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Biochemical and electron microscope radioautographic study of intestinal absorption of tritiated palmitic and oleic acids in control and actidione-cycloheximide-treated rats.

Intestinal absorption of tritiated palmitic and oleic acids was investigated in control and actidione-cycloheximide-treated rats. Pancreatic juice was collected and 24 hr later an intestinal loop was cannulated in situ. A 90 mumole-lipid emulsion composed of an equimolar mixture of monopalmitin, palmitic and oleic acids with bile was infused with either 3H-labeled palmitic or oleic acid. After 15 or 30 min biochemical analysis was carried out to follow the uptake and the transfer of the labeled fatty acids. Mucosa was removed for both biochemical analysis of lipid classes and the ultrastructural or radioautographic electron microscope study depending on the radioactive activity. Following actidione-cycloheximide treatment, the uptake of both fatty acids decreased, but the amount of lipids in the mucosa greatly increased, while amount of the reesterification of fatty acids in the mucosa diminished. Consequently the amount of infused palmitic acid which was transferred in 15 min decreased from 36% in the absence of treatment to 4.6% when treatment was used. The corresponding figures for oleic acid are 70% and 20.9%. Unstructured lipids were in the intercellular spaces, indicating that a cytotoxic effect had occurred which produced a defect in the lipoprotein particle organization. The Golgi complex, in the final step of the chylomicron synthesis before exocytosis, showed low level of radioautographic reaction indicating less participation by the complex in lipid transfer. The various processes which were inhibited during long-chain fatty acid absorption from the luminal area to the Golgi complex included fatty acid binding by proteins, enzymatic acylation and esterification, apoprotein participation. This inhibition explains why long-chain fatty acid absorption was greatly impaired. Moreover, our observations compared with those obtained during decanoic acid absorption, particularly our radioautography based observations, emphasize the important role of the Golgi complex which requires intense membrane turnover during lipid absorption.

Animals↗

Growth-inhibition effects of oleic acid, linoleic acid, and their methyl esters on transplanted tumors in mice.

We investigated the effects of oleic acid and linoleic acid on transplanted Ehrlich ascites carcinoma and Ehrlich solid carcinoma in ACR mice. Both acids significantly prolonged the life spans of Ehrlich ascites carcinoma-bearing mice and inhibited the growth of Ehrlich solid carcinoma in mice compared with the findings in untreated control mice. Methyl esters of these acids also prolonged the survival of Ehrlich ascites carcinoma-bearing mice, but they were less effective in lengthening the survival of mice given transplants of Ehrlich ascites carcinoma. In addition, gas-chromatography analysis of tumor cell lipids showed that appreciable changes occurred in the fatty acid composition of the tumor cell grown in mice treated with oleic acid or linoleic acid. Linoleic acid caused more pronounced alterations in fatty acid composition of tumor cell lipids than did oleic acid, a feature that parallels the intensity of the cytotoxicity potential of the two free fatty acids. These results suggest that (a) the free carboxyl group of free fatty acids plays a role in killing tumor cells and (b) the modification of the fatty acid composition of tumor cells also correlates with the antitumor effects of oleic and linoleic acids. In addition, these results indicate that free fatty acids may be of tumor-oriented distribution; as a consequence, free fatty acids selectively inhibit the growth of tumor cells.

Animals↗

Effect of arachidonic acid on proliferation, cytokines production and pleiotropic genes expression in Jurkat cells--a comparison with oleic acid.

The effects of arachidonic (AA) and oleic acids (OA) on proliferation, cytokine production and pleiotropic genes expression in Jurkat T cells were investigated. The following parameters were evaluated: cytotoxicity assessed by loss of membrane integrity and DNA fragmentation, cell proliferation as measured by [14C]-thymidine incorporation, production of IL-2, IL-4, IL-10, and INF-gamma, and expression of pleiotropic genes as determined by macroarray technique (83 genes in total). AA was more toxic for Jurkat cells than OA. However, the inhibiting effect of OA on Jurkat cells proliferation was more pronounced than that of AA. The reduction in the production of IL-2 and INF-gamma was more intense by OA (50 microM) than by AA (5 microM). The percentage of genes changed by the fatty acids was: 20.5% (17 genes) for AA (5 microM) and only 2.4% (2 genes) for OA (50 microM). AA markedly affected the expression of genes clustered as: signal transduction pathways, transcription factors and related genes, cell cycle, defense and repair, apoptosis, DNA synthesis, cell adhesion, cytoskeleton and related genes. In particular, AA induced marked changes in cell cycle, signal transduction, and anti-apoptosis genes expression. Therefore, the effect of AA on T-lymphocyte function does involve regulation of expression of important genes, whereas oleic acid did not markedly affect gene expression of Jurkat cells.

Arachidonic Acid↗

In vitro inhibition of human neutrophil elastase by oleic acid albumin formulations from derivatized cotton wound dressings.

Human neutrophil elastase (HNE) is elevated in chronic wounds. Oleic acid albumin formulations that inhibit HNE may be applicable to treatment modalities for chronic wounds. Oleic acid/albumin formulations with mole ratios of 100:1, 50:1, and 25:1 (oleic acid to albumin) were prepared and found to have dose response inhibition properties against HNE. The IC50 values for inhibition of HNE with oleic acid/albumin formulations were 0.029-0.049 microM. Oleic acid/albumin (BSA) formulations were bound to positively and negatively charged cotton wound dressings and assessed for elastase inhibition using a fiber bound formulation in an assay designed to mimic HNE inhibition in the wound. Cotton derivatized with both carboxylate and amine functional groups were combined with oleic acid/albumin formulations at a maximum loading of 0.030 mg oleic acid + 0.14 mg BSA/mg fiber. The IC50 values for inhibition of HNE with oleic acid/albumin formulations bound to derivatized cotton were 0.26-0.42 microM. Release of the oleic acid/albumin formulation from the fiber was measured by measuring oleic acid levels with quantitative GC analysis. Approximately, 35-50% of the fiber bound formulation was released into solution within the first 15 min of incubation. Albumin was found to enhance the rate of elastase hydrolysis of the substrate within a concentration range of 0.3-50 g/L. The acceleration of HNE substrate hydrolysis by albumin required increased concentration of inhibitor in the formulation to obtain complete inhibition of HNE. Oleic acid formulations prepared with albumin enable transport, solubility and promote dose response inhibition of HNE from derivatized cotton fibers under aqueous conditions mimicking the chronic wound.

Animals↗

Diabetes and the Mediterranean diet: a beneficial effect of oleic acid on insulin sensitivity, adipocyte glucose transport and endothelium-dependent vasoreactivity.

Abnormalities in endothelial function may be associated with increased cardiovascular risk in diabetic patients. We examined the effect of an oleic-acid-rich diet on insulin resistance and endothelium-dependent vasoreactivity in type 2 diabetes. Eleven type 2 diabetic patients were changed from their usual linoleic-acid-rich diet and treated for 2 months with an oleic-acid-rich diet. Insulin-mediated glucose transport was measured in isolated adipocytes. Fatty acid composition of the adipocyte membranes was determined by gas-liquid chromatography and flow-mediated endothelium-dependent and -independent vasodilatation were measured in the superficial femoral artery at the end of each dietary period. There was a significant increase in oleic acid and a decrease in linoleic acid on the oleic-acid-rich diet (p<0.0001). Diabetic control was not different between the diets, but there was a small but significant decrease in fasting glucose/insulin on the oleic-acid-rich diet. Insulin-stimulated (1 ng/ml) glucose transport was significantly greater on the oleic- acid-rich diet (0.56+/-0.17 vs. 0.29+/-0.14 nmol/10(5) cells/3 min, p<0.0001). Endothelium-dependent flow-mediated vasodilatation (FMD) was significantly greater on the oleic-acid-rich diet (3.90+/-0.97% vs. 6.12+/-1.36% p<0.0001). There was a significant correlation between adipocyte membrane oleic/linoleic acid and insulin-mediated glucose transport (p<0.001) but no relationship between insulin-stimulated glucose transport and change in endothelium-dependent FMD. There was a significant positive correlation between adipocyte membrane oleic/linoleic acid and endothelium-dependent FMD (r=0.61, p<0.001). Change from polyunsaturated to monounsaturated diet in type 2 diabetes reduced insulin resistance and restored endothelium-dependent vasodilatation, suggesting an explanation for the anti-atherogenic benefits of a Mediterranean-type diet.

Adipocytes↗

Action of oleic acid on the exocrine pancreatic secretion of the conscious rat: evidence for an anti-cholecystokinin-pancreozymin factor.

The effects on exocrine pancreatic secretion of an intraduodenal infusion of oleic acid (2 ml in 60 min) has been assessed in conscious rats provided with a new type of duodenal cannula permitting the normal flow of pancreatic juice, but not of bile, between experiments.1. Intraduodenal oleic acid infusion induces an increased secretion of water and bicarbonate which is still significantly above basal values 90 min after the end of infusion. Protein output increased during the infusion, but protein concentration and output significantly decreased under basal levels 120 min and 150 min after infusion (respectively -63 and -57% of basal values at 150 min).2. No inhibition was found when oleic acid was introduced into the caecum or into the first 20 cm of ileum isolated from the rest of small intestine. On the contrary, inhibition of protein secretion was induced immediately by intra-ileal oleic acid infusion.3. Inhibition of protein secretion secondary to intra-ileal oleic acid infusion was transmitted from a donor rat to a receiver rat by means of a cross-circulation.4. It is concluded that oleic acid induces an immediate and long lasting increase in water and bicarbonate secretion. During the infusion of oleic acid, protein output is increased, followed by an inhibition. This delayed inhibition stems from the second part of the small intestine and was transferred from one rat to another by cross-circulation: it is speculated that oleic acid releases in the conscious rat (from the distal part of the small intestine) a hormonal factor inhibiting pancreatic secretion.

Animals↗

Beneficial effects of ibuprofen in oleic acid induced lung injury.

Metabolites of arachidonic acid, particularly thromboxanes, have been implicated as mediators of lung injury. The formation of thromboxane A2 can be decreased by glucocorticoid steroids by inhibiting the enzyme phospholipase A2 or by ibuprofen which inhibits fatty acid cyclooxygenase. This study was performed to determine if ibuprofen, methylprednisolone, or a combination of both could improve the pulmonary injury induced by oleic acid. Five groups of dogs were instrumented with pulmonary artery and extravascular lung water (EVLW) catheters and ventilated with 100% O2. Serial determinations of hemodynamic and pulmonary parameters were performed before and after oleic acid infusion. Plasma immunoreactive thromboxane B2 (iTxB2) and ibuprofen levels were also determined. Oleic acid rapidly induced a significant pulmonary injury as evidenced by hypoxemia and increases in extravascular lung water. Plasma iTxB2 rose significantly in the control group receiving only oleic acid. Pulmonary function and hemodynamic parameters were not changed by ibuprofen infusion alone. Ibuprofen attenuated the oleic acid induced hypoxemia and increased EVLW but did not significantly reduce plasma iTxB2. Methylprednisolone did not prevent the increase in plasma iTxB2 and was less effective than ibuprofen in preventing hypoxemia and increases in EVLW. The combination of ibuprofen and methylprednisolone did significantly inhibit the production of iTxB2, however in combination they protected less against the hypoxemia and increased EVLW than either agent alone. These results indicate that ibuprofen may have a protective effect in oleic acid induced lung injury that is not mediated through the inhibition of fatty acid cyclooxygenase. The results are also further evidence that thromboxane is probably not a pathogenetic factor in oleic acid induced lung injury.

Animals↗

Synthesis of (S)-alpha-amino oleic acid.

An efficient synthesis of (S)-alpha-amino oleic acid was developed. The fully protected FA derivative was obtained in four steps starting from methyl (2S)-2-[bis(tert-butoxycarbonyl)amino]-5-oxopentanoate. These steps are (i) olefination of the starting aldehyde with the appropriate phosphonate anion, (ii) hydrogenation of the double bonds, (iii) controlled reduction of omega-ethyl ester to an aldehyde in the presence of alpha-methyl ester, and (iv) a Wittig reaction of the latter aldehyde with the suitable ylide. Free alpha-amino oleic acid was prepared after deprotection of the amino group followed by saponification in a total yield of 24%. N-tert-Butoxycarbonyl-protected amino oleic acid and the corresponding amino alcohol were prepared in high yield. The structures of the products have been established by various spectroscopic techniques.

Chromatography, Thin Layer↗

Polymorphonuclear leukocyte participation in acute oleic-acid-induced lung injury.

The purpose of this study was twofold: (1) to analyze the cellular components of bronchoalveolar lavage fluid throughout the development of oleic-acid-induced lung injury in the rat and (2) to investigate the role of polymorphonuclear leukocytes (PMN) in the pathogenesis of this disease. Animals were killed and lavaged at various times after a single intravenously administered injection of oleic acid. The results demonstrate that a significant influx of inflammatory cells appear in the lavage fluid as early as 4 h after the administration of oleic acid. The PMN are the first cells to appear, and significant levels persist through Day 5 after injection. There is a transient yet significant influx of lymphocytes between 3 and 7 days after treatment. Rats treated with oleic acid displayed significant increases in lung vascular permeability over control animals at 1 and 4 h after injection. Depletion of PMN by anti-PMN serum significantly decreased the permeability changes induced by oleic acid. Treatment of oleic-acid-injected animals with catalase, superoxide dismutase, or dimethyl sulfoxide failed to inhibit lung permeability changes induced in this model.

Acute Disease↗

Bimodal distribution of phosphatidic acid phosphohydrolase in NG108-15 cells. Modulation by the amphiphilic lipids oleic acid and sphingosine.

The properties and bimodal distribution of phosphatidic acid phosphohydrolase (PAP) were investigated in neuroblastoma X glioma hybrid NG108-15 cells. Two PAP activities distinguished by their differential sensitivity to Mg2+ and Triton X-100 were identified in the cytosolic and microsomal fractions. A digitonin permeabilization method was employed to study the basal distribution of the cytosolic PAP and its redistribution upon cell exposure to amphiphilic lipids. Under conditions which release 100% of the cytosolic marker enzyme lactate dehydrogenase, only 60% of total cellular PAP activity was released into the medium through the digitonin-induced membrane pores, suggesting that about 40% of the total are membrane associated. Elevated plasma-membrane levels of phosphatidic acid, accomplished by incubating cells with Streptomyces chromofuscus phospholipase D, did not affect the distribution of cytosolic PAP. In contrast, oleic acid induced a marked concentration-dependent redistribution of the cytosolic enzyme to the particulate fraction. PAP redistribution was completely abolished in the presence of the sphingoid base sphingosine, previously shown to inhibit PAP activity in vitro (Lavie, Y., Piterman, O. & Liscovitch, M. (1990) FEBS Lett. 277, 7-10). Thus, the distribution of cytosolic PAP is reciprocally regulated by a long-chain (fatty) acid and a long-chain (sphingoid) base which are breakdown products of phospholipids and sphingolipids, respectively. These effects might influence PAP function in glycerolipid metabolism and signal transduction under physiological and pathophysiological conditions.

Cations, Divalent↗

Synergistic activation of CTP:phosphocholine cytidylyltransferase by phosphatidylethanolamine and oleic acid.

CTP:phosphocholine cytidylyltransferase present in rat liver cytosol was activated almost 30-fold when assayed in the presence of liposomes containing 60 mole % dioleoyl phosphatidylethanolamine (DOPE). During the assay, some of the DOPE was degraded to lysoPE and oleic acid. Whereas cytidylyltransferase activity was not affected when assayed in the presence of liposomes containing lysoPE, liposomes containing oleic acid activated the enzyme. Activation by oleic acid could be eliminated by the addition of fatty acid-free bovine serum albumin (BSA) to the assay. When cytidylyltransferase activity was measured in the presence of both BSA and liposomes containing DOPE, enzyme activity was increased almost 20-fold, as compared with assays performed in the absence of added lipid. The 1.5-fold difference in cytidylyltransferase activity observed when cytosol was assayed with DOPE containing liposomes in the absence or presence of BSA (30-fold stimulation vs 20-fold stimulation) cannot be explained by the loss of activation attributable to oleic acid alone. Activation of the enzyme in the presence of liposomes containing DOPE and oleic acid is several-fold greater than the sum of the activations caused by the individual compounds. These data suggest that PE and oleic acid act synergistically in activating the cytidylyltransferase.

Animals↗

Binding and solubility of oleic acid to laboratory materials: a possible artifact.

The possibility that significant amounts of fatty acids were dissolved in or bound to the surfaces of common laboratory materials was examined. The uptake or adsorption of radioisotopically labeled oleic acid and cholic acid by plastic tubing of Tygon, Teflon, and polyethylene, and Pyrex, and borosilicate glass, and steel was measured. 3H-oleic acid and 14C-cholic acid were used in the presence of different concentrations of unlabeled oleic acid, cholic acid, and/or bovine serum albumin. Concentrations, composition, pH, and perfusion rates were varied. Relatively large amounts (10-95%) of oleic acid (25 microM) were lost by dissolving in plastic and adsorption to glass or metal. The degree of losses decreased in the presence of compounds in the perfusion solution which could bind or dissolve oleic acid. In contrast, cholic acid was not lost to plastic, glass or metal. The magnitude of and influence of perfusion rate, composition, pH, and sequence of perfusion solutions on oleic acid losses were sufficiently large that the results of certain studies, such as those of unstirred water layers of albumin - stimulated fatty acid uptake by hepatocytes may need to be reexamined.

Adsorption↗

Estimation of assimilation of simultaneously ingested 14C-triolein and 3H-oleic acid as a test of pancreatic digestive function.

The ratio between assimilation of simultaneously ingested 14C-triolein and 3H-oleic acid was investigated as a test of pancreatic digestive function in 48 consecutive patients suspected of malassimilation. Faecal excretion of 14C-triolein and 3H-oleic acid was measured by means of a combustion/liquid scintillation counting technique. Compared with the patients in whom the clinical investigation showed normal lipid assimilation (no. = 31) the assimilation of both 14C-triolein and 3H-oleic acid was significantly reduced in the patients with malabsorption (no. = 6) and maldigestion (no. = 11). However, in all except one patient with maldigestion the assimilation of 14C-triolein was more reduced than that of 3H-oleic acid, whereas there was no difference in 14C-triolein and 3H-oleic acid assimilation in the patients with malabsorption and normal lipid assimilation. Measurement of the postprandial serum radioactivities of 14C and 3H, like the faecal measurements, indicated more severely reduced assimilation of 14C-triolein than of 3H-oleic acid in the patients with maldigestion than in the other patient groups. In fact, the 2-h postprandial 3H/14C ratio at a level of 1.3 correctly classified digestive function in 47 of the 48 patients.

Digestion↗

Carotenoid pigment levels in Staphylococcus aureus and sensitivity to oleic acid.

Staphylococcus aureus mutants lacking pigment, or expressing only low levels of pigment, were more sensitive to oleic acid than were the parent strain and mutants making more pigment than the parent. One class of mutants (colour index 5), although possessing significant levels of pigment, were nevertheless quite sensitive to oleic acid. This suggested that only certain carotenoids in the biosynthetic pathway were capable of imparting resistance to fatty acids. The phenotypic expression of pigment also affected the sensitivity of a strain to oleic acid. The parent S. aureus strain 18Z, when grown to express its maximal pigment potential, was more resistant to oleic acid than when it was grown to express minimal levels of pigment.

Carotenoids↗

The distribution of oleic acid between salbutamol base drug and different propellant blends.

The distribution of oleic acid between Salbutamol base drug and the solvent in metered-dose inhalers (MDI's) has been investigated. The equilibrium surfactant concentration in the drug dispersions has been determined using a colorimetric method. The samples examined contained Salbutamol base drug particles and oleic acid dispersed in different propellant blends of freon 11 and 12. The maximum equilibrium concentration observed depended on the propellant blend used. The propellant blend and the distribution of the surfactant affected the dispersion stability. The effect of the surfactant is illustrated by the adsorption isotherm for oleic acid onto the Salbutamol particles. The results are correlated with zeta-potentials and particle size measurements made on similar systems in order to characterize the properties of surfactant stabilized MDI's.

Administration, Inhalation↗

The metabolic availability of dietary triacylglycerols from two high oleic oils during the postprandial period does not depend on the amount of oleic acid ingested by healthy men.

Monounsaturated oils, virgin olive oil (VOO) and high oleic sunflower oil (HOSO) are suggested to have selective physiologic effects on humans in the fasting state. The aim of the study was to evaluate whether two oils with equal amounts of oleic acid but with different compositions of minor fatty acids and triacylglycerol molecular species (TAG) could produce different triacylglycerol-rich lipoprotein (TRL)-TAG responses in the postprandial state. Eight normolipidemic men consumed the following three meals in random order on separate occasions with 2 wk between meals: control meal, control meal plus VOO and control meal plus HOSO. Plasma total TAG and TRL-TAG were measured hourly for 7 h after ingestion. TAG and sn-2 positional fatty acids within TAG were analyzed in the TRL fraction. Plasma total TAG concentrations in response to the dietary oils did not differ. However, TRL triglyceridemia was significantly lower after VOO intake (P < 0.05). The molecular species in the TRL fraction returned toward basal levels more quickly (P < 0.05) after VOO than HOSO intake. 2-Positional fatty acid analysis demonstrated higher proportions of stearic and palmitic acids and a lower proportion of oleic acid (P < 0.05) in TRL-TAG derived from HOSO. This study shows that VOO intake results in attenuated postprandial TAG concentration and faster TRL-TAG disappearance from blood compared with HOSO, suggesting that the oleic acid content may not be the main factor affecting TAG metabolism. Minor fatty acids such as linoleic acid and the 2-positional distribution of saturated stearic and palmitic acids into the TAG molecule may be important determinants of postprandial lipemia in normolipidemic men.

Adult↗