The Journal of Nutrition Vol. 128 No. 9 September 1998, pp. 1411-1414

Importance of Dietary -Linolenic Acid in Human Health and Nutrition

Yang-Yi Fan and Robert S. Chapkin¹

Faculty of Nutrition, Molecular and Cell Biology Group, Texas A&M University, College Station, TX 77843-2471

	ABSTRACT

Abstract Introduction References

Considerable debate remains regarding the distinct biological activities of individual polyunsaturated fatty acids (PUFA). One of the most interesting yet controversial dietary approaches has been the possible prophylactic role of dietary -linolenic acid (GLA) in treating various chronic disease states. This strategy is based on the ability of diet to modify cellular lipid composition and eicosanoid (cyclooxygenase and lipoxygenase) biosynthesis. Recent studies demonstrate that dietary GLA increases the content of its elongase product, dihomo--linolenic acid (DGLA), within cell membranes without concomitant changes in arachidonic acid (AA). Subsequently, upon stimulation, DGLA can be converted by inflammatory cells to 15-(S)-hydroxy-8,11,13-eicosatrienoic acid and prostaglandin E₁. This is noteworthy because these compounds possess both anti-inflammatory and antiproliferative properties. Although an optimal feeding regimen to maximize the potential benefits of dietary GLA has not yet been determined, it is the purpose of this review to summarize the most recent research that has focused on objectively and reproducibly determining the mechanism(s) by which GLA may ameliorate health problems.

	INTRODUCTION

Abstract Introduction References

On January 27, 1993, the United States Court of Appeals for the Seventh Circuit ruled that -linolenic acid [GLA, 18:3(n-6)]² containing oil is a single food ingredient and therefore not subject to food additive regulation. As a result of this legislation, GLA-containing oils (primrose oil, blackcurrant seed oil and borage oil) have become increasingly popular with retailers and are being sold as encapsulated supplements. In view of this burgeoning interest, it is estimated that a sustainable market for GLA-plant oils in the United States is developing. To evaluate GLA-related nutraceuticals critically, it is essential to elucidate the mechanisms underlying the relationship between dietary GLA and health maintenance. This review will focus on recent studies that address the physiologic functions and mechanisms of action of GLA in humans and relevant disease model systems.

GLA dietary sources.  GLA is found in human milk and in small amounts in a wide variety of common foods, notably organ meats (Horrobin 1990). It is found in relatively high abundance in the plant seed oils of evening primrose (7-10 g/100 g GLA), blackcurrant (15-20 g/100 g GLA), borage (18-26 g/100 g GLA) and fungal oil (23-26 g/100 g GLA). The triacylglycerol stereospecific structure of these oils is distinct, with GLA being concentrated in the sn-3 position of evening primrose oil and blackcurrant seed oil, the sn-2 position of borage oil and the sn-2 and sn-3 positions of fungal oil (Lawson and Hughes 1988). The development of oilseed crops designed to produce substantial quantities of GLA is a major goal of plant biotechnology, and the cyanobacterial 6 desaturase gene has recently been successfully expressed in transgenic tobacco, resulting in GLA accumulation (Reddy and Thomas 1996). In addition, the efficient production of GLA by mutants of Mortierella ramanniana has been investigated (Hiruta et al. 1996).

Although the ingestion of GLA-enriched oils results in the accumulation of dihomo--linolenic acid [DGLA, 20:3(n-6)] in tissue phospholipids and triacylglycerols, the absolute level of GLA in the oil may not be the sole determinant of biological efficacy. The precise triacylglycerol stereospecific composition and the cellular kinetics of phospholipases and acyltransferases (discussed below) may also influence GLA bioavailability (Fan et al. 1996a). For example, although the GLA concentration in borage oil is twofold higher than in primrose oil, GLA-related effects, such as formation of prostaglandin E₁ (PGE₁), are comparable for both dietary oils on a per gram basis (Fan and Chapkin 1992).

GLA metabolic elongation.  It is generally thought that all mammals, including humans, require 1-2% of total dietary energy as linoleic acid [LA, 18:2(n-6)] to prevent essential fatty acid deficiency (Chapkin 1998). LA is metabolized in a variety of tissues by 6 desaturase to form GLA, which is rapidly elongated to DGLA (Fig. 1). DGLA can be further desaturated to arachidonic acid [AA, 20:4(n-6)] by 5 desaturase. However, due to the limited activity of 5 desaturase in rodents and humans, only a small fraction of DGLA is converted to AA (Johnson et al. 1997, Zurier et al. 1996). These data indicate that in many cell types, DGLA, the elongase product of GLA, but not AA, accumulates after GLA supplementation. Because the metabolic pathways of biosynthesis of long-chain polyunsaturated fatty acids (PUFA) consist of a series of rate-determining desaturase and elongase steps, dietary GLA and AA may have superior biopotency compared to LA (Chapkin 1998).

View larger version (27K): [in this window] [in a new window]   Fig 1. Metabolism of -linolenic acid. In many animal tissues and cells, LA is converted to AA by an alternating sequence of 6 desaturation, chain elongation and 5 desaturation, in which hydrogen atoms are selectively removed to create new double bonds and then two carbon atoms are added to lengthen the fatty acid chain. Dietary GLA bypasses the rate-limited 6 desaturation step and is quickly elongated to DGLA by elongase, with only a very limited amount being desaturated to AA by 5 desaturase. DGLA can be converted to PGE1 via the cyclooxygenase pathway and/or converted to 15-HETrE via the 15-lipoxygenase pathway. 15-HETrE is capable of inhibiting the formation of AA-derived 5-lipoxygenase (proinflammatory) metabolites.

The increase in DGLA relative to AA is capable of attenuating the biosynthesis of AA metabolites, i.e., 2-series prostaglandins, 4-series leukotrienes and platelet-activating factor (PAF), and exerts an anti-inflammatory effect in human subjects (Johnson et al. 1997). In addition, because GLA bypasses a key regulatory rate-limiting enzymatic step (6 desaturase) that controls the formation of long-chain PUFA of the (n-6) series, it may serve to alleviate a systemic decline in 6 desaturation. Such a reduced capacity to convert LA to GLA has been associated with various physiologic/pathophysiologic states, including aging, diabetes, alcoholism, atopic dermatitis, premenstrual syndrome, rheumatoid arthritis, cancer and cardiovascular disease (Bolton-Smith et al. 1997, Horrobin 1990, Leventhal et al. 1993). Therefore, supplementation of GLA may be of value in alleviating some of the symptoms of these various diseases (discussed below).

DGLA metabolic oxidation.  Depending on the cell type, DGLA is cyclooxygenated (by Cox-1/2) to prostaglandins of the 1-series (PGE₁) and/or metabolized by the 15-lipoxygenase into 15-(S)-hydroxy-8,11,13-eicosatrienoic acid (15-HETrE) (Borgeat et al. 1976) (Fig. 1). These two oxidative metabolites of the GLA elongation product, DGLA, have been found to exert clinical efficacy in a variety of diseases, including suppression of chronic inflammation, vasodilation and lowering of blood pressure, and the inhibition of smooth muscle cell proliferation associated with atherosclerotic plaque development (Fan et al. 1995, Zurier et al. 1996).

One of the experimental approaches to exploit the desirable effects of PGE₁ on a variety of vascular/inflammatory disorders has been to infuse PGE₁. However, because of the very short half-life of PGE₁ in the body, this method can be used only in situations in which intravascular infusions are possible. Although other investigators have utilized stable analogs of PGE₁, which are present in the circulation for hours at slowly diminishing concentrations, these have unpredictable effects (Rossetti et al. 1994). In comparison, GLA supplementation studies conducted in humans (Zurier et al. 1996, Johnson et al. 1997) and rodents (Fan and Chapkin 1992, Fan et al. 1995) have shown that the synthesis of 1-series prostaglandins, and not the 2-series prostaglandins (PGE₂, derived from AA), is selectively elevated. Although the increases in the tissue levels of PGE₁ after GLA consumption are modest relative to PGE₂, effects are noteworthy because select biological properties of PGE₁ are ~20 times stronger than PGE₂ (Fan et al. 1996). In particular, PGE₁ elicits an array of intracellular responses by binding to select G protein coupled surface PGE (EP) receptors and/or the prostacyclin (IP) receptor (Fig. 2) (Negishi et al. 1993). Four subtypes of the EP-receptor, termed EP₁, EP₂, EP₃ and EP₄ have been identified. The EP₂, EP₄ and IP receptors couple to adenylate cyclase via a G_s-protein, and receptor activation results in increases in intracellular levels of cyclic 3',5'-adenosine monophosphate (cAMP) (Negishi et al. 1993). Elevation of cAMP stimulates the expression of numerous genes through the protein kinase A (PKA)-mediated phosphorylation of the nuclear cAMP response element binding proteins (CREB) (Foulkes and Sasone-Corsi 1996). Through this mechanism, PGE₁ has been shown to inhibit vascular smooth muscle cell (SMC) proliferation in vitro (Fan et al. 1996b). This is significant because agents that reduce the migration and proliferation of vascular SMC also retard the typical atherosclerotic plaque (Fan et al. 1995, 1998). These findings have been recently corroborated by Indolfi et al. (1997), who demonstrated that activation of cAMP-PKA signaling in vivo inhibits aortic SMC proliferation induced by vascular injury. Whether dietary GLA can modulate the atherogenic process in part by enhancing the release of PGE₁ is currently being investigated (described below).

View larger version (58K): [in this window] [in a new window]   Fig 2. Model for stimulation of DGLA-derived PGE1 biosynthesis by macrophages. Dietary GLA, via its metabolic elongation to DGLA, can enhance macrophage synthesis of PGE1, an anti-proliferative cyclooxygenase product. PGE1 elicits an array of biological responses by binding to select G protein coupled surface receptors on smooth muscle cells, increasing intracellular cAMP levels. This in turn stimulates the expression of numerous genes through the PKA-mediated phosphorylation of the nuclear CREB binding proteins. The transcriptional co-activator, CBP, in turn, mediates PKA-induced transcription by binding to the PKA phosphorylated activation domain of CREB. CREB proteins can also heterodimerize with other members of the b-ZIP or basic zipper family of transcription factors, including Fos proteins (c-fos, Fosb, Fra-1, Fra-2), and Jun proteins (c-jun, JunB, JunD). Through this mechanism, PGE1 has been shown to inhibit vascular smooth muscle cell proliferation. Abbreviations: CBP, CREB adapter binding protein; CRE, cyclic AMP response element.

Examination of the oxidative metabolism of DGLA into lipoxygenase products has shown that several cell types, including neutrophils, macrophage/monocytes and epidermal cells, metabolize DGLA into the 15-lipoxygenase product, 15-HETrE. There is increasing evidence to suggest that 15-lipoxygenase-derived hydroxy fatty acids inhibit the synthesis of AA-derived 5-lipoxygenase metabolites (Chapkin et al. 1988, Miller et al. 1991) (Fig. 1). These observations are significant because elevated levels of AA-derived 5-lipoxygenase products, e.g., LTC₄ and LTB₄, are associated with several pathologic inflammatory, hyperproliferative disorders (Goulet et al. 1994). Recent studies indicate that 15-HETrE can be incorporated into the membrane phospholipid, phosphatidylinositol 4,5-bisphosphate (PtdIns 4,5-P₂), and released as 15-HETrE-containing-diacylglycerol (15-HETrE-DAG) (Cho and Ziboh 1997). Interestingly, 15-HETrE-DAG is capable of inhibiting protein kinase C  (PKC ), a mediator of the cell cycle in select cell types (Cho and Ziboh 1997, Thompson and Fields 1996). The inhibitions of leukotriene biosynthesis and PKC-dependent signal transduction likely represent mechanisms by which dietary GLA attenuates inflammatory/hyperproliferative responses.

Phospholipid sources of metabolically elongated GLA.  It is generally thought that GLA-derived eicosanoid (PGE₁ and 15-HETrE) biosynthesis is dependent primarily on the abundance of nonesterified DGLA that is released from membrane phospholipids by phospholipase A₂ (PLA₂) hydrolysis. Although PLA₂ has long been considered the rate-determining step in eicosanoid biosynthesis (Yamashita et al. 1997), it is now recognized that the relative rates of PLA₂ hydrolysis and lysophospholipid reacylation regulate the levels of free GLA and DGLA (Fan and Chapkin 1993).

Efficacy of GLA in treating chronic disease.  The current perception in the scientific community is that dietary GLA, largely in the form of evening primrose oil (Oenothera biennis), is used to treat many conditions with little justification (Kleijnen 1994). As a result of this scientific skepticism, the issues of efficacy and safety have recently been reliably investigated. With regard to safety, dietary sources of GLA appear to be completely nontoxic. Although limited cases of soft stools, belching and abdominal bloating have been reported (DeLuca et al. 1995), several long-term human feeding trials have clearly shown that up to 2.8 g GLA/d is well tolerated (Leventhal et al. 1993, Zurier et al. 1996). This corresponds to the consumption of 8 × 500 mg capsules/d of GLA-70, a borage oil isolate containing ~70% GLA as a percentage of total fatty acids. Moreover, altered lipid peroxidation and susceptibility to infection have not been observed in long-term clinical trials (DeLuca et al. 1995). These data indicate that long-term GLA administration may be feasible.

Recent encouraging findings indicate that several disorders may be favorably affected by GLA administration. Perhaps the most promising series of work demonstrating the efficacy of dietary GLA has been in the treatment of rheumatoid arthritis (DeLuca et al. 1995). Patients with rheumatoid arthritis and active synovitis were treated with GLA (1.4-2.8 g/d) for up to 1 y in randomized, placebo-controlled trials (Leventhal et al. 1993, Zurier et al. 1996). Patients taking GLA for the entire year showed progressive improvement, suggesting that GLA might function as a slow-acting, disease-modifying antirheumatic drug. With respect to the mechanism(s) of action, data reported in the past few years indicate that DGLA suppresses human synovial cell proliferation in culture by increasing PGE₁ synthesis and intracellular cAMP levels (DeLuca et al. 1995). In addition, oral administration of GLA is capable of suppressing human T-cell proliferation (Rossetti et al. 1997). Further investigation indicates that GLA and DGLA suppress T-cell activation by interfering with early events in the TcR/CD3-receptor-mediated signal transduction cascade (Vassilopoulos et al. 1997). Although the precise mechanism(s) of action remains to be determined, it has been suggested that the incorporation of select diet-derived PUFA may alter the dynamic lipid environment that regulates protein lateral diffusion of anchored receptors, thereby modulating their function (Jolly et al. 1997). Clearly, these findings highlight the need for establishing a therapeutic GLA dose that will down-regulate autoimmune and cell-mediated responses and therefore reduce the need for concomitant antirheumatic medication. The use of GLA as a benign, adjunctive therapy is relevant because rheumatoid arthritis patients are at high risk for developing gastrointestinal complications from traditional non-steroidal anti-inflammatory drug and corticosteroid medications (DeLuca et al. 1995).

The potential for dietary GLA to favorably modulate cardiovascular risk factors was initially investigated well over 20 years ago (Kernoff et al. 1977). However, we have recently demonstrated that a very high dose of borage oil, administered at 72 mg GLA/(kg body weight·d) for 42 d, actually enhances platelet aggregation in healthy male subjects (Barre et al. 1993). Therefore, the issue of whether GLA alimentation is suitable for treating human blood platelet dysfunction (thromboembolic disease) remains to be vigorously tested in a large clinical trial. The efficacy of dietary GLA in down-modulating lesion development and progression of atherosclerosis in a mouse model has also been examined (Fan et al. 1995, 1996a and 1997). Our laboratory has shown that dietary GLA down-regulates atherogenic potential by enhancing macrophage PGE₁ biosynthesis. The macrophage-derived PGE₁ is capable of inducing SMC intracellular cAMP levels, resulting in the inhibition of vascular SMC proliferation, a hallmark of the atherogenic process (Fig. 2). The most recent advances indicate that dietary GLA reduces the average medial layer thickness of the vessel wall and reduces the size of atherosclerotic lesions in ApoE genetic knock-out mice (Fan et al. 1998). The progressive series of atherosclerotic lesions that develop in these animals are similar to those found in humans. Therefore, these data indicate that dietary GLA can retard the development of atherosclerosis in a highly relevant transgenic mouse model.

A growing number of studies suggest that GLA is unique among the (n-6) PUFA family members (LA, GLA and AA) in its potential to suppress tumor growth and metastasis. GLA has the ability to inhibit both motility and invasiveness of human colon cancer cells by increasing the expression of E-cadherin, a cell-to-cell adhesion molecule that acts as a suppressor of metastasis (Jiang et al. 1995). In addition, GLA reduces tumor-endothelium adhesion, a key factor in the establishment of distant metastases, partly by improving gap junction communication within the endothelium (Jiang et al 1997). These observations have been corroborated by Kokura et al (1997) who demonstrated that dietary GLA is effective in suppressing tumor growth in vivo. Whether oxidative metabolites of GLA are involved remains to be determined. These encouraging results indicate that further investigations should be given priority.

Because complications of diabetic neuropathy may be related to abnormal 6 desaturase activity and therefore membrane function (Horrobin 1990), the effect of GLA on neurovascular deficits in experimental diabetes has been investigated. Triacylglycerols containing GLA have been shown to normalize nerve conduction velocity and sciatic endoneurial blood flow (Dines et al. 1995). Although the mechanism of action has not been elucidated, GLA may correct nerve conduction abnormalities by enhancing the synthesis of the cyclooxygenase-derived vasodilator prostanoid, PGE₁, which is capable of increasing vasa nervorum perfusion (Cameron and Cotter 1996). Interestingly, the combination of GLA and ascorbate could have therapeutic advantage over GLA alone in correcting neurovascular deficits in diabetic rats (Cameron and Cotter 1996). It is possible that ascorbate may act by suppressing tissue oxidative damage associated with diabetes mellitus. Therefore, ascorbyl GLA may be a suitable candidate for clinical trials of diabetic neuropathy.

In summary, manipulation of dietary PUFA intake may have biological significance because many disease states are associated with an overproduction of eicosanoids derived from AA. Somewhat paradoxically, intracellular AA pools in humans and rodent species do not appear to be influenced by dietary GLA (Johnson et al. 1997, Zurier et al. 1996). Nevertheless, GLA alimentation reduces AA-derived LTB₄, LTC₄ and PAF synthesis, while increasing DGLA, PGE₁ and 15-HETrE synthesis (DeLuca et al. 1995, Johnson et al. 1997, Miller et al. 1991, Zurier et al. 1996). The data reported in the past few years have confirmed that although the average intake of GLA in the diet is more than 100 times lower than that of LA, its consumption may have physiologic relevance. Therefore, even though North Americans consume on average more than 10 times the amount of (n-6) PUFA required to meet minimal essential fatty acid requirements (Okuyama et al. 1997), the consumption of GLA may offer new strategies for treatment and prevention of certain chronic diseases. Potential candidates, e.g., rheumatoid arthritis patients, will have to take GLA supplements in order to mimic clinical dosages, because GLA is not readily found in common foods.

It is evident that large gaps exist in our present understanding of GLA functions in humans and the levels of individual PUFA required for optimal nutrition. Undoubtedly, elucidation of the mechanism(s) by which select dietary PUFA influence chronic disease progression and therapy will lead to the establishment of dietary guidelines designed to reduce the incidence and severity of inflammatory/hyperproliferative diseases, without compromising host defenses. One such preventative/palliative approach may involve the use of GLA supplementation.

	FOOTNOTES

Manuscript received 18 June 1998..

	LITERATURE CITED

Abstract Introduction References

• Barre D. E., Holub B.J., Chapkin R. S. The effect of borage oil supplementation on platelet aggregation, thromboxane B₂, prostaglandin E₁ and E₂ formation. Nutr. Res. 1993; 13:739-751
• Bolton-Smith C., Woodward M., Tavendale R. Evidence for age-related differences in the fatty acid composition of human adipose tissue, independent of diet. Eur. J. Clin. Nutr. 1997; 51:619-624[Medline]
• Borgeat P., Hamberg M., Samuelsson S. Transformation of arachidonic acid and homo-gamma-linolenic acid by rabbit polymorphonuclear leukocytes. Monohydroxy acids from novel lipoxygenase. J. Biol. Chem. 1976; 251:7816-7820[Abstract/Free Full Text]
• Cameron N. E., Cotter M. A. Comparision of the effects of ascorbyl gamma-linolenic acid and gamma-linolenic acid in the correction of neurovascular deficits in diabetic rats. Diabetologia 1996; 39:1047-1054[Medline]
• Chapkin, R.S. (1998) Reappraisal of the essential fatty acids. In: Fatty Acids in Food and Their Health Implications, 2nd ed. (Chow, C.K., ed.). Marcel Dekker, New York, NY (in press).
• Chapkin R. S., Miller C. C., Somers S. D., Erickson K. L. Ability of monohydroxyeicosatrienoic acid (15-OH-20:3) to modulate macrophage arachidonic acid metabolism. Biochem. Biophys. Res. Commun. 1988; 153:799-804[Medline]
• Cho Y., Ziboh V. A. A novel 15-hydroxyeicosatrienoic acid-substituted diacylglycerol (15-HETrE-DAG) selectively inhibits epidermal protein kinase C . Biochim. Biophys. Acta 1997; 1349:67-71[Medline]
• DeLuca P., Rothman D., Zurier R. B. Marine and botanical lipids as immunomodulatory and therapeutic agents in the treatment of rheumatoid arthritis. Rheum. Dis. Clin. N. Am. 1995; 21:759-777[Medline]
• Dines K. C., Cameron N. E., Cotter M. A. Comparison of the effects of evening primrose oil and triglycerides containing -linolenic acid on nerve conduction and blood flow in diabetic rats. J. Pharmacol. Exp. Ther. 1995; 273:49-55[Abstract/Free Full Text]
• Fan Y.-Y., Chapkin R. S. Mouse peritoneal macrophage prostaglandin E₁ synthesis is altered by dietary -linolenic acid. J. Nutr. 1992; 122:1600-1606
• Fan, Y.-Y. & Chapkin, R.S. (1993) Phospholipid sources of metabolically elongated gammalinolenic acid: conversion of prostaglandin E₁ in stimulated mouse macrophages. J. Nutr. Biochem. 4:602-607.
• Fan Y.-Y., Ramos K. S., Chapkin R. S. Dietary -linolenic acid modulates macrophage-vascular smooth muscle cell interactions: evidence for a macrophage-derived soluble factor that downregulates DNA synthesis in smooth muscle cells. Arterioscler. Thromb. Vasc. Biol. 1995; 15:1397-1403[Abstract/Free Full Text]
• Fan Y.-Y., Ramos K. S., Chapkin R. S. Dietary lipid source alters murine macrophage/vascular smooth muscle cell interactions in vitro. J. Nutr. 1996a; 126:2083-2088
• Fan Y.-Y., Ramos K. S., Chapkin R. S. Cell cycle-dependent inhibition of DNA synthesis in vascular smooth muscle cells by prostaglandin E₁: relationship to intracellular cAMP levels. Prostaglandins Leukot. Essent. Fatty Acids 1996b; 54:101-107[Medline]
• Fan Y.-Y., Ramos K. S., Chapkin R. S. Dietary -linolenic acid enhances mouse macrophage-derived prostaglandin E₁ which inhibits vascular smooth muscle cell proliferation. J. Nutr. 1997; 127:1765-1771[Abstract/Free Full Text]
• Fan, Y.-Y., Ramos, K. S. & Chapkin, R. S. (1998) Combined dietary gamma-linolenic acid and n-3 polyunsaturated fatty acids retard atherosclerotic progression in ApoE knock out mice. In: Eicosanoids and Other Bioactive Lipids in Cancer, Inflammation and Related Diseases, Vol. 4 (Honn, K. V., Nigam, S., Marnett, L. J. & Dennis, E., eds.) (in press).
• Foulkes N.S., Sasone-Corsi P. Transcription factors coupled to the cAMP signalling pathway. Biochim. Biophys. Acta 1996; 1288:F101-F121[Medline]
• Goulet J. L., Snouwaert J. N., Latour A. M., Coffman T. M., Koller B. H. Altered inflammatory responses in leukotriene-deficient mice. Proc. Natl. Acad. Sci. U.S.A. 1994; 91:12852-12856[Abstract/Free Full Text]
• Hiruta O., Futamura T., Takebe H., Satoh A., Kamisaka Y., Yokochi T., Nakahara T., Suzuki O. Optimization and scale-up of -linolenic acid production by Mortierella ramanniana MM 15-1, a high -linolenic acid producing mutant. J. Ferment. Bioeng. 1996; 82:366-370
• Horrobin D. F. Gamma-linolenic acid. Rev. Contemp. Physiol. 1990; 1:1-41
• Indolfi C., Avvedimento V., DiLorenzo, Esposito G., Rapacciuolo A., Giuliano P., Gieco D., Cavuto L., Stingone A., Ciullo I., Condorelli G., Chiariello M. Activation of cAMP-PKA signaling in vivo inhibits smooth muscle cell proliferation induced by vascular injury. Nat. Med. 1997; 3:775-779[Medline]
• Jiang W. G., Hiscox S., Hallett M. B., Horrobin D. F., Mansel R. E., Puntis M. C. Regulation of the expression of E-cadherin on human cancer cells by gamma-linolenic acid (GLA). Cancer Res. 1995; 55:5043-5048[Abstract/Free Full Text]
• Jiang W. G., Hiscox S., Horrobin D.F., Bryce R. P., Mansel R.E. Gamma linolenic acid regulates expression of Maspin and the motility of cancer cells. Biochem. Biophys. Res. Commun. 1997; 237:639-644[Medline]
• Johnson M. M., Swan D. D., Surette M. E., Stegner J., Chilton T., Fontech A. N., Chilton F. H. Dietary supplementation with -linolenic acid alters fatty acid content and eicosanoid production in healthy humans. J. Nutr. 1997; 127:1435-1444[Abstract/Free Full Text]
• Jolly C. A., Jiang Y. H., Chapkin R. S., McMurray D. N. Dietary (n-3) polyunsaturated fatty acid modulation of murine lymphoproliferation and interleukin-2 secretion: correlation with alterations in diacylglycerol and ceramide mass. J. Nutr. 1997; 127:37-43[Abstract/Free Full Text]
• Kernoff P.B.A., Willis A. L., Stone K. J., Davies J. A., McNicol G. P. Antithrombotic potential of dihomo-gamma-linolenic acid in man. Br. Med. J. 1977; 2:1441-1444
• Kleijnen J. Evening primrose oil. Currently used in many conditions with little justification. Br. Med. J. 1994; 309:823-824[Free Full Text]
• Kokura S., Yoshikawa T., Kaneko T., Iinuma S., Nishimura S., Matsuyama K., Naito Y., Yoshida N., Kondo M. Efficacy of hyperthermia and polyunsaturated fatty acids on experimental carcinoma. Cancer Res. 1997; 57:2200-2202[Abstract/Free Full Text]
• Lawson L. D., Hughes B. G. Triacylglycerol structure of plant and fungal oils containing -linolenic acid. Lipids 1988; 23:313-317
• Leventhal L. J., Boyce E. G., Zurier R. B. Treatment of rheumatoid arthritis with gammalinolenic acid. Ann. Intern. Med. 1993; 119:867-873[Abstract/Free Full Text]
• Miller C. C., Tang W., Ziboh V. A., Fletcher M. P. Dietary supplementation with ethyl ester concentrates of fish oil (n-3) and borage oil (n-6) polyunsaturated fatty acids induces epidermal generation of local putative anti-inflammatory metabolites. J. Investig. Dermatol. 1991; 96:98-103[Medline]
• Negishi M., Sugimoto Y., Ichikawa A. Prostanoid receptors and their biological actions. Prog. Lipid Res. 1993; 32:417-434[Medline]
• Okuyama H., Kobayashi T., Watanabe S. Dietary fatty acids-the n-6/n-3 balance and chronic elderly diseases. Excess linoleic acid and relative n-3 deficiency syndrome seen in Japan. Prog. Lipid. Res. 1997; 35:409-457
• Reddy A. S., Thomas T. L. Expression of a cyanbacterial 6-desaturase gene results in -linolenic acid production in transgenic plants. Nat. Biotechnol. 1996; 14:639-642[Medline]
• Rossetti R.G., Braithwaite K., Zurier R. B. Suppression of acute inflammation with liposome associated prostaglandin E₁. Prostaglandins 1994; 48:187-195[Medline]
• Rossetti R. G., Seiler C. M., DeLuca P., Laposata M., Zurier R. B. Oral administration of unsaturated fatty acids: effects on human peripheral blood T lymphocyte proliferation. J. Leukoc. Biol. 1997; 62:438-443[Abstract]
• Thompson L. J., Fields A. P. Beta II protein kinase C is required for the G2/M phase transition of cell cycle. J. Biol. Chem. 1996; 271:15045-15053[Abstract/Free Full Text]
• Vassilopoulos D., Zurier R. B., Rossetti R. G., Tsokos G. C. Gammalinolenic acid and dihomogammalinolenic acid suppress the CD3-mediated signal transduction pathway in human T cells. Clin. Immunol. Immunopathol. 1997; 83:237-244[Medline]
• Yamashita A., Sugiura T., Waku K. Acyltransferases and transacylases involved in fatty acid remodeling of phospholipids and metabolism of bioactive lipids in mammalian cells. J. Biochem. 1997; 122:1-16[Abstract/Free Full Text]
• Zurier R. B., Rossetti R. G., Jacobson E. W., DeMarco D. M., Liu N. Y., Temming J. E., White B. M., Laposata M. Gamma-linolenic acid treatment of rheumatoid arthritis. A randomized, placebo-controlled trial. Arthritis Rheum. 1996; 39:1808-1817[Medline]

0022-3166/98 $3.00 ©1998 American Society for Nutritional Sciences