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Purified halorhodopsin was isolated from Halobacterium halobium as previously described (Duschl, A. et al. (1988) J. Biol. Chem. 263, 17016-17022). Two purple bands were eluted from phenyl-Sepharose column, indicating the presence of differently retained halorhodopsin forms; the absorption spectra of the two halorhodopsin bands in the dark were not different. By gas chromatography/mass spectrometry we could identify palmitate (which is only a minor lipid component of archaeal cells) among lipids associated with purple fractions. Typically the palmitate content of the first eluted band was higher than that of the second, indicating a correlation between the palmitate content and the retention time; from one to two fatty acid molecules per halorhodopsin molecule were present depending on the fraction analysed. Very little or no palmitate was released from denatured halorhodopsin. By adding palmitate to buffers used in the phenyl-Sepharose chromatography, only one sharp purple band was collected, corresponding to the less retained halorhodopsin fraction. Pentadecanoic fatty acid could also affect the halorhodopsin chromatography. Chromatography of halorhodopsin in the presence of beta-mercaptoethanol showed only one band, corresponding to the more retrained halorhodopsin form. The two halorhodopsin fractions had different photoreactivity; the less retained halorhodopsin fraction (at higher palmitate content) showed an higher rate of decay of the absorbance at 570 nm upon illumination. By following the decay of the absorbance at 570 nm upon addition of alkali in the dark, we found that the two halorhodopsin fractions had different pKa values of deprotonation.
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Male Sprague-Dawley rats were fed diets that varied qualitatively and quantitatively in antioxidants. Kidney, heart, lung, and spleen homogenates were incubated at 37 degrees C with and without hydroperoxide or Fe+2. Protection of antioxidants against oxidative damage to tissue was determined by measurement of oxidized heme proteins. Tissues from rats supplemented with dietary vitamin E and selenium showed protection compared to tissues from rats on the basal diet. Tissues from rats with diets containing larger quantities of antioxidants and both fat soluble antioxidants: vitamin E, beta-carotene, coenzyme Q10, ascorbic acid 6-palmitate and water soluble antioxidants: selenium, trolox C, acetylcysteine, coenzyme Q0, (+)-catechin, showed the highest protection.
We report on the synthesis, biological function, and a plausible mode of action of a new group of lipopeptides with potent antifungal and antibacterial activities. These lipopeptides are derived from positively charged peptides containing d- and l-amino acids (diastereomers) that are palmitoylated (PA) at their N terminus. The peptides investigated have the sequence K(4)X(7)W, where X designates Gly, Ala, Val, or Leu (designated d-X peptides). The data revealed that PA-d-G and PA-d-A gained potent antibacterial and antifungal activity despite the fact that both parental peptides were completely devoid of any activity toward microorganisms and model phospholipid membranes. In contrast, PA-d-L lost the potent antibacterial activity of the parental peptide but gained and preserved partial antifungal activity. Interestingly, both d-V and its palmitoylated analog were inactive toward bacteria, and only the palmitoylated peptide was highly potent toward yeast. Both PA-d-L and PA-d-V lipopeptides were also endowed with hemolytic activity. Mode of action studies were performed by using tryptophan fluorescence and attenuated total reflectance Fourier transform infrared and circular dichroism spectroscopy as well as transmembrane depolarization assays with bacteria and fungi. The data suggest that the lipopeptides act by increasing the permeability of the cell membrane and that differences in their potency and target specificity are the result of differences in their oligomeric state and ability to dissociate and insert into the cytoplasmic membrane. These results provide insight regarding a new approach of modulating hydrophobicity and the self-assembly of non-membrane interacting peptides in order to endow them with both antibacterial and antifungal activities urgently needed to combat bacterial and fungal infections.
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The use of 13C-labelled compounds to study lipid metabolism is increasing. Typically less than 40% of the orally administered label is recovered in breath CO2. The remainder must be either absorbed and not oxidised or not absorbed and remain in the faeces. Two methods of determining how much tracer passes through the body, and is present in the stool, were compared. Compound specific analysis of tert.-butyldimethylsilyl [13C]hexadecanoic acid by gas chromatography-mass spectrometry (GC-MS) with electron impact ionisation was compared with bulk analysis of whole stool and lipid extract by continuous flow isotope ratio mass spectrometry (CF-IRMS) with a combustion interface. The mean difference between the IRMS and GC-MS methods was -0.02 mmol 13C d(-1) with a mean excretion of 14.2 mmol 13C d(-1). Combustion IRMS is both simpler and cheaper, when the objective is to determine how much administered dose appears in stool, and information about the form of the label is not required.
The incorporation of exogenously supplied fatty acids, palmitic acid, palmitoleic acid, oleic acid and linoleic acid, was examined in the yeast Schizosaccharomyces pombe at two growth temperatures, 20 degrees C and 30 degrees C. Fatty acids supplied to S. pombe in the growth medium were found to be preferentially incorporated into the cells, becoming a dominant species. The relative increase in exogenous fatty acids in cells came at the expense of endogenous oleic acid as a proportion of total fatty acids. Lowering the temperature at which the yeast were grown resulted in decreased levels of incorporation of the fatty acids palmitic acid, palmitoleic acid and linoleic acid compared to cells supplemented at 30 degrees C. In addition, the relative amount of the endogenously produced unsaturated fatty acid oleic acid, while greatly reduced compared to unsupplemented cells, was increased in cells supplemented with fatty acids at 20 degrees C compared to supplemented cells at 30 degrees C. The differential production of oleic acid in S. pombe cells indicates that regulation of unsaturated fatty acid levels, possibly by control of the stearoyl-CoA desaturase, is an important control point in membrane composition in response to temperature and diet in this species.
High-fat diet is a significant risk factor for the development of Alzheimer's disease (AD). In addition, the AD brain is characterized by elevated levels of fatty acids as compared to that of healthy controls. Despite this, it is unclear how elevated levels of fatty acids are related to the pathogenesis of AD. The present study examines the role of saturated fatty acid, palmitic acid (PA), in causing BACE1 upregulation and consequent amyloidogenic processing of beta-amyloid precursor protein (APP), one of the main characteristic signatures of AD pathology. Here, primary rat cortical neurons and astrocytes were treated with pathological concentration of PA. There was no change in the BACE1 levels in the rat cortical neurons treated directly with PA as compared to controls. The conditioned medium from PA-treated astrocytes, however, caused BACE1 upregulation in the cortical neurons. Moreover, there was a consequent increase in the cleavage of APP leading to the accumulation of the C-terminal fragment of APP (C99) in the cortical neurons. Co-treatment of neurons with 1,3-dimethyl urea (DMU), an antioxidant, decreased PA-induced upregulation in the levels of BACE1 and C99. The present results establish an important role of saturated fatty acids in AD-associated amyloidogenesis through astroglia-mediated oxidative stress.
To obtain further information about the effects of specific dietary saturated fatty acids, weanling male rats were fed for 6 weeks on low fat (7.7% by weight) or high fat (17.8% by weight) diets which differed according to the principal fatty acids present. The diets were rich in caprylic and capric acids (medium chain triacylglycerols; MCT), lauric acid, palmitic acid at the sn-1(3) position, palmitic acid at the sn-2 position or stearic acid. The total proportions of saturated (42-46%), monounsaturated (36%), n-6 polyunsaturated (15%) and n-3 polyunsaturated (2.2%) fatty acids were the same in all diets. Serum cholesterol concentrations were not different among rats fed the different diets, except that the concentration in the serum of rats fed the high fat diet with palmitic acid in the sn-2 position was high. This was reflected in higher HDL and LDL cholesterol concentrations in the serum of animals fed this diet. Triacylglycerol (TAG) concentrations tended to be higher in the serum of rats fed the low fat diets compared with those fed the high fat diets. They were lowest in the serum of MCT-fed rats irrespective of the level of fat in the diet and were highest in the serum of rats fed the low fat diet rich in stearic acid. These differences were due to lower chylomicron and VLDL TAG concentrations in the serum of MCT-fed rats and higher chylomicron and VLDL TAG concentrations in the serum of low fat, stearic acid-fed animals. The fatty acid compositions of the serum and of spleen lymphocytes were influenced by that of the diet fed. The ex vivo proliferation of lymphocytes from the spleens of rats fed the high fat diet rich in palmitic acid at the sn-2 position was greater than that of lymphocytes from animals fed the other diets. Natural killer (NK) cell activity tended to be lower for spleen lymphocytes from rats fed high fat diets than for those fed low fat diets irrespective of the principal saturated fatty acid present. NK cell activity was highest for spleen lymphocytes from animals fed the diets rich in palmitic acid and was lowest for those from animals fed the high fat diet rich in stearic acid. Spleen lymphocytes from the latter animals had the lowest proportion of CD16+ cells, a marker for NK cells. Thus, this study shows that the type of saturated fatty acid present in the diet not only has subtle effects upon blood lipid and lipoprotein levels but can significantly affect lymphocyte functions. Spleen lymphocyte NK cell activity is decreased as the fat content of the diet increases. NK cell number and activity are reduced by a high fat diet rich in stearic acid. Spleen lymphocyte proliferation is enhanced by palmitic acid-rich diets, particularly if palmitic acid is in the sn-2 position of dietary TAG.
We have previously shown that saturated fatty acids induce DNA damage and cause apoptotic cell death in insulin-producing beta-cells. Here we examine further the effects of single or combined dietary fatty acids on RINm5F survival or cell death signalling. Palmitate and stearate, but not linoleate, oleate or palmitoylmethyl ester, induced growth inhibition and increased apoptosis in RINm5F cells following 24 h exposure. Co-incubation with inhibitors of ceramide synthesis, myriocin or fumonisin B(1), did not improve viability of palmitic acid treated RINm5F cells. The inhibitor of inducible nitric oxide synthase, 1400 W, similarly had no protective effect. However, linoleic acid protected against palmitic acid-induced apoptotic and necrotic cell death. The specific pharmacological inhibitors of phosphatidylinositol 3-kinase, LY294002 and wortmannin, abolished the protective effect of linoleic acid on apoptosis but not on necrosis. These data show that the growth inhibitory and apoptosis-inducing effect of the saturated fatty acid palmitate on RINm5F cells is prevented by co-incubation with the polyunsaturated fatty acid linoleate but not inhibitors of ceramide or nitric oxide generation. A key role for phosphatidylinositol 3-kinase in mediating the linoleic-acid reduction in apoptosis is suggested.
BACKGROUND: There is increasing evidence that postprandial triacylglycerol-rich lipoproteins may be related to atherogenic risk. OBJECTIVE: The objective was to investigate the effect of individual fatty acid intakes on postprandial plasma lipoprotein triacylglycerol and cholesterol concentrations, plasma fatty acids, and preheparin lipoprotein lipase and cholesterol ester transfer protein (CETP) activities. DESIGN: Six test fats high (approximately 43% by wt) in stearic acid, palmitic acid, palmitic + myristic acid, oleic acid, elaidic acid (trans 18:1), and linoleic acid were produced by interesterification. After having fasted for 12 h, 16 healthy young men were served the individual test fats incorporated into meals (1 g fat/kg body wt) in random order on different days separated by washout periods. Blood samples were drawn before and 2, 4, 6, and 8 h after the meals. RESULTS: Different responses to the test-fat meals were observed for plasma lipoprotein triacylglycerol and cholesterol concentrations, plasma fatty acid concentrations, and lipoprotein lipase and CETP activities (diet x time interaction: 0.001 < P < 0.05). Intake of the long-chain saturated fatty acids stearic and palmitic acids resulted in a relatively lower lipemic response than did intake of the unsaturated fatty acids, probably because the saturated fatty acids were absorbed less and at a lower rate; therefore, the lipemic response took longer to return to postabsorptive values. CONCLUSIONS: Fatty acid chain length and degree of saturation appear to affect the extent and duration of lipemia and affect hepatic output indirectly. These effects may not be mediated via effects on lipoprotein lipase and CETP activities.
Cyclohexyl hexadecanoate, hexadecyl propionate, and N-(3-hydroxypropionyl)pentadecanamide, respectively ester, retroester, and retroamide derivatives of N-palmitoylethanolamine, represent the first selective inhibitors of "N-palmitoylethanolamine hydrolase" described so far. These compounds are devoid of affinity for CB(1) and CB(2) receptors and characterized by high percentages of inhibition of N-palmitoylethanolamine-selective acid amidase (84.0, 70.5, and 76.7% inhibition at 100 microM, respectively) with much lower inhibitory effect on either fatty acid amide hydrolase or the uptake of anandamide.