Showing papers in "Prostaglandins Leukotrienes and Essential Fatty Acids in 1995"

Curcumin, a major component of food spice turmeric (Curcuma longa) inhibits aggregation and alters eicosanoid metabolism in human blood platelets

Abstract: In traditional medicine, Ayurveda, several spices and herbs are held to possess medicinal properties. Earlier we have reported that extracts from several spices, including turmeric, inhibit platelet aggregation and modulate eicosanoid biosynthesis. Due to their eicosanoid-modulating property, it was suggested that the spices may serve to provide clues to drugs directed to arachidonic acid (AA) pathway enzymes as pharmacological targets. Curcumin, a major component of turmeric, inhibited platelet aggregation induced by arachidonate, adrenaline and collagen. This compound inhibited thromboxane B2 (TXB2) production from exogenous [14C] arachidonate in washed platelets with a concomitant increase in the formation of 12-lipoxygenase products. Moreover, curcumin inhibited the incorporation of [14C]AA into platelet phospholipids and inhibited the deacylation of AA-labelled phospholipids (liberation of free AA) on stimulation with calcium ionophore A23187. Curcumin's anti-inflammatory property may, in part, be explained by its effects on eicosanoid biosynthesis.

The control of prostaglandin production by the endometrium in relation to luteolysis and menstruation.

Abstract: Oestradiol acting on a progesterone-primed uterus stimulates prostaglandin (PG) F2 alpha synthesis by the endometrium. In some species (notably the sheep, cow and goat) oxytocin released from the ovary also forms part of the physiological stimulus for increased endometrial PGF2 alpha production. The corpus luteum contains high concentrations (> 1 microgram/g tissue) of this peptide in these species. The intracellular mechanisms by which these three hormones control endometrial PGF2 alpha synthesis and release are far from clear. Oxytocin stimulates the synthesis of inositol phosphates and diacylglycerol in the endometrium of some species, but whether this pathway is involved in endometrial PGF2 alpha synthesis is still open to question. There is evidence that increased endometrial PGF2 alpha synthesis is dependent upon increased endometrial protein synthesis but, apart from the recorded effects of steroid hormones on the concentrations of phospholipase A2, prostaglandin H synthase and oxytocin receptors, it is not known what other endometrial proteins are involved. Some disorders of menstruation are associated with abnormal PG production by the endometrium, but the reasons for this abnormality are not clear. During early pregnancy an increase in PGF2 alpha synthesis by the endometrium is prevented, except in the pig where the PGF2 alpha produced is directed from the venous drainage to the uterine lumen. In those species in which endometrial PGF2 alpha synthesis is dependent upon oxytocin secreted by the ovary, the conceptus secretes an interferon-tau (previously named trophoblast protein-1) which prevents oestradiol and oxytocin acting on a progesterone-primed uterus from stimulating endometrial PGF2 alpha synthesis. The identities of the factors produced by the conceptus which prevent endometrial PGF2 alpha synthesis during early pregnancy in other species are not known, although it is clear that they are not interferons.

Fatty Acids in Cell Signalling: Modulation by Lipid Binding Proteins

Abstract: Long-chain fatty acids and several of their metabolites have now been shown to be involved as primary or secondary messengers in specific cell signalling pathways. In view of their extremely low aqueous solubility, the extracellular as well as intracellular transport of these compounds is assumed to be facilitated by specific lipid binding proteins, such as cytoplasmic fatty acid-binding protein (FABP). In this paper a survey is given on the biological significance and possible modulatory action of intracellular lipid binding proteins for fatty acid-mediated signal transduction pathways.

Essential fatty acid metabolism in patients with essential hypertension, diabetes mellitus and coronary heart disease.

Abstract: Mortality and morbidity from coronary heart disease (CHD), diabetes mellitus (DM) and essential hypertension (HTN) are higher in people of South Asian descent than in other groups. There is evidence to believe that essential fatty acids (EFAs) and their metabolites may have a role in the pathobiology of CHD, DM and HTN. Fatty acid analysis of the plasma phospholipid fraction revealed that in CHD the levels of gamma-linolenic acid (GLA), arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are low, in patients with HTN linoleic acid (LA) and AA are low, and in patients with non-insulin dependent diabetes mellitus (NIDDM) and diabetic nephropathy the levels of dihomo-gamma-linolenic acid (DGLA), AA, alpha-linolenic acid (ALA) and DHA are low, all compared to normal controls. These results are interesting since DGLA, AA and EPA form precursors to prostaglandin E1, (PGE1), prostacyclin (PGI2), and PGI3, which are potent platelet anti-aggregators and vasodilators and can prevent thrombosis and atherosclerosis. Further, the levels of lipid peroxides were found to be high in patients with CHD, HTN, NIDDM and diabetic nephropathy. These results suggest that increased formation of lipid peroxides and an alteration in the metabolism of EFAs are closely associated with CHD, HTN and NIDDM in Indians.(ABSTRACT TRUNCATED AT 250 WORDS)

Consumption of a garlic clove a day could be beneficial in preventing thrombosis

Abstract: The effect of the consumption of a fresh clove of garlic on platelet thromboxane production was examined. A group of male volunteers in the age range 40-50 years participated in the study. Each volunteer consumed one clove (approximately 3 g) of fresh garlic daily for a period of 16 weeks. Each participant served as his own control. Thromboxane B2 (TXB2, a stable metabolite of thromboxane A2), cholesterol and glucose were determined in serum obtained after blood clotting. After 26 weeks of garlic consumption, there was an approximately 20% reduction of serum cholesterol and about 80% reduction in serum thromboxane. No change in the level of serum glucose was observed. Thus, it appears that small amounts of fresh garlic consumed over a long period of time may be beneficial in the prevention of thrombosis.

Omega-3 fatty acids and endothelial leukocyte adhesion molecules.

Abstract: Although dietary fatty acids can modulate atherogenesis and inflammation, the mechanisms by which this occurs are poorly understood. Induction in endothelial cells of adhesion molecules for circulating leukocytes and of inflammatory mediators by cytokines likely contributes to early phases of atherogenesis and inflammation. We report here that incorporation into cellular lipids of one specific fatty acid of the ω-3 family, docosahexaenoic acid (DHA), decreases cytokine-induced expression of endothelial leukocyte adhesion molecules, secretion of inflammatory mediators, and leukocyte adhesion to endothelial cells. These properties of DHA may contribute to antiatherogenic and antiinflammatory effects of ω-3 fatty acids.

The effect of different n-6/n-3 essential fatty acid ratios on calcium balance and bone in rats

Abstract: Prostaglandins (PGs) are known to have various effects on bone metabolism. The supplementation of essential fatty acids (EFAs), the precursors of PGs, leads to increased intestinal calcium absorption and calcium balance. It is, however, not known whether increased calcium absorption and calcium balance will enhance the calcium content in bone. Male Sprague-Dawley rats (n = 40) aged 5-12 weeks were supplemented with EFAs. The main dietary EFAs, linoleic acid (LA) and alpha-linolenic acid (ALA) were administered in a ratio of 3:1 as a control group. The conversion of LA to ALA to the PG precursors is slow, with the first step, delta-6-desaturation being rate limiting. Fatty acids beyond this rate-limiting step, gamma-linolenic acid (GLA, n-6) and eicoapentaenioc acid (EPA, n-3), were administered to different groups in the ratios 3:1, 1:1 and 1:3 to explore the impact of different ratios of n-6 and n-3 EFAs. Intestinal calcium absorption (mg/24 h) increased by 41.5% in the 3:1 supplemented group, compared with the control group. The decrease in urinary calcium (mg/24 h) correlated with the increase in n-3 level. The calcium balance (mg/24 h) and bone calcium (mg/g bone ash) increased significantly in the 3:1 (41.5% and 24.7%) group, compared with the control. The increase in bone calcium might be attributed to an EFA-induced increase in circulating PGs. An increased synthesis of PGs acting on target bone cells, as well as changes in membrane fluidity, may underlie these observations.

Analysis of anandamide, an endogenous cannabinoid substance, and of other natural N-acylethanolamines

Abstract: Recent reports have suggested that N-arachidonoylethanolamine (anandamide) acts as an endogenous ligand for cannabinoid receptors in mammalian brain Here we describe methods for the extraction, purification and analysis of anandamide and related N-fatty acyl-ethanolamines (NAEs) Liquid-phase extraction, silica gel G column chromatography and thin-layer chromatography (TLC) were employed for sample fractionation Three analytical high-performance liquid chromatography (HPLC) methods for purification of NAEs were developed Finally, analyses of NAEs by gas chromatography/mass spectrometry (GC/MS) are described The applications of these analytical methods to the identification of anandamide and related NAEs in cell cultures as well as of artifacts in biosynthetic studies are described

Mechanism by which garlic (Allium sativum) inhibits cyclooxygenase activity. Effect of raw versus boiled garlic extract on the synthesis of prostanoids.

Abstract: We have studied the effect of aqueous extract of raw garlic and boiled garlic on cyclooxygenase activity in rabbit tissues. Raw garlic inhibited cyclooxygenase activity non-competitively and irreversibly. A dose-dependent inhibition of cyclooxygenase activity was observed in tissues treated with raw garlic. The garlic concentrations required for 50% inhibition of platelets, lung and vascular aortic cyclooxygenase activities of rabbits were 0.35, 1.10 and 0.90 mg, respectively. Cyclooxygenase activity of rabbit platelets was more sensitive to inhibition by raw garlic than the enzyme from blood vessels or lungs. Boiled garlic was found to have little effect on cyclooxygenase activity as compared to raw garlic in these tissues. This may be because the active component of raw garlic is destroyed upon heating. These results indicate that garlic may be beneficial in the prevention of thrombosis if ingested raw rather in a cooked form.

Eicosanoids and asthma: an update.

Abstract: There have been significant advances in our understanding of the role of eicosanoids as mediators in inflammation since their discovery over 50 years ago. Our more recent understanding of asthma as an inflammatory disease has led to the appreciation of eicosanoids potentially being pivotal mediators in promoting some of the changes in asthma. Of particular importance are the cysteinyl LTs in producing bronchospasm and bronchial hyperresponsivenss, and PGE2 in modulating the bronchospastic and inflammatory response. Evidence from clinical studies suggests that other eicosanoids may also contribute, but their importance is secondary and their relative contributions vary between individuals. The development of new drugs based on our partial understanding of the role that eicosanoid mediators may play in asthma promises new approaches to the treatment of this common chronic inflammatory condition.

Coupling the cholesterol- and tumor-suppressive actions of palm oil to the impact of its minor constituents on 3-hydroxy-3-methylglutaryl coenzyme a reductase activity

Abstract: The impact of palm oil on cardiovascular disease and cancer may be explained by the mevalonate-suppressive action of constituent isoprenoid end products of plant secondary metabolism. Assorted monoterpenes, sesquiterpenes, carotenoids and tocotrienols down regulate, post-transcriptionally, 3-hydroxy-3-methylglutaryl coenzyme A reductase activity thereby modestly decreasing cholesterol synthesis and concomitantly decreasing LDL cholesterol. The reductase activity in tumor tissues differs from that of liver in being resistant to sterol feedback regulation. Tumor reductase activity retains sensitivity to the post-transcriptional regulation. As a consequence, the isoprenoid-mediated suppression of mevalonate synthesis depletes tumor tissues of two intermediate products, farnesyl pyrophosphate and geranylgeranyl pyrophosphate, which are incorporated post-translationally into growth control-associated proteins.

Cytotoxic action of cis-unsaturated fatty acids on human cervical carcinoma (HeLa) cells in vitro

Abstract: The effect of n-3 and n-6 fatty acids (FAs) on the growth of human cervical carcinoma (HeLa) cells was studied. Of all the FAs tested, docosahexaenoic acid (DHA, 22:6 n-3) and eicosapentaenoic acid (EPA, 20:5 n-3) were found to be the most potent in their cytotoxic action on HeLa cells and the potency of various fatty acids with regard to their cytotoxic action was as follows: DHA > EPA > dihomo-gamma-linolenic acid (DGLA) = gamma-linolenic acid (GLA) > linoleic acid (LA) > arachidonic acid (AA) > alpha-linolenic acid (ALA). The cycloxygenase inhibitor indomethacin, the lipoxygenase inhibitor nordihydroguaretic acid (NDGA), the antioxidants vitamin E, butylated hydroxyanisole (BHA), and butylated hydroxytoluene (BHT), the superoxide anion quencher superoxide dismutase (SOD), the hydroxyl and hydrogen peroxide quenchers mannitol and catalase, respectively, and the calmodulin antagonists trifluoperazine (TFP) and chlorpromazine (CPZ) could all block the cytotoxic action of GLA, which was used as a representative cytotoxic FA, on HeLa cells. On the other hand, copper and iron salts and buthionine sulfoxamine, a glutathione (GSH) depletor, potentiated the cytotoxic action of suboptimal doses of GLA. GLA-induced radical generation and lipid peroxidation in HeLa cells could be blocked by indomethacin, NDGA and calmodulin antagonists. The cytotoxic action of cis-unsaturated fatty acids (c-UFAs) is not dependent on the alteration in the protein kinase C levels since no alteration in the diacylglycerol levels was observed. Hydroxy and hydroperoxy products of GLA were found to be toxic to HeLa cells, whereas prostaglandin (PG)E1, PGF2 alpha, and prostacyclin stimulated cell growth. From these results, it is evident that radicals are the modulators of the cytotoxic action of c-UFAs, that their formation is a calmodulin-dependent process, and that lipoxygenase products may mediate the tumoricidal action of FAs.

Abnormal membrane concentrations of 20 and 22-carbon essential fatty acids: a common link between risk factors and coronary and peripheral vascular disease?

Abstract: Although elevated levels of cholesterol are associated with increased risks of coronary and peripheral vascular disease, the association frequently fails to provide a causative explanation at the individual level. New hypotheses are required which, whether or not they are correct, will provide new lines of research. It is proposed here that the causes of vascular disease are abnormal membrane phospholipid concentrations of the 20-carbon and 22-carbon essential fatty acids (EFAs) of the n-6 and n-3 series. These levels become abnormal with ageing, with stress and in response to smoking, high cholesterol levels and high saturated fat intakes. They are also abnormal in patients with diabetes and hypertension. The effects of these EFAs and their metabolites include lowering of triglycerides, elevation of high-density lipoprotein (HDL)-cholesterol, reduction of blood pressure, vasodilatation, reduction of fibrinogen levels and inhibition of platelet aggregation and of cardiac arrhythmias. Prospective studies have shown that abnormal levels of these fatty acids are predictive of future coronary death. Controlled trials of treatment have demonstrated that provision of the fatty acids reduces both coronary and total mortality. Further experimental and clinical investigations of the roles of appropriate membrane concentrations of these fatty acids are justified.

Eugenol : an inhibitor of lipoxygenase-dependent lipid peroxidation

Abstract: The effect of eugenol on enzymatic lipid peroxidation catalyzed by soybean lipoxygenase was studied in an in vitro system. Lipid peroxidation was inhibited by eugenol in a concentration-dependent manner. The half-maximal inhibition (IC50) was found to be 380 microM eugenol. Enzyme kinetic studies showed that eugenol non-competitively inhibited lipid peroxidation by altering the maximum velocity (Vmax) and without any change in Michaelis-Menten constant (Km) values. The inhibitory mechanism implies that eugenol does not inactivate the enzyme directly but may interfere with fatty acid radical intermediates due to its hydroxy radical scavenging ability and thus play a role in inhibiting the propagation of lipid peroxidation.

Omega-3 fatty acids and prevention of ventricular fibrillation.

Abstract: Interest in the potential cardiovascular benefits of omega-3 long chain polyunsaturated fatty acids has been largely focused on possible antiatherothrombotic effects. In addition, however, definitive antiarrhythmic effects of these dietary omega-3 fatty acids have been reported by Charnock & McLennan. Our studies commenced with the observation that two of these fatty acids, eicosapentaenoic (C20:5n-3, EPA) and docosahexaenoic acid (C22:6n-3, DHA) prevented contracture and fibrillation of isolated neonatal cardiac myocytes when exposed to toxic levels of ouabain (0.1 mM). This protection was associated with prevention of excessively high intracellular calcium concentrations in the myocyte. Further, it was shown that these fatty acids modulate calcium currents through L-type calcium channels and that the effect occurs within a few minutes of adding EPA or DHA to the medium perfusing the cultured cardiac myocytes. Infusing an emulsion of the omega-3 fatty acids intravenously just prior to compression of a coronary artery in a conscious, prepared dog will prevent the expected subsequent ischemia-induced ventricular fibrillation.

Effects of fatty acids on hepatic gene expression.

Abstract: Polyunsaturated fatty acids (PUFA) have dramatic effects on hepatic lipid metabolism by regulating the transcription of specific genes encoding enzymes involved in glycolysis and lipogenesis. The S14 gene, a putative lipogenic protein, has been used as a model to define the molecular basis of PUFA action on hepatic gene expression. We have shown that PUFA-regulated hepatic transcription factors target cis-regulatory elements located between −220 and −80 bp upstream from the 5′ end of the S14 gene. Peroxisomal proliferators (PP) also have dramatic effects on hepatic lipid metabolism through effects on gene expression. The mechanism of PP action is mediated, at least in part, through nuclear receptors, i.e. PP activated receptor (PPAR). We found that the potent PP, i.e. WY14,643, suppressed mRNA S14 and the activity of an S14CAT fusion gene in cultured primary hepatocytes. Preliminary mapping studies showed that WY14,643 cis-regulatory elements were located either within the S14 proximal promoter (−290 and +19), the S14 TRE (−2900 to −2500) or both regions. Gel shift analysis showed that PPAR did not bind S14 promoter elements. These studies suggest that PUFA- and PP-regulated factors may share common cis-acting elements within the S14 promoter. However, if PUFA control of S14 gene transcription is mediated by PPAR, this mechanism does not involve direct interaction of PPAR with the S14 proximal promoter.

Regulation of pituitary-adrenocortical activity by free fatty acids in vivo and in vitro

Abstract: Virtually every metabolic disorder characterized by elevated plasma free fatty acid (FFA) levels is also associated with hypercorticoidism. For example, the glucocorticoid response to insulin-hypoglycemia is shown in this report to be greatly potentiated in Type I diabetic rats. Since glucocorticoids (corticosterone, in rats) potentiate lipolysis and promote gluconeogenesis, they exacerbate diabetes. We found that elevation of circulating FFA levels in normal rats (via Intralipid/heparin infusion) increased plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone, and resulted in hyperglycemia. In vitro, however, cultured pituitary cells were relatively unaffected by FFA except at very high concentrations. Neither basal ACTH secretion nor the ACTH response to corticotropin-releasing hormone (CRH) was affected by pathophysiological molar ratios of FFA:BSA. Thus, the ACTH secretory response to FFA in vivo likely is mediated via neuroendocrine activation. Cultured adrenocortical cells, however, were stimulated by oleic acid and, to a lesser extent, by linoleic acid; saturated fatty acids were without effect. The latencies of oleic acid-induced steroidogenesis in vitro and Intralipid-induced corticosterone secretion in vivo were both about 60 min. We conclude that pathophysiological levels of circulating FFA (typical of diabetes, obesity, starvation, and consumption of high-fat diets) initiate a positive feedback loop between the adipocyte and the HPA axis, which ultimately exacerbates the symptoms of these disorders.

Protein kinase C: cellular target of the second messenger arachidonic acid?

Abstract: Protein kinase C (PKC) is a family of serine/threonine protein kinases which play a critical role in signal transduction, tumor promotion and cell regulation. Initially characterized as a calcium-and phospholipid-dependent protein kinase, early studies demonstrated that PKC was activated potently by diacylglycerol (DAG), a product of phosphatidylinositol turnover, establishing a role for PKC in signal transduction. More recently, PKC has been shown to be activated by free fatty acids, both in vitro and in vivo. Since arachidonic acid and other free fatty acids have been characterized as second messengers, this connection has strengthened the role of PKC in signal transduction. The activation of PKC by the classical activators of PKC, phosphatidylserine (PS), DAG and calcium has been reviewed recently (1-3). This review will focus on the activation of PKC by free fatty acids in vitro and in vivo. We will begin by presenting an overview of PKC to (1) review classical activation of PKC (by PS/DAG) to use as a point of reference and comparison to fatty acid-induced activation and (2) elaborate on the methodology currently used to study PKC including the advantages and disadvantages of these approaches. We will then review the activation of PKC by free fatty acids both in vitro and in vivo. Finally, we will end by presenting a model for free fatty acid activation of PKC.

Effects of piroxicam and esculetin on the MDA-MB-231 human breast cancer cell line.

Abstract: We investigated the effects of piroxicam, esculetin, prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) on a human breast cancer cell line (MDA-MB-231). Both piroxicam and esculetin suppressed cell growth and thymidine incorporation, though esculetin was more active in inhibiting cell growth in the presence of linoleic acid (LA). Esculetin reduced the secretion of LTB independent of LA. Piroxicam reduced the secretion of PGE in the absence of LA but only at higher concentrations in the presence of LA. When the relationship between cell growth and PGE and LTB concentration was evaluated by multivariate regression analysis, cell growth was associated with the PGE and LTB concentration when the cells were treated with esculetin alone or with esculetin and LA. Cell growth was associated only with the PGE concentration when they were treated with piroxicam alone or with piroxicam and LA. Therefore, it appears that the growth of MDA-MB-231 cells in vitro is affected by both lipoxygenase and cyclooxygenase products, though lipoxygenase inhibition is more active than cyclooxygenase inhibition on suppression of cell growth in the presence of LA.

Diets rich in eicosapentaenoic acid and γ-linolenic acid affect phospholipid fatty acid composition and production of prostaglandins E1, E2 and E3 in turbot (Scophthalmus maximus), a species deficient in Δ5 fatty acid desaturase

Abstract: Duplicate groups of juvenile turbot, ( Scophthalmus maximus ), were fed diets containing either Marinol K (MO), a marine fish oil rich in eicosapentaenoic acid (EPA; 20:5, n-3) or borage oil (BO), rich in γ-linolenic acid (GLA; 18:3, n-6), for a period of 12 weeks. Individual phospholipid fatty acid compositions from hearts of fish fed BO had significantly more 18:2, n-6, GLA, 20:2, n-6, dihomo-γ-linolenic acid (DHGLA; 20:3, n-6) and total n-6 polyunsaturated fatty acids (PUFA), but significantly less arachidonic acid (AA; 20:4, n-6), compared to fish fed MO. In both phosphatidylcholine (PC) and phosphatidylethanolamine (PE) from heart, the DHGLA was increased by over 50-fold in fish fed BO while AA was reduced by over two-thirds, compared to fish fed MO. In brain, EPA was the major C 20 PUFA, i.e. potential eicosanoid precursor in all phospholipids from fish fed MO, with the EPA level being twice that of AA in brain phosphatidylinositol (PI). DHGLA was the major C 20 PUFA in all phospholipid classes from fish fed BO. In kidney and gill, EPA was the predominant C 20 PUFA in all phospholipid classes, except PI, in fish fed MO. In kidney of fish fed BO, DHGLA was the major C 20 PUFA in all phospholipid classes, except PE. In gill of fish fed BO, DHGLA was the major C 20 PUFA in all phospholipid classes, including PI, where DHGLA was over 2.5-fold greater than AA. In homogenates of heart, kidney and gill from BO-fed fish the prostaglandin E 1 (PGE 1 ) concentration was significantly increased compared to MO-fed fish. In heart and kidney homogenates from fish fed MO the PGE 3 concentration was significantly increased compared to fish fed BO. The ratio of PGE2PGE1 was significantly reduced in brain, heart, kidney and gill homogenates from fish fed BO compared to those fed MO.

Fatty acids: Ancestral ligands and modern co-regulators of the steroid hormone receptor cell signalling pathway

Abstract: Long chain fatty acids derived from endogenous metabolism and/or nutrition are regulators of cell signalling pathways. They can be lipid second messengers of signal transduction systems or modulators and regulators of intracellular signalling pathways such as those involved in the mechanism of action of steroid hormones. Fatty acids have been shown to activate gene transcription under the control of some evolutionarily primitive members of the steroid/thyroid superfamily of receptors. They may represent ancestral ligands of this superfamily of receptors. Fatty acids are also known to regulate the activity of protein kinases, particularly protein kinase C, and thereby phosphorylation of intracellular proteins involved in regulation of gene transcription. Fatty acids may be co-regulators in the cross-talk between membrane-triggered signal transduction and the intracellular steroid hormone signalling pathway. Fatty acids are known to affect either negatively and/or positively the binding of steroid hormones to their specific plasma transport proteins and their specific intracellular receptors and, very recently, fatty acids have also been shown to co-regulate glucocorticoid-dependent gene expression. The mechanism of action of steroid hormones will be used as an illustration of how fatty acids can intervene at different levels of cellular organization to regulate biological activity, with a focus on the glucocorticoid receptor.

Fatty acid ethyl esters: Non-oxidative metabolites of ethanol

Abstract: Fatty acid ethyl esters are esterification products of fatty acids and ethanol. These compounds have been detected in the serum and cells of individuals following ethanol ingestion. Fatty acid ethyl esters can be quantitated by gas chromatography-mass spectroscopy (GC-MS) in the serum following ethanol ingestion and have been found in concentrations up to 42 microM. Fatty acid ethyl esters have also been isolated from adipose tissue of subjects ingesting fatty acid ethyl ester capsules as well as from subjects ingesting ethanol. HepG2 cells, a human hepatoblastoma cell line, have also been shown to generate fatty acid ethyl esters when incubated with 1.25 microM fatty acid and 0.17 M ethanol. Fatty acid ethyl esters were found to be toxic to HepG2 cells when presented to the cells in the core of low density lipoprotein particles.

Direct effects of fatty acids and other charged lipids on ion channel activity in smooth muscle cells

Abstract: A variety of fatty acids increase the activity of certain types of K+ channels This effect is not dependent on the three enzymatic pathways that convert arachidonic acid to various bioactive oxygenated metabolites One type of K+ channel in toad stomach smooth muscle cell membranes in activated by fatty acids and other single chain lipids which possess both a negatively charged head group and a sufficiently hydrophobic acyl chain Neutral lipids have no effect on K+ channel activity, while positively charged lipids with a sufficiently hydrophobic acyl chain suppress channel activity Acyl Coenzyme A's, which do not flip across the bilayer, act only from the cytosolic surface of the membrane, suggesting that the binding site for channel activation is also located there This fatty acid-activated channel is also activated by membrane stretch Moreover, this mechanical response is either mediated or modulated by fatty acids Thus, fatty acids and other charged single chain lipids may comprise another class of first or second messenger molecules that target ion channels

Fatty acyl CoA esters as regulators of cell metabolism.

Abstract: Long chain fatty acyl CoA esters have the ability to interact with certain proteins and thereby serve as effectors in cell metabolism. In particular, they can displace nucleotides from specific nucleotide dependent or binding proteins and interfere with their action. The ADP/ATP carrier and uncoupling protein are two examples where the interplay of nucleotide and acyl CoA binding to the proteins regulate their function. Other proteins such as glucokinase can be considered in this group. In certain tissues like liver they are affected during fasting and insulin deficiency, and when serum fatty acids and liver acyl CoA levels are elevated. More recently, an acyl CoA binding protein in E. coli has been found to be a transcription factor for gene regulation of fatty acid metabolism enzymes. There appears to be some consensus in the amino acid sequence for acyl CoA binding sites on these proteins which serve a variety of important roles in cellular metabolism.

Essential fatty acids are antagonists of the leukotriene B4 receptor.

Abstract: A series of essential fatty acids and fatty acid derivatives were evaluated for their ability to inhibit [3H] leukotriene B4 (LTB4) binding to pig neutrophil membranes. The fatty acids varied in chain length, extent of unsaturation, position of unsaturation, and isomerization. Generally, fatty acids with two or more unsaturated sites and chain lengths of 18-22 were potent inhibitors of [3H]LTB4 binding; both n-3 and n-6 fatty acids were inhibitory. The most potent compounds tested were homogammalinolenic acid and ricinelaidic acid which gave Ki values of 1 microM and 2 microM in the binding assay. Ricinelaidic acid was also tested for its ability to inhibit LTB4-mediated chemotaxis (IC50 = 10 microM) and LTB4-induced calcium fluxes (IC50 = 7 microM) in isolated human neutrophils. Ricinelaidic acid did not show agonist activity in these assays. In an in vivo model of LTB4-induced bronchoconstriction, ricinelaidic acid and homogammalinolenic acid gave 46% and 53% inhibition, respectively, at a 1 mg/kg i.v. dose. These results indicate that essential fatty acids are LTB4 receptor antagonists, which may account in part for their reported anti-inflammatory activities.

Eicosanoids, fatty acids and neutrophils: Their relevance to the pathophysiology of disease

Abstract: PUFA and their eicosanoid metabolites are potent biological modifiers. They have beneficial effects in a number of diseases, which may result in part from their direct actions on neutrophils as well as from their ability to modulate eicosanoid biosynthesis. A consideration of their interactions with other cell types, e.g. lymphocytes and macrophages, is beyond the scope of this review. Small alterations in structure can result in large changes in the neutrophil response. This will have important implications for the further development and use of fatty acids for therapeutic purposes.

Platelet activation and platelet lipid composition in pulmonary cancer

Abstract: In order to investigate the possible mechanisms underlying platelet functional changes in patients affected by neoplasms, platelet lipid composition, plasma beta-thromboglobulin (Beta-TG) and serum thromboxane B2 (TXB2) were investigated in 16 male patients affected by pulmonary carcinoma and in 16 comparable control subjects. In patients high levels of plasma Beta-TG (67 +/- 9 versus controls 14 +/- 4 ng/ml, p < 0.001) and serum TXB2 (434 +/- 56 versus 223 +/- 48 ng/ml, p < 0.001) were observed. Also platelet lipid composition was found altered in patients with respect to controls (lower percent levels in n-3 fatty acids and in linoleic acid esterified in the main platelet phospholipid fractions: at least p < 0.05). These results indicate that in vivo platelet activation is detectable in neoplastic patients and it is associated with alterations in platelet lipid composition. In the light of the important role played by membrane lipids in platelet functions related to thrombosis and haemostasis we conclude that platelet lipid changes could cooperate in platelet activation and increased thrombotic risk so frequently observed in neoplastic disease.