Phospholipid Arachidonic Acid Research Articles

Pathogenesis of Idiopathic Calcium Nephrolithiasis: Update 1997

Idiopathic calcium nephrolithiasis (ICN) is a frequent disease in Western countries. The physicochemical theory of lithogenesis, which explains stone formation by the precipitation, growth, and crystalline aggregation of lithogenic salts in the urine, has contributed greatly to the understanding of the pathogenesis of calcium urolithiasis. However, several aspects are still unexplained; the co-existence of familial occurrence, primary tubular dysfunctions with ICN, and anomalies in the systemic handling of oxalate and calcium led to the development of a cellular hypothesis of ICN. A number of cellular defects in the handling of ions has been reported that involves both anion and cation transport. These anomalies are probably the expression of a still unknown cellular defect in idiopathic calcium stone formers. We suggested that an anomaly in the cell membrane composition might be responsible for the complex array of cell ion flux abnormalities observed in ICN. Recently, a disorder in the n-6 polyunsaturated fatty acid series has been described; it is characterized by a lower linoleic acid content and a higher arachidonic acid concentration in both plasma and erythrocyte membrane phospholipids of renal calcium stone patients. This anomaly could cause an increased activity of ion carriers; furthermore, it may lead to increased prostaglandin synthesis and to secondary phenomena at the kidney, skeletal, and intestinal level. As a consequence, critical conditions for lithogenesis in the kidney may ensue. The data suggest a common pathogenesis for hypercalciuria and hyperoxaluria. The systemic defect in the phospholipid arachidonic acid level may be both of dietary or genetic origin; experimental data suggest that the increase in delta-6 desaturase activity, the limiting enzyme in the metabolic pathway of polyunsaturated fatty acids, might be relevant to the pathogenesis of lipid abnormalities observed in nephrolithiasis and to the pathogenesis of ICN and its related problems (at the kidney, intestinal, and bone level).In conclusion, the review describes a unifying pathogenetic hypothesis of nephrolith-iasis that accounts for the many cell abnormalities observed in this disease, as well as the different clinical-biochemical features observed in renal stone patients and explains the multisystemic manifestations described in ICN.

Low levels of arachidonic acid in phospholipids of rbc membranes in schizophrenia reflected in functional test of cyclo-oxygenase pathway: Ward PE, Sutherland J, Glen EMT, Glen AIM, Highland Psychiatric Research Group, Inverness IV3 6JU

Low levels of arachidonic acid in phospholipids of rbc membranes in schizophrenia reflected in functional test of cyclo-oxygenase pathway: Ward PE, Sutherland J, Glen EMT, Glen AIM, Highland Psychiatric Research Group, Inverness IV3 6JU

Relation of Smoking and Alcohol Consumption to Serum Fatty Acids

To examine the relation of cigarette smoking and alcohol consumption to serum fatty acid levels, the authors conducted a cross-sectional study of 190 men who were enrolled in the Multiple Risk Factor Intervention Trial between 1973 and 1976. After controlling for dietary fat, cholesterol, energy intake, and other potential confounders, the authors found that smoking and alcohol intake were associated with the serum cholesterol ester and phospholipid levels of several fatty acids. As the number of cigarettes smoked per day increased, the levels of cholesterol ester and phospholipid palmitoleic acid (16:1) and oleic acid (18:1) and the levels of phospholipid dihomogammalinolenic acid (20:3) and omega-9 eicosatrienoic acid (20:3) increased (all p's < or = 0.01). Serum levels of phospholipid omega-3 docosahexaenoic acid (22:6) and cholesterol ester and phospholipid arachidonic acid (20:4) were inversely associated with smoking (all p's < or = 0.01). As the number of alcoholic drinks per week increased, levels of cholesterol ester and phospholipid palmitic acid (16:0) and oleic acid (18:1), cholesterol ester myristic acid (14:0), and phospholipid palmitoleic acid (16:1), adrenic acid (22:4), and omega-9 eicosatrienoic acid (20:3) increased (all p's < 0.05), whereas levels of cholesterol ester and phospholipid linoleic acid (18:2) and phospholipid stearic acid (18:0) and the serum polyunsaturated fat: saturated fat ratio decreased (all p's < or = 0.01). These results suggest that smoking and alcohol consumption may influence the absorption, synthesis, or metabolism of serum fatty acids. Studies that use serum fatty acid levels as indicators of dietary fat intake should control for the effects of cigarette smoking and alcohol consumption.

Docosahexaenoic and arachidonic acid content of serum and red blood cell membrane phospholipids of preterm infants fed breast milk, standard formula or formula supplemented with n-3 and n-6 long-chain polyunsaturated fatty acids.

The contents of docosahexaenoic (DHA) and arachidonic acid (AA) of plasma and red blood cell membrane phospholipids were studied in 41 very low birth weight infants fed either breast milk (n = 18), a standard formula without long-chain polyunsaturated fatty acids with 20 or 22 carbon atoms (LCP) but with alpha-linolenic acid and linoleic acid (n = 11) or a formula additionally supplemented with n-3 and n-6 LCP in relations typical for human milk (n = 12) after 2, 6, and 10 weeks of feeding. The content of DHA and AA in plasma phospholipids declined in the infants fed the LCP-free formula but remained more or less constant during the whole feeding period in those infants fed breast milk as well as in those fed the LCP-supplemented formula. The differences between the group fed the LCP-free standard formula and the two groups fed LCP-containing diets became significant during the first 2 weeks of feeding. In contrast, there were no differences between the group fed breast milk and the group fed the supplemented formula during the study period. Similar effects could be observed regarding the composition of red blood cell membrane phospholipids, but the differences between the infants fed the LCP-free standard formula and the two other groups with LCP-containing diets were significant only for AA. The data indicate that very low birth weight infants are unable to synthesize LCP from alpha-linolenic acid and linoleic acid in sufficient amounts to prevent a decline of LCP in plasma and red blood cell phospholipids. Additionally, the data show, that supplementation of formulas with n-3 and n-6 LCP in amounts typical for human milk fat results in similar fatty acid profiles of plasma and red blood cell membrane phospholipids as found during breast milk feeding. Supplementation of formula with long-chain polyunsaturated fatty acids improves the LCP status of very low birth weight infants.

68. - Temporal lobe structure angulation in first-episode schizophrenia

s 1l10L IlSYCHrATRY 1996;39:S00-M 2Velerans Affairs Medical Cenler. Augusta. GA; ~Dwight David Eisenhower Anny Medical Center. Fort Gordon, GA A specific functional consequencc of lhe lower levels of plasma membrane phospholipids and their esterified polyunsaturated essential fatly acids (EPUFAs) rc-P'Orted in red blood cells, brain and in cultured skin fibroblasts from schizophrenic patients is unclear. It is well establishetlthat the melllbolie products (e.g.. diacylglycerol. arachidonic tlcid. and inositol phosphatcs) of phospholipids generated following membrnne receptor-mediated processes contribute to cell signal transduction, which is suggested to be altered in schizophrenia. Since cullurcd skin fibroblasts from schizophrenic patienls contain lower levels of membrane phospholipids and lheir esterificd EPUFAs. and Iheyexpress receptors to several neurotrnnsmiltc:rs, we studied the release of phospholipid-arachidonic acid induced by muscarinic agonist Fibroblasts from 5 patients at the lirst·cpisode of psychosis and 5 matched nOl1l1nl controls were grown in log phasc. and phospholipids were prclnbcled wilh 1_14C-AA by continuing growth for 24 hrs. Labeled cells wcn~ washed with medium containing futty acid free albumin, suspended in phosphate buffered saline containing fatl)' odd free lIlburnln and with or without 5 uM carbacol for 5 minules. Mcdium was collecled. centrifuged llnd radioactivlly was detennined. There was n signifietlnlly lowcr level of AA rclctlscd from fibroblnsts of patients LIS compared with thnt released from normal controls (92,8 ::t 25.0 vs IS 1.2 :!: 13.8 pmoles AA reletlsedlhr/mg cell protein. rcspcctively; P = right (9.B3::5.60) a.c;ymmctry WllS also nOled in lateral ventricles of schizophrenics [group x side; F(2,26)=:::!.9&6. p=O.0680) (left. 9.50±3.3l: right, 9.62±4.73 in affcctivc disorder: left, 8.19±5.07; righi, 8.61 ±4.60 in controls). Both left (0.572::!:0.232) and right (0.669::!:0,255) temporal horns in schizophrenia were larger than lho.~e in affective disorder (left, 0.334::0.148: right. 0.392±0.IS6) ami controls (Icfl. O.38S±O.l57; right, O.360±O, 197) [F(2.26)=6, II B. p'0.OO66]. No asymmctry was observed in thc temporal horns among three groups, These findings suggest thai some structural abnormalitics in schizophrenia nrc prescnt at curly stages or the illness. 70. BASELINE AND FOLLOW~UP MESIOTEMPORAL VOLUMES IN FIRST EPISODE SCHIZOPHRENICS R.D. Straus, J, Schenkler, M. Ashtari, R.M. Bilder,

Rapid modulation of lung and liver macrophage phospholipid fatty acids in endotoxemic rats by continuous enteral feeding with n-3 and gamma-linolenic fatty acids

Dienoic eicosanoids derived from phospholipid arachidonic acid (AA) in lung and liver macrophages promote leukosequestration, thrombosis, and tissue injury. Current enteral diets (diet A) are enriched with linoleic acid (LA), a precursor of AA. Novel diets low in LA and containing eicosapentaenoic acid (EPA) and gamma-linolenic acid (GLA) foster formation of less inflammatory eicosanoids. The study objective was to assess the rapidity and extent of LA and AA displacement in vivo from alveolar macrophage (AM phi), lung, and liver Kupffer and endothelial (KE) cell phospholipids in rats fed enterally with diets enriched with 5.3% (by wt) EPA and either 1.2% or 4.6% GLA (diets B and C, respectively). After surgical placement of catheters, the rats were fed enterally and co-infused intravenously with either endotoxin or vehicle continuously for 3 or 6 d. Rats given either diet B or C had significantly lower (P < 0.01) relative percentages of AA and LA within the AM phi, lung, and KE cell phospholipids, and concomitantly higher percentages of EPA compared with rats infused with diet A after 3 d of enteral feeding irrespective of endotoxin co-infusion. Incorporation of dihomo-gamma-linolenic acid (DHGLA), the metabolite of GLA, into lung and KE phospholipids was significant in rats given diet C. Most of the changes in fatty acid composition occurred by day 3. The polyunsaturated fatty acid composition of AM phi, lung, and KE cell phospholipids can be rapidly modified by continuous short-term enteral feeding with EPA- and GLA-enriched diets irrespective of concurrent endotoxemia.

Dietary modulation of phospholipid fatty acid composition and lipoxygenase products in mouse lung homogenates

This study investigated the potential of dietary fats to modulate the arachidonic acid content of mouse lung phospholipids and the formation of lipoxygenase products from arachidonic and eicosapentaenoic acids. Prior to breeding, female mice were fed for five months diets with 10 wt% of either olive oil, safflower oil, fish oil, or linseed oil. The same diets were fed to the females during gestation and to the pups from day 18 to day 42 postpartum. On day 42, the phospholipids were extracted from fresh lung tissue and separated into classes [phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylcholine (PC), and phosphatidylinositol (PI)] by thin-layer chromatography. Methyl esters of phospholipid fatty acids and unesterified fatty acids were analyzed by gas chromatography. At comparable dietary n-3/n-6 ratios, arachidonic acid was reduced 85 and 75% in lungs from mice fed linseed oil and fish oil, respectively, compared to lungs of safflower oil-fed mice. Dietary fats affected the proportion of arachidonic acid in phospholipids in the order: PE > PC > PS > PI. Following incubation of homogenized lung tissue, the total amount of 12-lipoxygenase products was lowest in lungs from mice fed olive oil, and 12-hydroxyeicosatetraenoic acid was lowest in incubated lungs from mice fed linseed oil. Comparison of the amounts of lipoxygenase substrate fatty acids in the individual phospholipids with the lipoxygenase products suggested that the major substrate pool for the 12-lipoxygenase pathway in mouse lung homogenates was PC.

Acetylated low density lipoprotein inhibits the incorporation of arachidonic acid in phospholipids with a concomitant increase of cholesterol arachidonate in rat peritoneal macrophages

The aim of our work was to evaluate the influence of native low density lipoproteins (LDL) and LDL chemically modified by acetylation (acLDL) on incorporation and release of arachidonic acid (AA) in rat peritoneal macrophages. Compared to a control group without treatment, 100 μg/ml of acLDL for 15 h considerably increased the incorporation of [ 3H]AA in cholesterol-ester (CE) of rat peritoneal macrophages and induced a decrease of 3H-labeled membrane phospholipids (PL). No effect was shown with LDL treatment. In the presence of acLDL, LS3251 (100 nM), an acyl-coenzyme A:cholesterol acyltransferase (ACAT) inhibitor, inhibited the [ 3H]AA incorporation into CE in macrophages. [ 3H]AA-prelabeled macrophages cultured for 15 h with acLDL (compared to macrophages untreated or treated with LDL) showed an increase of labeled CE and a decrease of labeled PL and of cyclooxygenase and lipoxygenase eicosanoid production. After zymosan stimulation of macrophages prelabeled with [ 3H]AA and treated with or without LDL or acLDL, AA release and eicosanoid production increased in all groups of macrophages. The inhibition of eicosanoid production in foam cells does not seem to be linked to an inhibition of phospholipase but rather paralleled to an increase of the cholesterol [ 3H]arachidonate. A significant portion of cellular arachidonate released from phospholipids, in particular from phosphatidylcholine, could serve as a substrate to ACAT in this foam cell.

Inhibition of the human platelet cyclooxygenase response by the naturally occurring phenazine derivative, 1-hydroxyphenazine

The phenazine derivative, 1-hydroxyphenazine (OHP), is produced in vivo by Pseudomonas aeruginosa, an organism that colonises the airways of patients with cystic fibrosis. While known to inhibit leukotriene production by human neutrophils, the effects of OHP on cyclooxygenase pathways have not previously been reported. We used [ 3H]arachidonic acid (AA) under conditions of concurrent labelling-stimulation or pre-labelling for one hour followed by stimulation to determine the effects of OHP on the production of cyclooxygenase metabolites by human platelets stimulated with the calcium ionophore, A23187. Thromboxane B 2 (TxB 2) and 12-hydroxyheptadecatrienoic acid (HHT) production was inhibited in a dose-dependent manner by OHP using either pre-labelled or concurrently labelled platelets. However, production of 12-hydroxyeicosatetraenoic acid (12-HETE) was not diminished. Determination of the amount of total free label (AA + non-esterified AA metabolites) after stimulation of pre-labelled platelets indicated a dose-dependent inhibition of the release of AA from phospholipid by OHP. This was reflected in a corresponding increase in phospholipid AA content. These data indicate that phenazine derivatives of bacterial origin exhibit complex interactions with pathways of arachidonic acid metabolism in host cells. These effects may prove to be of pharmacological importance.

Effects of a Low Birthweight Infant Formula Containing Human Milk Levels of Docosahexaenoic and Arachidonic Acids

Summary:Long‐chain (LC) polyunsaturated fatty acids (PUFA) (LCP) are considered conditionally essential nutrients for low birth weight infants (LBWI). Therefore, enrichment of LBWI formulae with metabolites both linoleic (ω‐6) and α‐linolenic (ω‐3) acids at levels typical for human milk has been recommended. However, previous feeding trials with LCP‐enriched formulae evaluated only a dietary supplementation with ω‐3 LCP from fish oils alone or with both ω‐3 and ω‐6 LCP at levels considerably lower than usual human milk contents. We studied the effects of an LBWI formula providing the major ω‐3 and ω‐6 LCP, docosahexaenoic and arachidonic acids, in amounts similar to those in average human milk. Twenty‐seven LBWIs were enrolled in this study when they tolerated full enteral feeding (≥ 130 ml milk/kg/day). Infants either received their own mother's milk (n = 8, birth‐weight 1218 ± 146 g, gestational age 30.2 ± 1.5 weeks, mean ± SD) fortified with protein and minerals (FM‐85, Nestle Ag, Munchen, Germany; dosage 5 g/100 ml milk) or were randomly assigned to blinded batches of an LBWI formula (Prematil, Milupa AG, Friedrichsdorf, Germany) without LCP (n = 10, 1280 ± 229 g, 31.1 ± 3.1 weeks) or with LCP (n = 9, 1253 ± 334 g, 30.4 ± 3.3 wks.). During the study period of 21 days, the three feeding groups did not differ in growth and feeding tolerances as assessed by occurrence of gastric residuals, spitting, or abdominal distention; however, firms stools were noted more frequently in the two formula groups. Compared to infants fed human milk, those on formula without LCP showed significant depletion of plasma phospholipid arachidonic acid (reduced to 74% of levels found in infants fed human milk) and, even more marked, of docosahexaenoic acid (reduced to 64%) as well as total LCP (74%), within 3 weeks of full enteral feeding. In contrast, infants receiving the LCP‐enriched formula achieved an LCP status equal to that of human milk‐fed babies. Results indicate that LBWI absorb formula LCPs and incorporate them into endogenous phospholipids. There were no adverse effects of LCP enrichment on vitamin‐E status. We conclude that the LCP enrichment of the formula used in this study was well tolerated, did not interfere with short‐term growth or vitamin‐E status, and provided sufficient amounts of essential fatty acids to match the ω‐3 and ω‐6 LCP status of infants fed human milk.

INCREASED PHOSPHOLIPID MASS WITH DECREASED ARACHIDONOYL MOLECULAR SPECIES IS ASSOCIATED WITH DECREASED EICOSANOID SYNTHESIS AND INCREASED TUMOR NECROSIS FACTOR SYNTHESIS BY THIOGLYCOLLATE-ELICITED RAT PERITONEAL MACROPHAGES

Because the activation state of macrophages may alter their response to endotoxin, we compared phospholipid arachidonic acid content, and synthesis of eicosanoids and tumor necrosis factor by resident and thioglycollate-elicited rat peritoneal macrophages. Thioglycollate elicitation increased macrophage phospholipid mass twofold, increased the relative percentages of 16:0-20:4 diacylglycerophosphocholine (PtdCho) and 18:0-20:4 diacylglycerophosphoethanolamine (PtdEtn), and decreased the relative percentages of 18:0-20:4 alkenylacylglycerophosphoethanolamine (PlsEtn) and 18:0-20:4 alkylacylglycerophosphocholine (PakCho) compared with resident peritoneal macrophages. Thioglycollate-elicited macrophages synthesized significantly less thromboxane B2, 6-keto-prostaglandin F1 alpha, and prostaglandin E2 and more tumor necrosis factor (TNF) activity in response to both endotoxin and A23187 than did resident macrophages. These results suggest that thioglycollate elicitation decreases specific arachidonic acid-containing molecular species in PlsEtn and PakCho, which may, in part, explain the decrease in eicosanoid and increase in TNF synthesis by thioglycollate-elicited macrophages. The differences between resident and thioglycollate-elicited macrophages in the synthesis of the eicosanoids and TNF activity was not altered by increasing either the concentration of either stimulus or the incubation time.

Eicosanoid synthesis in cardiomyocytes: influence of hypoxia, reoxygenation, and polyunsaturated fatty acids

The synthesis of eicosanoids was investigated in cultured rat ventricular myocytes. Under normoxia, the cardiomyocytes released 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) and prostaglandin (PG) E2 and smaller amounts of PGF2 alpha and thromboxane B2. Hypoxia enhanced the production of PGE2 and PGF2 alpha, whereas the synthesis of 6-keto-PGF1 alpha was not affected. Conversely, posthypoxic reoxygenation greatly increased the synthesis of 6-keto-PGF1 alpha, whereas the synthesis of PGF2 alpha, was not affected and that of PGE2 was reduced. The cardiomyocyte polyunsaturated fatty acid (PUFA) profile was altered by arachidonic acid or eicosapentaenoic acid and docosahexaenoic acid. Under normoxia, the eicosanoid production appeared to be roughly related to the cell phospholipid arachidonic acid content. Conversely, during posthypoxic reoxygenation, the production of eicosanoids was related to the cell phospholipid n-3 PUFA content, with the n-3-rich cells displaying a marked inhibition of the synthesis. This inhibition was mainly attributed to eicosapentaenoic acid and/or docosapentaenoic acid. Whether this inhibition occurs in vivo during postischemic reperfusion, it may contribute to the beneficial effect of n-3 PUFA on the heart.

Prostaglandin H synthase and lipoxygenase gene families in the epithelial cell barrier.

Epithelial barrier cells (in skin, gut, and airway) are both active modulators and important targets of the inflammatory response, and some of these cellular events may be regulated at a molecular level by products of phospholipid-arachidonic acid metabolism. Accordingly, we have defined some of the characteristics of gene expression and enzyme regulation for distinct members of the PGH synthase and lipoxygenase gene families in normal and inflamed epithelial tissues and in epithelial cells isolated from mucosal and epidermal tissue (Table 1). A unifying scheme for our findings includes the following enzymatic systems: (i) a PGH synthase-1/PG isomerase pathway responsible for constitutive generation of prostaglandins (e.g., PGE2) and maintenance of physiologic epithelial function; (ii) a PGH synthase-2/PG isomerase and synthase pathway capable of producing additional prostaglandins (e.g., excess PGE2 and/or PGF2 alpha and PGD2) especially after stimulation by growth factors and cytokines; and (iii) a family of arachidonate 12- and 15-lipoxygenases that may serve to generate hydroxy acids (e.g., 12- and 15-HETE) as mediators of basal epithelial function and that (after overexpression and oxidant activation) may also catalyze membrane peroxidation that contributes to epithelial damage during inflammation. The regulatory mechanisms inherent in the control of this scheme provide a biochemical rationale for balancing constitutive and inducible oxygenation activities and maintaining epithelial barrier function.

Lovastatin increases arachidonic acid levels and stimulates thromboxane synthesis in human liver and monocytic cell lines.

The effect of lovastatin (LOV), the inhibitor of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase, on linoleic acid (LA, 18:2n-6) metabolism was examined in human monocytic Mono Mac 6 (MM6) and hepatoma Hep G2 cells. The desaturation of LA was examined after LOV (72 h, 10 microM) or dimethylsulfoxide (LOV carrier, < 0.1%) and [14C]LA (last 18 h, 0.3 microCi, 5 microM). In both cell lines, LOV reduced the percentage of 14C label associated with LA and increased the percentage of label in the 20:4n-6 and the 22:5n-6 fractions. In Hep G2 but not MM6 cells, this effect was fully reversible by means of coincubation with mevalonic acid (500 microM), but not with cholesterol or lipoproteins. In both cell lines, the LOV-mediated increase in LA desaturation resulted in dose-dependent reductions of LA and elevations of AA in cellular phospholipids. The lipids secreted by LOV-treated Hep G2 cells were also enriched in arachidonic acid (AA). In the MM6 cells, LOV increased release of thromboxane upon stimulation with the calcium ionophore A23187. In summary, our findings of higher LA desaturation and AA enrichment of lipids secreted by the Hep G2 cells suggest that LOV treatment may increase the delivery of AA from the liver to extrahepatic tissues. The changes in membrane fatty acid composition can influence a variety of cellular functions, such as eicosanoid synthesis in monocytic cells. The mechanism appears to be related to the reduced availability of intermediates of cholesterogenesis.

Plasma total phospholipid arachidonic acid and eicosapentaenoic acid in normal and hypertensive pregnancy.

Plasma total phospholipid arachidonic acid and eicosapentaenoic acid in normal and hypertensive pregnancy.

Hydrolysis of phosphatidylethanolamine by human pancreatic phospholipase A2. Effect of bile salts.

The 2-ester bond of 14C-2-arachidonyl phosphatidylethanolamine (PE) was hydrolyzed faster than that of 3H-2-arachidonyl phosphatidylcholine (PC) by human pancreatic phospholipase A2 (PLA2) with mixed PE-PC (1:9 w/w) liposomes of pure sonicated PE or PC as substrate. The PC portion of the mixed PE-PC liposomes was more readily attacked by PLA2 than the PC of pure PC liposomes. At different bile salt concentrations (sodium taurocholate (NaTC), 0-3 mM, and sodium taurodeoxycholate (NaTDC), 0-4 mM) the rates of hydrolysis varied with similar patterns for both phospholipids of the mixed liposomes. The rate of hydrolysis was optimal at a bile salt concentration of 0.75-1.5 mM NaTC and 1.0-2.0 mM NaTDC and decreased at higher concentrations. The pure PE substrate was efficiently hydrolyzed also without bile salts. This may have implications for the absorption of polyunsaturated phospholipid fatty acids in patients with bile salt deficiency. Separation of phospholipid classes from human bile by high-performance liquid chromatography and analysis of fatty acid composition indicated that PE contained 5.3% of the phospholipid arachidonic acid and 9.8% of the docosahexaenoic acid mass, but only 1.7% of the total phospholipid mass. Bile and dietary PE should not be overlooked as sources of arachidonic and docosahexaenoic acid for the small intestine.

Abnormal polyunsaturated lipid metabolism in the obese Zucker rat, with partial metabolic correction by γ-linolenic acid administration

Below-normal proportions of phospholipid (PL) arachidonic acid (20:4ω6) have been reported in serum from obese humans and in liver from obese Zucker rats. This implies an abnormality of 20:4ω6 formation from linoleic acid (18:2ω6), possibly in the Δ6 desaturase step, or alternatively an abnormality in the catabolism or distribution of arachidonate. We previously speculated that a reduced proportion of 20:4ω6 in hepatic PL could contribute to the etiology of genetic obesity. Providing 18:3ω6 would bypass Δ6 desaturase and possibly normalize hepatic PL 20:4ω6. Therefore weanling Zucker rats were given free access to a defined diet (11% of energy as soy oil) and gavaged daily with 100 μL of either black currant oil concentrate ([BCO] 8% 18:2ω6 and 70% 18:3ω6) or soy oil ([Soy] 55% 18:2ω6 and <0.1% 18:3ω6). Groups of eight lean and eight obese animals were randomized to receive Soy or BCO in a 2 × 2 design; 10 obese and 10 lean rats were fed a stock diet (nongavaged reference). All groups of lean rats had identical weight gain; food intake for Soy lean and BCO lean did not differ. The obese reference animals and Soy obese animals did not differ in weight gain. However, BCO obese animals ate less food ( P < .06), gained less weight ( P < .0001), and had lower percent body fat ( P < .05) compared with the Soy obese animals. The fatty acid constituents from serum, liver, and adipose tissue showed marked differences between lean and obese animals. Hepatic PL 20:4ω6 was lower in Soy obese than in lean ( P < .002), but was normalized by BCO gavage (diet effect, P < .007). The paucity of hepatic PL 20:4ω6 was not due to reduced desaturase activity, as the proportions of other desaturase products (20:3ω6, 20:3ω9, 20:5ω3) were significantly elevated in Soy obese rat liver and serum. Serum and hepatic cholesteryl ester 20:4ω6 levels were elevated in obese versus lean rats ( P < .02 and P < .0001), indicating abnormal arachidonate distribution in the obese Zucker rat. Because BCO selectively reduced weight gain and percent body fat in obese Zucker rats, our results imply a role for abnormal ω6 fatty acid metabolism in the etiology of Zucker obesity. However, due to the potential risks of enhancing tissue 20:4ω6, great caution is advised in extrapolating our results with BCO to the treatment of obesity in humans.

Time-Dependent Effects of Progressive Gamma -Linolenate Feeding on Hyperphagia, Weight Gain, and Erythrocyte Fatty Acid Composition During Growth of Zucker Obese Rats

Obese Zucker rats (fa/fa) have low levels of arachidonic acid (AA) in liver phospholipids (PL). We have previously shown that a 70% gamma-linolenate concentrate (GLA; an AA intermediate) fed at a fixed dose (0.07 g/day) normalized hepatic PL AA and reduced weight gain selectively in the obese animals. In a follow-up study, 16 obese (fa/fa) and 16 lean (Fa/Fa) 4-week-old male rats were randomized into 4 groups of 8 each and gavaged daily with soybean oil (SOY) containing 55% 18:2omega6 (an AA precursor) or GLA, using a progressive dose (< or = 5% of total calories) based on body weight. A defined diet with 11% of energy as SOY was fed ad libitum for 60 days. GLA obese had lower body weight (p<0.0001) and 60-day cumulative food intake (p<0.05) compared to SOY obese, but neither parameter differed between the lean groups. For the last twenty days cumulative food intake was identical for GLA obese and SOY lean, whereas SOY obese consumed 18% more (p<0.05). Thus the progressive dose of GLA selectively suppressed hyperphagia in obese Zucker rats. Erythrocytes collected at 15-day intervals showed parallel increases in AA in both genotypes over time, suggesting normal AA availability during rapid growth. Thus, the reduced PL AA in the livers from the obese rats probably reflects impaired distribution in selected tissues rather than reduced hepatic production. Due to the potential health risks of enriching tissue lipids with AA, great caution is advised in considering GLA as therapy for human obesity.

Diets containing N-3 fatty acids decrease the concentrations of arachidonic acid in phospholipids, free fatty acid, and diacylglycerol fractions of submandibular salivary glands

The purpose of this study was to determine if feeding diets supplemented with n-3 fatty acids would result in reduced levels of arachidonic acid in major phospholipids, free fatty acid (FFA), and diacylglycerol (DAG) fractions of the salivary glands. Phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine plus phosphatidylinositol, FFA, and DAG fractions were isolated from the submandibular salivary glands (SMSG) of rats fed nutritionally adequate, semi-purified diets enriched with n-6 or n-3 fatty acids for 6 weeks. The fatty acid composition of the major phospholipids present in the SMSG and the concentrations of arachidonic acid were measured by gas chromatography-mass spectrometry after the addition of 18:4n-3 as an internal standard and transesterification. Arachidonic acid concentrations were significantly lower in each of the lipid fractions of the SMSG of rats fed diets rich in n-3 fatty acids than those of the control group. The results suggest that the diet-induced decrease in the potentially available sources of free arachidonic acid may result in a decrease in the levels of endogenous PGE 2 and in vitro synthesis of LTC 4, which was previously observed in the SMSG of rats fed diets containing n-3 fatty acids.

Effect of vegetable and marine oils in preterm infant formulas on blood arachidonic and docosahexaenoic acids

Adding docosahexaenoic acid (DHA) (22:6n-3) to formulas is more effective than increasing formula alpha-linolenic acid (18:3n-3) in maintaining blood phospholipid DHA levels similar to those in breast-fed infants. However, in long-term trials supplementary DHA given as marine oil reduces blood phospholipid arachidonic acid (AA) in preterm infants. This effect is not seen in short-term trials unless the total n-3 intake from marine oil exceeds 0.5% of the total fatty acids. In addition, there is considerable variability among individual preterm infants in blood phospholipid AA and DHA levels that is not dependent on diet. Within dietary treatments, a significant positive correlation between AA and DHA concentrations suggests that factor(s) other than marine oil supplementation affect both AA and DHA status. Docosahexaenoic acid and AA concentrations in plasma phospholipids are significantly correlated with DHA and AA concentrations in red blood cell phospholipids, suggesting that the observed individual differences in DHA and AA within groups represent true differences in fatty acid status. Preterm infants appear to be vulnerable to a poor status of both DHA and AA; further feeding trials are needed to identify the optimal balance of fatty acids for feeding these infants.