-3 fats.

GLA & EPA: Complementary Actions

One concern related to DGLA, is that it could be further metabolized to arachidonic acid with subsequent pro-inflammatory effects. This is not relevant in inflammatory cells such as neutrophils, since these cells lack enzyme (delta-5-desaturase) activity needed to convert DGLA to arachidonic acid (7). Importantly, inflammatory cells from subjects supplemented with GLA produce significantly less pro-inflammatory leukotriene B4 (8,9) .

In contrast to inflammatory cells, high levels of supplemental GLA have been shown in some but not other studies to elevate serum arachidonic acid levels. Human studies, however, have demonstrated that the addition of fish-derived omega-3 EPA in a balanced ratio to GLA, blocks the activity of delta-5-desaturase and prevents elevations in serum arachidonic acid (10,11).

Co-ingesting similar levels of EPA and GLA increases cellular membrane content of both DGLA and EPA (precursor to anti-inflammatory eicosinoids). In short, this supplementation strategy successfully maintains the anti-inflammatory capacity of GLA and increases serum EPA, without causing accumulation of arachidonic acid.

Flaxseed oil is a concentrated source of omega-3 alpha linolenic acid. However, conversion of this fatty acid to EPA is limited, and further metabolism to DHA is very low or negligible (12). Typically, only 15-40% of alpha linoleic is converted to EPA This may, in part, explain why omega-3 fatty acids from fish or fish-oil supplements, but not alpha-linolenic acid, have been found to benefit cardiovascular disease outcomes in primary- and secondary-prevention studies (13). Thus GLA-enriched oils are more effectively paired with fish oil rather than flaxseed oil to promote the complementary actions of GLA and EPA.

References

1. Kapoor R, et al. Gamma Linolenic Acid: An anti-inflammatory omega-6 fatty acid (Review) Curr Pharm Biotech 7:531-34, 2006.
2. Wu D, et al. Effect of dietary supplementation with black currant seed oil on the immune response of healthy elderly subjects. Am J Clin Nutr 70: 536-543, 1999.
3. van der Merwe, et al. The effect of gamma-linolenic acid, an in vitro cytostatic substance contained in evening primrose oil, on primary liver cancer. A double- blind placebo controlled trial. Prostaglandins Leukot Essent Fatty Acids 40:199-202, 1992.
4. Zurier RB, et al. Gamma-linolenic acid treatment of rheumatoid arthritis. A randomized, placebo-controlled trial. Arthritis Rheum39:1808-17, 1996.
5. Keen H, et al. Treatment of diabetic neuropathy with gamma-linolenic acid. The gamma-Linolenic Acid Multicenter Trial Group. Diabetes Care 16:8-15, 1993.
6. Physicians' Desk Reference for Nutritional Supplements, 1st Edition, ISBN 1-56363-364-7, p. 173.
7. Chilton-Lopez T, et al. Metabolism of GLA in human neutrophils. J Immunol 156:2941-47, 1996.
8. Johnson M, et al. Dietary supplementation with GLA alters fatty acid content and eicosanoid production in healthy humans. J Nutr 127:1435-44, 1997.
9. Ziboh VA, et al. Dose-response effects of dietary GLA-enriched oils on human polymorphonuclear-neutrophil biosynthesis of leukotriene B4. Am J Clin Nutr 55:39-45, 1992.
10. Barham JB, et al. Addition of eicosapentaenoic acid to gamma-linolenic acid-supplemented diets prevents serum arachidonic acid accumulation in humans. J Nutr 130:1925-31, 2000.
11. Laidlaw M, et al. Effects of supplementation with fish oil-derived n-3 fatty acids and gamma-linolenic acid on circulating plasma lipid profiles in women. Am J Clin Nutr 77:37-42, 2003.
12. Burdge G, et al. Alpha linolenic metabolism in adult humans. Eur J Lipid Sci Tech 107:426-39, 205, 2005.
13. Wang C, et al. n-3 Fatty acids from fish or fish-oil supplements, but not alpha-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary-prevention studies: a systematic review. Am J of Clin Nutr 84:5-17, 2006.