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PubMed2000

Dietary ratio of (n-6)/(n-3) polyunsaturated fatty acids alters the fatty acid composition of bone compartments and biomarkers of bone formation in rats.

The effects of dietary polyunsaturated fatty acids (PUFA) on ex vivo bone prostaglandin E(2) (PGE(2)) production and bone formation rate were evaluated in rats. Weanling male Sprague-Dawley rats were fed AIN-93G diet containing 70 g/kg of added fat for 42 d. The dietary lipid treatments were formulated with safflower oil and menhaden oil to provide the following ratios of (n-6)/(n-3) fatty acids: 23.8 (SMI), 9.8 (SMII), 2.6 (SMIII), and 1.2 (SMIV). Ex vivo PGE(2) production in liver homogenates and bone organ cultures (right femur and tibia) were significantly lower in rats fed diets with a lower dietary ratio of (n-6)/(n-3) fatty acids than in those fed diets with a higher dietary ratio. Regression analysis revealed a significant positive correlation between bone PGE(2) and the ratio of arachidonic acid (AA)/eicosapentaenoic acid (EPA), but significant negative correlations between bone formation rate and either the ratio of AA/EPA or PGE(2) in bone. Activities of serum alkaline phosphatase isoenzymes, including the bone-specific isoenzyme (BALP), were greater in rats fed a diet high in (n-3) or a low ratio of (n-6)/(n-3), further supporting the positive action of (n-3) fatty acids on bone formation. These results demonstrated that the dietary ratio of (n-6)/(n-3) modulates bone PGE(2) production and the activity of serum BALP in growing rats.

Animals↗
PubMed1979

Sex differences in long chain fatty acid utilization and fatty acid binding protein concentration in rat liver.

Female sex and estrogen administration are associated with increased hepatic production of triglyceride-rich lipoproteins; the basis for this has not been fully elucidated. Inasmuch as hepatic lipoprotein production is also influenced by FFA availability and triglyceride biosynthesis, we investigated sex differences in FFA utilization in rat hepatocyte suspensions and in the components of the triglyceride biosynthetic pathway. Isolated adult rat hepatocyte suspensions were incubated with albumin-bound [(14)C]oleate for up to 15 min. At physiological and low oleate concentrations, cells from females incorporated significantly more (14)C into glycerolipids, especially triglycerides, and into oxidation products than did male cells, per milligram cell protein. At 0.44 mM oleate, incorporation into triglycerides in female cells was approximately twice that in male cells. Comparable sex differences were observed in cells from fasted animals and when [(14)C]-glycerol incorporation was measured. At higher oleate concentrations, i.e., fatty acid:albumin mole ratios in excess of 2:1, these sex differences were no longer demonstrable, suggesting that maximal rates of fatty acid esterification and oxidation were similar in female and male cells. In female and male hepatic microsomes, specific activities of long chain acyl coenzyme A synthetase, phosphatidate phosphohydrolase, and diglyceride acyltransferase were similar, but glycerol-3-phosphate acyltransferase activity was slightly greater in females at certain substrate concentrations. Microsomal incorporation of [(14)C]oleate into total glycerolipids was not significantly greater in females. In further contrast to intact cells, microsomal incorporation of [(14)C]oleate into triglycerides, although significantly greater in female microsomes, accounted for only a small fraction of the fatty acid esterified.The binding affinity and stoichiometry of partially purified female hepatic fatty acid binding protein (FABP) were similar to those of male FABP. In contrast, the concentration of FABP, per milligram cytosolic protein, was 44% greater in female liver than in male, as indicated by measurement of [(14)C]oleate binding and of 280 nm OD in the FABP fraction of 105,000 g supernate after gel filtration chromatography. These experiments demonstrate profound sex differences in hepatocyte utilization of long chain fatty acids at concentrations within and below the physiological range, and suggest that these are attributable at least in part to corresponding differences in cytosolic FABP concentration. At higher FFA concentrations, sex differences in hepatocyte FFA utilization are virtually eliminated, suggesting that under these conditions, differences in FABP concentration are not rate determining. Sex differences in hepatic lipoprotein production may largely reflect these important differences in the initial stages of hepatocyte FFA utilization.

Albumins↗
PubMed1980

Sex steroid modulation of fatty acid utilization and fatty acid binding protein concentration in rat liver.

The mechanism by which sex steroids influence very low density hepatic lipoprotein triglyceride production has not been fully elucidated. In previous studies we showed that [(14)C]oleate utilization and incorporation into triglycerides were greater in hepatocyte suspensions from adult female rats than from males. The sex differences were not related to activities of the enzymes of triglyceride biosynthesis, whereas fatty acid binding protein (FABP) concentration in liver cytosol was greater in females. These findings suggested that sex differences in lipoprotein could reflect a sex steroid influence on the availability of fatty acids for hepatocellular triglyceride biosynthesis. In the present studies, sex steroid effects on hepatocyte [(14)C]oleate utilization and FABP concentration were investigated directly. Hepatocytes from immature (30-d-old) rats exhibited no sex differences in [(14)C]oleate utilization. With maturation, total [(14)C]oleate utilization and triglyceride biosynthesis increased moderately in female cells and decreased markedly in male cells; the profound sex differences in adults were maximal by age 60 d. Fatty acid oxidation was little affected. Rats were castrated at age 30 d, and received estradiol, testosterone, or no hormone until age 60 d, when hepatocyte [(14)C]oleate utilization was studied. Castration virtually eliminated maturational changes and blunted the sex differences in adults. Estradiol or testosterone largely reproduced the appropriate adult pattern of [(14)C]oleate utilization regardless of the genotypic sex of the treated animal. In immature females and males, total cytosolic FABP concentrations were similar. In 60-d-old animals, there was a striking correlation among all groups (females, males, castrates, and hormone-treated) between mean cytosolic FABP concentration on the one hand, and mean total [(14)C]oleate utilization (r = 0.91) and incorporation into triglycerides (r = 0.94) on the other. In 30-d-old animals rates of [(14)C]oleate utilization were greater, relative to FABP concentrations, than in 60-d-old animals. The sex differences that characterize fatty acid utilization in adult rat hepatocytes are not present in cells from immature animals, and reflect in part the influence of sex steroids. It remains to be determined whether the observed relationship of hepatic FABP concentration to [(14)C]oleate utilization in adult cells is causal or secondary to changes in cellular fatty acid uptake effected through another mechanism. In either case, modulation of triglyceride-rich lipoprotein production by six steroids appears to be mediated to a significant extent by their effects on hepatic fatty acid utilization.

Aging↗
PubMed2001

Adenoviral gene transfer of Caenorhabditis elegans n--3 fatty acid desaturase optimizes fatty acid composition in mammalian cells.

Omega--3 polyunsaturated fatty acids (PUFAs) are essential components required for normal cellular function and have been shown to exert many preventive and therapeutic actions. The amount of n--3 PUFAs is insufficient in most Western people, whereas the level of n--6 PUFAs is relatively too high, with an n--6/n--3 ratio of >18. These two classes of PUFAs are metabolically and functionally distinct and often have important opposing physiological functions; their balance is important for homeostasis and normal development. Elevating tissue concentrations of n--3 PUFAs in mammals relies on chronic dietary intake of fat rich in n--3 PUFAs, because mammalian cells lack enzymatic activities necessary either to synthesize the precursor of n--3 PUFAs or to convert n--6 to n--3 PUFAs. Here we report that adenovirus-mediated introduction of the Caenorhabditis elegans fat-1 gene encoding an n--3 fatty acid desaturase into mammalian cells can quickly and effectively elevate the cellular n--3 PUFA contents and dramatically balance the ratio of n--6/n--3 PUFAs. Heterologous expression of the fat-1 gene in rat cardiac myocytes rendered cells capable of converting various n--6 PUFAs to the corresponding n--3 PUFAs, and changed the n--6/n--3 ratio from about 15:1 to 1:1. In addition, an eicosanoid derived from n--6 PUFA (i.e., arachidonic acid) was reduced significantly in the transgenic cells. This study demonstrates an effective approach to modifying fatty acid composition of mammalian cells and also provides a basis for potential applications of this gene transfer in experimental and clinical settings.

Adenoviridae↗
PubMed2001

Compared with saturated fatty acids, dietary monounsaturated fatty acids and carbohydrates increase atherosclerosis and VLDL cholesterol levels in LDL receptor-deficient, but not apolipoprotein E-deficient, mice.

Heart-healthy dietary recommendations include decreasing the intake of saturated fatty acids (SFA). However, the relative benefit of replacing SFA with monounsaturated fatty acids (MUFA), polyunsaturated fatty acids (PUFA), or carbohydrates (CARB) is still being debated. We have used two mouse models of atherosclerosis, low density lipoprotein receptor-deficient (LDLRKO) and apolipoprotein E-deficient (apoEKO) mice to measure the effects of four isocaloric diets enriched with either SFA, MUFA, PUFA, or CARB on atherosclerotic lesion area and lipoprotein levels. In LDLRKO mice, compared with the SFA diet, the MUFA and CARB diets significantly increased atherosclerosis in both sexes, but the PUFA diet had no effect. The MUFA and CARB diets also increased very low density lipoprotein-cholesterol (VLDL-C) and LDL-cholesterol (LDL-C) in males and VLDL-C levels in females. Analysis of data from LDLRKO mice on all diets showed that atherosclerotic lesion area correlated positively with VLDL-C levels (males: r = 0.47, P < 0.005; females: r = 0.52, P < 0.001). In contrast, in apoEKO mice there were no significant dietary effects on atherosclerosis in either sex. Compared with the SFA diet, the CARB diet significantly decreased VLDL-C in males and the MUFA, PUFA, and CARB diets decreased VLDL-C and the CARB diet decreased LDL-C in females. In summary, in LDLRKO mice the replacement of dietary SFA by either MUFA or CARB causes a proportionate increase in both atherosclerotic lesion area and VLDL-C. There were no significant dietary effects on atherosclerotic lesion area in apoEKO mice. These results are surprising and suggest that, depending on the underlying genotype, dietary MUFA and CARB can actually increase atherosclerosis susceptibility, probably by raising VLDL-C levels through a non-LDL receptor, apoE-dependent pathway.

Adipose Tissue↗
PubMed1995

Effects of fatty acids and fatty acyl CoA esters on Cu(2+)-induced conversion of xanthine dehydrogenase to oxidase in rabbit liver.

Effects of various fatty acids and fatty acyl CoA esters on Cu(2+)-induced conversion of xanthine dehydrogenase to oxidase in rabbit liver were examined. Cu2+ (2-10 microM) brought about the conversion of xanthine dehydrogenase to oxidase in a dose-dependent manner. Oleic, arachidonic, eicosapentaenoic, and docosahexaenoic acids (50-200 microM) prevented the conversion of xanthine dehydrogenase to oxidase catalyzed by 6 microM-Cu2+. The effect of these four fatty acids was concentration-dependent, whereas palmitic, stearic, and linoleic acids had no effect on the conversion of xanthine dehydrogenase to oxidase at the same concentration range. On the other hand, palmitoyl, linoleoyl, and arachidonoyl CoAs elicited the inhibition of 6 microM-Cu(2+)-induced conversion of xanthine dehydrogenase to oxidase at concentrations of 50, 100, and 200 microM. These results suggest that oleic, arachidonic, eicosapentaenoic and docosahexaenoic acids, and fatty acyl CoAs have the potential to inhibit the conversion of xanthine dehydrogenase to oxidase in rabbit liver.

Acyl Coenzyme A↗
PubMed2004

Conjugated linoleic acid isomers and trans fatty acids inhibit fatty acid transport in hepatoma 7288CTC and inguinal fat pads in Buffalo rats.

Conjugated linoleic acid (CLA) and some trans fatty acids (FA) decrease tumor growth and alter tumor and host lipid uptake and storage. The goal of this study was to test the hypothesis that the acute inhibitory effects of CLA isomers and trans FAs on FA transport in tumors and white adipose tissue are mediated via an inhibitory G-protein coupled (GPC), FFA receptor (FFAR). Experiments were performed in hepatoma 7288CTC and inguinal fat pads in Buffalo rats during perfusion in situ. CLA isomers and trans FAs (0.03-0.4 mmol/L, in plasma) were added to the arterial blood, and FA uptake or release was measured by arterial minus venous difference. In hepatoma 7288CTC, the CLA isomers, t10,c12-CLA > (+/-)-9-HODE [13-(S)-hydroxyoctadecadienoic acid] > t9,t11-CLA, and the trans FAs, linolelaidic = vaccenic > elaidic, decreased cAMP content and inhibited FA uptake, 13(S)-HODE release, extracellular signal-regulated kinase p44/p42 phosphorylation, and [(3)H]thymidine incorporation. Other CLA isomers, c9,t11-CLA, 13-(S)-HODE, c9,c11-CLA, and c11,t13-CLA, had no effect. In inguinal fat pads, FA transport was inhibited by t10,c12-CLA = linolelaidic acid > trans vaccenic acid, whereas c9,t11-CLA had no effect. In both hepatoma 7288CTC and inguinal fat pad, addition of either pertussis toxin or 8-Br-cAMP to the arterial blood reversed the inhibitions of FA transport. These results support the idea that an inhibitory GPC FFAR reduces cAMP and controls FA transport by CLA isomers and trans FAs. Ligand activity is conferred by the presence of a trans double bond proximal to the carboxyl group.

Adipose Tissue↗
PubMed1987

Selective incorporation of n-3 and n-6 fatty acids in essential fatty acid deficient rats in response to short-term oil feeding.

Essential fatty acid deficient male Sprague Dawley rats were fed for 7 days a fat-free semi-synthetic diet supplemented with 10% by weight of different oil supplements. The oil supplement was a mixture of olive, safflower and linseed oils prepared at different proportions so the dietary n-9/n-6/n-3 ratios were approximate 2/1/1, 1/2/1, 1/1/2, and 1/1/1. The fatty acid compositions of plasma and liver lipids were then examined. Our results show polyunsaturated n-6 and n-3 fatty acids were selectively incorporated into plasma and liver phospholipids, and also into plasma cholesteryl esters. A preferential incorporation of n-6 over n-3 fatty acids into plasma cholesteryl esters and phospholipids was also observed.

Animals↗
PubMed1984

Nicotinic acid, free fatty acids and myocardial function during coronary occlusion and reperfusion in the dog.

The effect of nicotinic acid on regional myocardial blood flow, percentage of segment shortening and myocardial uptake of free-fatty acids during a 15-min occlusion of the left anterior descending coronary artery and 3-hr reperfusion period was compared to a saline-treated control group. Nicotinic acid (2.4 mumol/kg/min i.v.) was infused 30 min before and throughout the occlusion period. Heart rate, arterial blood pressure and left ventricular systolic and end diastolic pressures were not different during occlusion and reperfusion in the nicotinic acid or saline-treated groups. However, left ventricular dP/dt, an index of global myocardial function and percentage of segment shortening in the ischemic region were greater during occlusion and reperfusion after nicotinic acid. Even though myocardial blood flow was unaltered in the normal or ischemic region during nicotinic acid infusion, subendocardial blood flow during reperfusion was enhanced significantly when compared to the control group. Nicotinic acid also decreased free-fatty acid uptake by the heart during occlusion which returned gradually to the pretreatment control during 3 hr of reperfusion. Thus, the improvement in percentage of segment shortening, dP/dt and subendocardial blood flow during reperfusion may be related to the ability of nicotinic acid to reduce free-fatty acid uptake by the heart during coronary occlusion.

Animals↗
PubMed2003

Comparison of adipose tissue fatty acids with dietary fatty acids as measured by 24-hour recall and food frequency questionnaire in Black and White Adventists: the Adventist Health Study.

PURPOSE: To calibrate and compare intake of different fats and individual fatty acids as assessed with a food frequency questionnaire (FFQ) against that estimated with (i) a series of dietary recalls and; (ii) the relative fat concentration in an adipose tissue biopsy. The FFQ was specially designed for use in a cohort of Seventh-day Adventists. In preparation for a large cohort study investigating the effect of diet on risk of colon, prostate and breast cancer. METHODS: The association of adipose tissue fatty acids and dietary fat intake was assessed in 49 black and 72 white Seventh-day Adventists subjects using 8 different 24-hour recalls, a 200-item food frequency questionnaire (FFQ) and adipose tissue biopsies from each subject. RESULTS: Pearson correlation between fatty acids in adipose tissue and dietary intake as assessed by multiple 24-hour recalls were as follows: Linoleic acid: 0.77 in black and 0.71 in white subjects, respectively; Linolenic acid: 0.68 (blacks) and 0.62 (whites); Total Polyunsaturated fat (PUFA): 0.78 (blacks) and 0.70 (whites); Total Monounsaturated fat (MUFA): 0.35 (blacks) and 0.03 (whites); Total Saturated fat (SFA): 0.46 (blacks) and 0.56 (whites). Correlations between fatty acids in adipose tissue and dietary intake as assessed by FFQ were: Linoleic acid: 0.61 (blacks) and 0.52 (whites), respectively; Linolenic acid: 0.29 (blacks) and 0.49 (whites); PUFA: 0.62 (blacks) and 0.53 (whites); MUFA: 0.07 (blacks) and 0.31 (whites), SFA: 0.21 (blacks) and 0.31 (whites). CONCLUSIONS: Our study confirms findings of others that 24-hour recalls are valid for assessing dietary intake of different types of fat. The FFQ we developed and used in this study gave reasonably valid measures of fatty acid intake in our population and is thus suitable for use in large cohort studies. It had validity comparable to that observed for other FFQs.

Adipose Tissue↗
PubMed1991

Differential interaction of fatty acids and fatty acyl CoA esters with the purified/reconstituted brown adipose tissue mitochondrial uncoupling protein.

Proteoliposomes containing highly purified uncoupling protein generated by a modified purification/reconstitution procedure carried out active GDP dependent proton conductance. It was further established that long chain acyl CoA esters as well as fatty acids stimulated proton influx by the uncoupling protein, and, moreover, that the acyl CoA esters were partially effective in overcoming the inhibition by GDP. GDP binding to the purified uncoupling protein was inhibited by acyl CoA esters but not fatty acids. Phenylglyoxal which prevents GDP binding to the uncoupling protein eliminated the acyl CoA but not the fatty acid effect on proton conductance. These results substantiate the fact that nucleotides and acyl CoA esters act at the same regulatory site on the uncoupling protein, whereas, fatty acids act at a separate site. The properties of the purified/reconstituted uncoupling protein confirm they are identical to those inherent in brown adipose tissue mitochondria.

Acyl Coenzyme A↗
PubMed2002

Trans monounsaturated fatty acids and saturated fatty acids have similar effects on postprandial flow-mediated vasodilation.

OBJECTIVE: Several studies suggest that a fatty meal impairs flow-mediated vasodilation (FMD), a measure of endothelial function. We tested whether the impairment was greater for trans fats than for saturated fats. We did this because we previously showed that replacement of saturated fats by trans fats in a controlled diet decreased FMD after 4 weeks. DESIGN: We fed 21 healthy men two different test meals with 0.9-1.0 g fat/kg body weight in random order: one rich in saturated fatty acids (Sat), mainly from palm kernel fat, and one rich in trans fatty acids (Trans) from partially hydrogenated soy bean oil. The study was performed in our metabolic ward. We had complete data for both diets of 21 men. RESULTS: FMD increased from a fasting value of 2.3+/-2.0% of the baseline diameter to 3.0+/-1.7% after the Sat test meal (95% CI for change -0.33, 1.70) and from 2.7+/-2.3 to 3.1+/-2.0% after the Trans test meal (95% CI for change -0.57, 1.29). The increase after the Sat meal was 0.22 (-1.18-1.61) FMD% higher than after the Trans meal. Serum triacylglycerols increased by 0.46+/-0.36 mmol/l after the Sat test meal and by 0.68+/-0.59 mmol/l after the Trans test meal; a difference of 0.23 (0.07, 0.39) mmol/l. Serum HDL-cholesterol was hardly affected by the test meals. The activity of serum paraoxonase, an esterase bound to HDL, increased slightly after the two test meals but the difference between meals was not significant. CONCLUSION: FMD was not impaired and not different after test meals with saturated or trans fatty acids. Thus, differences in long-term effects of these fats are not caused by differences in acute effects on the vascular wall.

Adult↗
PubMed1999

Comparative effects of polyunsaturated- to saturated fatty acid ratio versus polyunsaturated- and monounsaturated fatty acids to saturated fatty acid ratio on lipid metabolism in rats.

This study examined the effects of various polyunsaturated fatty acid (PUFA, P)/saturated fatty acid (SFA, S) ratio versus PUFA + monounsaturated fatty acid (MUFA, M)/SFA ratio on lipid metabolism. The P/S ratio of dietary fat was fixed at a certain level (0.5, 1, 2, or 4, respectively) for each of four pairs of rat groups respectively, and then the P + M/S ratio was changed for the four pairs of rat groups. When the P/S ratio was fixed at 0.5, 1, 2, or 4, the plasma total cholesterol, LDL-cholesterol (C), and HDL-C levels did not show any significant difference in each pair of groups with different P + M/S ratios. However, when the P/S ratio was fixed at 1.0, the higher P + M/S ratio of 5.7 (M/S=4.7, P/M=0.2) resulted in significantly higher plasma total triacylglycerol (TAG), VLDL-TAG, VLDL-C, and VLDL-phospholipid (PL) than the lower P + M/S ratio of 1.4 (M/S=0.4, P/M=2.4). Whereas when SFA was fixed at a similar level, it therefore had approximately the same P + M/S ratio(5.3, 5.6, 5.7), and by increasing the P/S ratio from 1, 2 to 4 (70.4, 52.7 and 23.2% of the total fatty acids as MUFA respectively), the plasma VLDL-C, VLDL-TAG, and VLDL-PL concentrations decreased progressively. When PUFA or MUFA was kept on a similar level (14.9 or 53% respectively), the higher P + M/S ratio (5.7 or 5.3, respectively) resulted in significantly greater accumulation of liver cholesterol than the lower P + M/S ratio of 2.2. When the P/S ratio was fixed at 1 or 4, the diet of higher P + M/S ratio in a pair of the groups also resulted in greater accumulation of liver cholesterol. The results of the study suggests that if the P + M/S ratio was below 3, the change in the P/S ratios (0.5, 1 or 2) did not affect the levels of plasma total and lipoprotein cholesterol and TAG. Increases in the plasma VLDL-C and VLDL-TAG were related to increased MUFA content in the diet. And high MUFA content resulted in greater accumulation of liver cholesterol. It seems that the prerequisites for keeping low plasma and liver cholesterol are (a) low M/S ratio and (b) high P/M ratio and (c) P + M/S ratio not to exceed 3.

Animals↗
PubMedDate not supplied

[Effect of a diet with various amounts of essential fatty acid on the fatty acid spectrum of lipids in the kidneys in spontaneously hypertensive rats].

Fatty acid composition of phospholipids and triglycerides was studied by means of gas chromatography in kidney of rats with spontaneous hypertension, kept on rations containing various amounts of essential fatty acids. Deficiency of essential fatty acids caused an increase in content of oleic acid (18:1 omega 9) and of its metabolite--eucosetrienic acid (20:3 omega 9). Feeding of the animals with large amounts of linoleic (18:2 omega 6) and linoleic (18:3 omega 3) acids led to an increase of their content in kidney lipids as well as to elevation of prostaglandin precursors level. With an increase in deficiency of linoleic acid activity of delta 5-desaturation of its derivatives was decreased. Decrease in the rate of arterial pressure was observed in those spontaneously hypertensive rats, in kidney of which the content of linoleic, linoleic acids and eucosepentanic acid of the linoleic species (20:5 omega 3) was increased after the alimentary treatments.

Animals↗
PubMed1994

Fatty acid binding site of the mitochondrial uncoupling protein. Demonstration of its existence by EPR spectroscopy of 5-DOXYL-stearic acid.

Fatty acid binding site on isolated mitochondrial uncoupling protein (UcP) is demonstrated using EPR spectroscopy of 5-DOXYL-stearic acid (5-SASL), which also activated H+ transport in proteoliposomes containing UcP. In the presence of UcP the EPR spectrum showed reproducible broadening of the low field peak as well as an increase in h+1I/h+1M ratio, rotational correlation time and in order parameter. The half-height width of the low field peak was even doubled in the presence of another UcP ligand, GDP. Palmitic acid reversed the effect of 5-SASL and non-ionizable 5-DOXYL-decane did not exhibit it.

Adipose Tissue, Brown↗
PubMed1995

Surface lysine residues modulate the collisional transfer of fatty acid from adipocyte fatty acid binding protein to membranes.

The transfer of unesterified fatty acids (FA) from adipocyte fatty acid binding protein (A-FABP) to phospholipid membranes is proposed to occur via a collisional mechanism involving transient ionic and hydrophobic interactions [Wootan & Storch (1994) J. Biol. Chem. 269, 10517-10523]. In particular, it was suggested that membrane acidic phospholipids might specifically interact with basic residues on the surface of A-FABP. Here we addressed whether lysine residues on the surface of the protein are involved in this collisional transfer mechanism. Recombinant A-FABP was acetylated to neutralize all positively charged surface lysine residues. Protein fluorescence, CD spectra, and chemical denaturant data indicate that acetylation did not substantially alter the conformational integrity of the protein, and nearly identical affinities were obtained for binding of the fluorescently labeled FA [12-(9-anthroyloxy)oleate] to native and acetylated protein. Transfer of 2-(9-anthroyloxy)palmitate (2AP) from acetylated A-FABP to small unilamellar vesicles (SUV) was 35-fold slower than from native protein. In addition, whereas the 2AP transfer rate from native A-FABP was directly dependent on SUV concentration, 2AP transfer from acetylated protein was independent on the concentration of acceptor membranes. Factors which alter aqueous-phase solubility of FA, such as ionic strength and acyl chain length and saturation, affected the AOFA transfer rate from acetylated but not native A-FABP. Finally, an increase in the negative charge density of the acceptor SUV resulted in a marked increase in the rate of transfer from native A-FABP but did not increase the rate from acetylated A-FABP.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylation↗
PubMed2003

The first total synthesis of the marine fatty acid (+/-)-2-methoxy-13-methyltetradecanoic acid: a cytotoxic fatty acid to leukemia cells.

The recently discovered marine fatty acid (+/-)-2-methoxy-13-methyltetradecanoic acid was synthesized for the first time in six steps (26% overall yield) starting from commercially available methyl 12-methyltridecanoate. The synthetic approach provided enough material to corroborate the structure of the acid, which was recently identified in the sponge Amphimedon complanata from Aguadilla, Puerto Rico, and to test its cytotoxicity to three leukemia cell lines. The key step in the synthesis was the addition of trimethylsilyl cyanide to 12-methyltridecanal under triethylamine catalysis. Nuclear magnetic resonance data are provided for the first time for this methoxylated fatty acid and the synthetic approach utilized is of general applicability since it can be used in the synthesis of other methyl-branched 2-methoxylated fatty acids. We also report that the acid (+/-)-2-methoxy-13-methyltetradecanoic acid is cytotoxic to human chronic myelogenous leukemia K-562 (EC50=238 microM), histiocytic lymphoma U-937 (EC50=250 microM), and promielocytic leukemia HL-60 (EC50=476 microM) in RPMI 1640 medium.

Animals↗