Elsevier

European Journal of Pharmacology

Volume 785, 15 August 2016, Pages 77-86
European Journal of Pharmacology

Gamma-linolenic acid, Dihommo-gamma linolenic, Eicosanoids and Inflammatory Processes

https://doi.org/10.1016/j.ejphar.2016.04.020Get rights and content

Abstract

Gamma-linolenic acid (GLA, 18:3n-6) is an omega-6 (n-6), 18 carbon (18C-) polyunsaturated fatty acid (PUFA) found in human milk and several botanical seed oils and is typically consumed as part of a dietary supplement. While there have been numerous in vitro and in vivo animal models which illustrate that GLA-supplemented diets attenuate inflammatory responses, clinical studies utilizing GLA or GLA in combination with omega-3 (n-3) PUFAs have been much less conclusive. A central premise of this review is that there are critical metabolic and genetic factors that affect the conversion of GLA to dihommo-gamma linolenic acid (DGLA, 20:3n-6) and arachidonic acid (AA, 20:4n-6), which consequently affects the balance of DGLA- and AA- derived metabolites. As a result, these factors impact the clinical effectiveness of GLA or GLA/(n-3) PUFA supplementations in treating inflammatory conditions. Specifically, these factors include: 1) the capacity for different human cells and tissues to convert GLA to DGLA and AA and to metabolize DGLA and AA to bioactive metabolites; 2) the opposing effects of DGLA and AA metabolites on inflammatory processes and diseases; and 3) the impact of genetic variations within the fatty acid desaturase (FADS) gene cluster, in particular, on AA/DGLA ratios and bioactive metabolites. We postulate that these factors influence the heterogeneity of results observed in GLA supplement-based clinical trials and suggest that “one-size fits all” approaches utilizing PUFA-based supplements may no longer be appropriate for the prevention and treatment of complex human diseases.

Introduction

Gamma-linolenic acid (GLA, 18:3n-6) is an omega-6 (n-6), 18 carbon (18C) polyunsaturated fatty acid (PUFA) found in human milk and several botanical seed oils (borage [~21% GLA], blackcurrant [~17%GLA] and evening primrose [~9%GLA]), and is typically consumed as a part of a dietary supplement. The scientific literature examining the clinical effects of GLA-containing supplements is both complex and confusing. While there have been numerous in vitro and in vivo animal models illustrating that GLA-supplemented diets attenuate various inflammatory responses, the clinical literature has been less conclusive (for a review, see (Fan and Chapkin, 1998)). The introduction of GLA supplementation strategies to achieve symptomatic relief of atopic dermatitis/eczema was historically preceded by the use of relatively large daily doses of oral linoleic acid (LA, 18:2n-6) containing oils. This was based on the premise that patients with atopic dermatitis/eczema had hallmark cutaneous signs of essential fatty acid deficiency and an impairment in PUFA biosynthesis at an early desaturase step (FADS2; Δ-6 desaturase) (Burr and Burr, 1929, Burr et al., 1932, Horrobin, 2000). It was hypothesized that GLA supplements could restore needed PUFAs and mitigate the disease.

Numerous studies primarily carried out in the 1980s and 1990s demonstrated that GLA-enriched botanical oils (evening primrose, borage, blackcurrant seed, and fungal-derived) had the capacity to relieve the signs and symptoms of several chronic inflammatory diseases, including rheumatoid arthritis (RA) and atopic dermatitis (Andreassi et al., 1997, Foolad et al., 2013, Kunkel et al., 1981, Leventhal et al., 1994, Leventhal et al., 1993, Lovell et al., 1981, Morse et al., 1989, Tate et al., 1989, Zurier et al., 1996). However, several more recent reviews and meta-analyses have questioned these earlier studies and raised doubts about the clinical effectiveness of GLA-enriched supplements particularly in the context of atopic dermatitis and RA (Bamford et al., 2013, Belch and Hill, 2000, Kitz, 2006, Macfarlane et al., 2011, Van Gool et al., 2004) (Table 1). A variety of issues complicate these studies including the fact that many of the trials have: 1) relatively low subject numbers; 2) less than ideal study designs (e.g. the absence of washout period in cross-over design trials); 3) variations in the types of GLA supplements and how they are administered (e.g. dose, duration); and 4) differences in selection/inclusion criteria (e.g. population demographics and disease states)(Foster et al., 2010, Van Gool et al., 2004).

Several studies have also investigated the effects of GLA when given in combination with botanical or marine omega-3 (n-3) enriched PUFA supplements. Enteral diets enriched with marine oils containing (n-3) LC-PUFAs (i.e. eicosapentaenoic acid [EPA, 20:5n-3] and docosahexaenoic acid [DHA, 22:6n-3]) and GLA have been shown to reduce cytokine production and neutrophil recruitment into the lung resulting in fewer days on ventilation and shorter stays in the intensive care unit in patients with acute lung injury or acute respiratory distress syndrome (Gadek et al., 1999, Pontes-Arruda et al., 2006, Singer et al., 2006). Importantly, these dietary combinations of GLA and (n-3) LC-PUFAs were also shown to reduce both morbidity and mortality of critically ill patients (Gadek et al., 1999, Li et al., 2015, Pontes-Arruda et al., 2006, Singer et al., 2006). However, as with the studies of GLA alone, the results combining GLA and (n-3) LC-PUFAs have not been reproducible. Other clinical studies, such as the OMEGA trial, did not show a benefit of these GLA/(n-3) LC-PUFA combinations on patient outcomes (Rice et al., 2011).

Supplementation strategies providing GLA together with (n-3) LC-PUFAs (i.e. EPA and DHA) have also been utilized in patients with atopic asthma (Surette et al., 2003a, Surette et al., 2003b, Surette et al., 2008) and have been shown to block ex vivo synthesis of leukotrienes from whole blood and isolated neutrophils. Importantly when provided as an emulsion, daily consumption of these combinations was associated with an improved quality of life in asthma patients and a decreased reliance on rescue medication (Surette et al., 2008). These results compared favorably with quality of life scores obtained in mild asthmatics treated with montelukast or zafirlukast (Riccioni et al., 2004). However, to our knowledge, no randomized, placebo-controlled trials have been conducted to investigate the effect of these combinations on the improved quality of life or other relevant clinical outcomes in asthma patients.

Alternatively, botanical oil combinations (e.g. borage and echium oils) containing GLA, the (n-3) 18C-PUFAs, alpha-linolenic acid (ALA, 18:3n-3) and stearidonic acid (SDA, 18:4n-3), have been shown to reduce leukotriene generation and forced expiratory volume in mild asthmatics (Arm et al., 2013, Kazani et al., 2014), improve glucose tolerance in insulin-resistant monkeys (Kavanagh et al., 2013) and reduce total and LDL cholesterol levels in patients with diabetes and metabolic syndrome (Lee et al., 2014). These botanical oil studies, however, have yet to be replicated in larger human clinical trials.

Together, these data indicate that the outcomes of clinical studies utilizing GLA supplementation, alone or in combination with other fatty acid-based supplements, while promising are highly inconsistent. These observations raise serious questions about our current understanding of the highly complex and dynamic nature of PUFA metabolism. More recent studies suggest that there are important metabolic and genetic factors within the human host that significantly impact the study of GLA or GLA/(n-3) PUFAs combinations and reveal that a “one size fits all” model of supplementation may not be appropriate. Further, these studies suggest that it may be necessary to better understand key metabolic and genetic issues regarding GLA metabolism before GLA-enriched supplements can be effectively used to address human disease. This review will focus on potential key metabolic and genetic factors that may impact the use and clinical effectiveness of GLA or GLA/(n-3) PUFA combinations.

Section snippets

Long chain polyunsaturated fatty acid biosynthesis

In mammals, (n-6) and (n-3), long chain (>20 carbons, LC) PUFAs such as arachidonic acid (AA, 20:4n-6), dihommo-gamma linolenic acid (DGLA, 20:3n-6), EPA (20:5n-3) and DHA (22:6n-3) can be synthesized from their respective precursors, (n-6) and (n-3) 18C-PUFAs such as LA, GLA, ALA, and SDA. The PUFA pathways and attendant enzymes are illustrated in Fig. 1. Biologically important (n-6) LC-PUFAs, DGLA and AA can be synthesized from LA using either two (one desaturation and one elongation step) or

Differential metabolism of GLA to DGLA and AA in human cells and tissues

Since metabolites of DGLA have predominantly anti-inflammatory effects and AA products generally enhance inflammation, it stands to reason that the balance of AA to DGLA (i.e. the ratio of AA/DGLA) in circulation, cells and tissues is a critical factor that impacts inflammatory processes. Several factors determine the levels of AA and DGLA and thus the ratio of AA metabolites and DGLA metabolites within cells and tissues. One is the differential capacities of cells or tissues to elongate GLA to

The impact of genetic variation in the fatty acid desaturase (FADS) gene cluster on AA/DGLA ratios and eicosanoid production

Until recently, the conversion of LA and ALA to AA and DHA, respectively, via the pathway shown in Fig. 1 was thought to be inefficient and uniform for all populations. However, mounting evidence indicates that common genetic and epigenetic variations in close proximity to and within the FADS cluster markedly affect the rate of conversion of 18C-PUFAs, including GLA, to LC-PUFAs and thus affecting the amount of circulating and tissue LC-PUFA levels. Specifically, single nucleotide polymorphisms

Discussion and future directions

This review emphasizes that the study of GLA and DGLA metabolism and its relationship to eicosanoid biosynthesis and inflammatory processes is a complex area of research. On the one hand, there are promising studies that suggest that supplementation with GLA and particularly combinations of GLA with (n-3) long chain-PUFAs have great potential to dampen inflammatory processes and improve signs and symptoms of several inflammatory diseases. However, as a whole, this field of study is currently

Conflict of interest

Floyd H. Chilton is a paid consultant for Eagle Wellness, LLC. This information has been revealed to Wake Forest Baptist Medical Center and is institutionally managed. Other authors have no conflict of interest.

Acknowledgement

This work was supported by NIH P50 AT002782, United States (FHC, PI) and NIH, United States AT008621-01A1 (FHC, PI).

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