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PubMed2002

Synthesis and initial evaluation of 17-(11)C-heptadecanoic acid for measurement of myocardial fatty acid metabolism.

UNLABELLED: Fatty acid oxidation defects are being increasingly identified as causes of abnormal heart function and sudden death in children. Children with medium-chain acyl-coenzyme A (acyl-CoA) dehydrogenase defects can metabolize fatty acids labeled in the carboxylic acid end of the compound. Accordingly, our goal was to label a long-chain fatty acid in the omega-position and evaluate its myocardial kinetics. METHODS: Heptadecanoic acid, a 17-carbon fatty acid, was labeled in the C-17 position with (11)C by the general process of coupling (11)C-methyliodide to t-butyl-15-hexadecanoate. Yield was approximately 5%-10% end-of-bombardment. Subsequently, evaluation studies were performed on isolated perfused rat hearts and in intact, anesthetized dogs. The myocardial uptake and efflux of 17-(11)C-heptadecanoic acid were compared with those of 1-(11)C-palmitate. RESULTS: With the exception of delayed efflux of tracer reflecting the temporal delay for beta-oxidation, the washout of 17-(11)C-heptadecanoic acid from the heart mirrored that of 1-(11)C-palmitate in isolated rat hearts and in intact dogs with PET. CONCLUSION: 17-(11)C-Heptadecanoic acid may be a useful tracer for the identification of defects in fatty acid metabolism in subjects with medium- and short-chain fatty acid oxidation defects.

Animals↗
PubMed1991

Different changes of n-6 fatty acids in lipoproteins from hyperlipemic subjects after diets supplemented with n-3 fatty acids.

After diets supplemented with canned mackerel or herring, in a cross-over design, containing different amounts of long-chain n-3 fatty acids (eicosapentaenoic acid, C20:5n-3-EPA, and docosahexaenoic acid, C22(6)n-3-DHA) an increase of both EPA and DHA was confirmed in triglycerides (TG), cholesterol esters (CE) and phospholipids (PL) of very low density (VLDL) and low density lipoproteins (LDL) as well as in high density lipoproteins (HDL) from hyperlipidemic subjects. An unexpected finding was the simultaneous increase of arachidonic acid (C20:4n-6-AA) in TG and CE and its constant portion in PL of lipoproteins, whereas linoleic acid (C18:2n-6-LA) appeared lower in CE and in PL of VLDL + LDL and HDL. In general, the changes were minor after a diet supplemented with canned herring providing a lower dose of n-3 fatty acids. The results indicate dose-related changes not only of n-3 fatty acids, but also of n-6 fatty acids in serum lipids after fish diets. This different behavior of LA and AA in serum lipids might be a new aspect in the interrelations and the dietary modulation of both families of polyunsaturated fatty acids (PUFA). The accumulation of AA in neutral lipids could be linked with an elevation of prostaglandin I2, which was found apart from an increased formation of prostaglandin I3 after diets supplemented with n-3 fatty acids. The concomitant increase of prostaglandins I2 and I3 spotlights widely ignored interrelations within the eicosanoid pathway, which become evident after diets enriched with long-chain n-3 fatty acids.

Adult↗
PubMed1975

Splanchnic and leg exchange of glucose, amino acids, and free fatty acids during exercise in diabetes mellitus.

The influence of exercise on leg and splanchnic exchange of substrates was examined in eight insulin-dependent diabetics 24 h after withdrawal of insulin and in eight healthy controls studied at rest and after 40 min of bicycle ergometer exercise at 55-60% of maximal capacity. In four of the diabetic subjects, basal arterial ketone acid levels were 3-4 mmol/ liter (ketotic diabetics) and in the remainder, below 1 mmol/liter (nonketotic diabetics). ,ree fatty acid (FFA) turnover and regional exchange were evaluated with 14-C- labeled oleic acid. Leg uptake of blood glucose rose 13-18 fold during exercise in both the diabetics and controls and accounted for a similar proportion of the total oxygen uptake by leg muscles (25-28%) in the two groups. In contrast, leg uptake of FFA corresponded to 39% of leg oxygen consumption in the diabetic group but only 27% in controls. Systemic turnover of oleic acid was similar in the two groups. Splanchnic glucose output increased during exercise 3-4 fold above resting levels in both groups. In the diabetics, splanchnic uptake of lactate, pyruvate, glycerol, and glycogenic amino acids rose more than twofold above resting levels and was fourfold greater than in exercising controls. Total precursor uptake could account for 30% of the splanchnic glucose output in the diabetic group. In contrast, in the controls, total splanchnic uptake of glucose precursors was no greater during exercise than in the resting state and could account for no more than 11% of splanchnic glucose output. The augmented precursor uptake during exercise in the diabetics was a consequence of increased splanchnic fractional extraction as well as increased peripheral production of gluconeogenic substrates. The arterial glucagon concentration was unchanged by exercise in both groups, but was higher in the diabetics. In the diabetic subjects with ketosis in the resting state, exercise elicited a rise in arterial glucose and FFA, an augmented splanchnic uptake of FFA, and a 2-3 fold increase in splanchnic output of 3-hydroxybutyrate. Uptake of 3-hydroxybutyrate by the exercising leg rose more rapidly than splanchnic production, resulting in a fall in arterial levels of 3-hydroxybutyrate. It is concluded that (a) glucose uptake by exercising muscle in hyperglycemic diabetics is no different from that of controls; (b) splanchnic glucose output rises during exercise to a similar extent in diabetics and controls, while uptake of gluconeogenic substrates is markedly higher in diabetics and accounts for a greater proportion of total splanchnic glucose output; (c) exercise in diabetic patients with mild ketosis is associated with a rise in blood glucose and FFA levels as well as augmented splanchnic production and peripheral uptake of ketone bodies.

Abdomen↗
PubMed1980

Effects of ascorbic acid, vitamin E, and fatty acids on lipid composition in cockerels.

Serum, aorta, heart, and liver tissues of cockerels reflected numerous changes in cholesterol and triglyceride composition when 5 or 10% oleic or palmitic acid, ascorbic acid, and vitamin E were added to their diets. Heart cholesterol concentration and liver cholesteryl ester content increased with the 10% oleic acid diet. Heart and liver cholesterol increased when ascorbic acid was added to 5% fatty acid diets, and heart cholesterol increased when ascorbic acid was added to the 10% palmitic acid diet. Vitamin E exerted a cholesterol- or cholesteryl ester-lowering effect on both 10% palmitic and 10% oleic acid diets. Heart and liver triglycerides were lower with the 5% oleic acid diet than with the 5% palmitic acid diet. The opposite effect was observed with the 10% fatty acid diet. Dietary ascorbic acid appeared to have some triglyceride-lowering effect. Dietary fatty acid composition was reflected in cockerel aorta, heart, liver, and serum fatty acid distribution, with oleic acid having the greater influence.

Animals↗
PubMed1993

Study of a fatty acid binding site of interphotoreceptor retinoid-binding protein using fluorescent fatty acids.

Interphotoreceptor retinoid-binding protein (IRBP) is a 140-kDa glycolipoprotein which constitutes about 70% of the soluble protein of the retinal interphotoreceptor matrix. Much is known concerning its role in the transport of retinoids between photoreceptor cells and pigment epithelium but little is known about its interactions with lipids. Here we have examined the physicochemical characteristics of a fatty acid binding site of IRBP using a set of fluorescent fatty acid analogs with an anthracene moiety attached at different positions along the hydrocarbon chain. The results show that fatty acids are bound in a hydrophobic environment as indicated by a blue shift in fluorescence maxima and by a increase in quantum yield of the bound ligand. There is a single specific fatty acid binding site for each molecule of IRBP with an apparent Kd = 3.6 x 10(-7) M. There is a nonradiative energy transfer from tryptophan residues to bound ligand. The interactions of IRBP and bound fatty acid are sensitive to denaturation by increasing concentrations of urea as judged by changes in nonradiative energy transfer efficiency and the quantum yield of bound probe. Quantum yields of bound fatty acid analogs varied with position of the fluorophore along the hydrocarbon chain and had the lowest values for the fluorophore located at the midpoint. Probing of the microenvironment of bound fluorophore with a quencher indicated a highly structured binding site.

Animals↗
PubMed1996

Peroxisomal fatty acid oxidation capacity is more resistant to ischaemic and reperfusion injury than mitochondrial fatty acid oxidation capacity in feline hearts.

We investigated ischaemic and postischaemic mitochondrial and peroxisomal fatty acid oxidation capacity, ATP levels and regional function in 40 anaesthetized open chest cats subjected to 10 or 40 min of regional myocardial ischaemia with or without 3 h of reperfusion (n = 10 in each situation). Following 10 min of ischaemia, the mitochondrial fatty acid oxidation capacity measured in tissue extracts from ischaemic tissue (nmol min-1 mg protein-1) was reduced in both subepi- and subendocardium, but was normalized in reperfused tissue extracts from both wall layers (0.29 +/- 0.03 and 0.30 +/- 0.04 vs. 0.57 +/- 0.05 and 0.59 +/- 0.05. P < 0.05). Peroxisomal fatty acid oxidation capacity in tissue extracts was unaffected by ischaemia and reperfusion. ATP levels and regional function measured in the LAD region was partly restored transmurally. After 40 min of LAD occlusion, mitochondrial fatty acid oxidation capacity was reduced, with higher activity in subepi- than in subendocardium (0.27 +/- 0.05 vs. 0.19 +/- 0.04. P < 0.05). Reperfusion did not restore mitochondrial fatty acid oxidation capacity. Peroxisomal fatty acid oxidation capacity was increased in the ischaemic subendocardium compared with levels in non-ischaemic subendocardium (0.53 +/- 0.02 vs. 0.45 +/- 0.03, P < 0.05), with normalization at the end of reperfusion. ATP levels were non-uniformly reduced during ischaemia and not repleted during reperfusion. Regional function recovered in circumferential segments but not in longitudinal segments following 40 min of ischaemia. In conclusion fatty acid oxidation enzymes seem to be more resistant to ischaemia in peroxisomes than in mitochondria. Mitochondrial fatty acid oxidation is fully reversible following shortlasting ischaemia, but remains depressed following prolonged ischaemia and reperfusion.

Adenine Nucleotides↗
PubMed2004

Novel signaling molecules implicated in tumor-associated fatty acid synthase-dependent breast cancer cell proliferation and survival: Role of exogenous dietary fatty acids, p53-p21WAF1/CIP1, ERK1/2 MAPK, p27KIP1, BRCA1, and NF-kappaB.

A biologically aggressive subset of human breast cancers has been demonstrated to overexpress fatty acid synthase (FAS), the key enzyme of endogenous FA biosynthesis. This breast cancer-specific activation of FAS-dependent lipogenesis, an anabolic-energy-storage pathway of minor importance in normal cells, would render breast cancer cells more vulnerable to anti-metabolite interventions with FAS as therapeutic target. Not surprisingly, pharmacological inhibitors of FAS have been reported to produce both cytostatic and cytotoxic effects in human breast cancer cells, as well as to suppress DNA replication. However, the signal transduction pathway(s) that link FAS hyperactivity and breast cancer cell growth has been unresolved. Here, we have attempted to provide a systematic approach to assess the role of FAS signaling on the survival and proliferation of human breast cancer cells. First, we assessed the level of FAS protein in a panel of human breast cancer cell lines (MCF-7, MDA-MB-231, MDA-MB-453, MDA-MB-435, ZR-75B, T47-D, BT-474, and SK-Br3). FAS expression was graded from ++++ (overexpression) in SK-Br3 cells to + (very low expression) in MDA-MB-231 cells. No correlation was noted between FAS overexpression and estrogen receptor (ER) or progesterone receptor (PR) status, whereas a positive correlation was found between high levels of FAS expression and the amplification and/or overexpression of HER-2/neu oncogene. Because metabolic adaptation of breast cancer cells to the ambient fatty acid concentration may be relevant to the goal of utilizing FAS inhibition as a chemotherapeutic target, we evaluated the effect of exogenous dietary fatty acids on the cytotoxicity resulting from the inhibition of FAS activity. Pharmacological inhibition of FAS activity by the natural antibiotic cerulenin [(2S,3R)-2,3-epoxy-4-oxo-7E,10E-dodecadienamide] resulted in a dose-dependent cytotoxicity which positively paralleled the endogenous level of FAS. Supraphysiological levels of exogenous oleic acid (OA), a omega-9 monounsaturated fatty acid synthesized from a primary-end product of FAS palmitate, significantly diminished cell toxicity caused by cerulenin. Indeed, OA exposure significantly reduced FAS activity and expression by 55% in FAS-overexpressing SK-Br3 cells. omega-3 (alpha-linolenic acid, eicosapentaenoic acid and docosahexaenoic acid) and omega-6 (linoleic acid and arachidonic acid) polyunsaturated fatty acids (PUFAs), however, were unable to rescue breast cancer cells from cerulenin-induced cytotoxicity. Pharmacological blockade of FAS activity in FAS-overexpressing SK-Br3 cells resulted in apoptosis as determined by an enzyme-linked immunosorbent assay for histone-associated DNA fragments, and confirmed by TUNEL DNA-end labeling experiments. We further characterized signaling molecules that participate in the cellular events that follow inhibition of FAS activity and precede apoptosis in breast cancer cells. In SK-Br3 cells, cerulenin-induced inhibition of FAS activity resulted in down-regulation of p53, and up-regulation of cyclin-dependent kinase inhibitor (CDKi) p21WAF1/CIP1. Treatment with cerulenin or a novel small-molecule inhibitor of FAS C75 resulted in a dramatic accumulation of CDKi p27KIP1, which was accompanied by a noteworthy translocation of p27KIP1 from cytosol to cell nuclei. Strikingly, FAS inhibition also caused a significant activation of the Raf-mitogen-activated protein kinase (MEK) extracellular signal-regulated kinase (ERK1/2) cell survival pathway. Interestingly, we demonstrated that inhibition of FAS activity increased the nuclear-to-cytoplasmic ratio of BRCA1, a breast cancer tumor suppressor protein, as well as it induced a nuclear translocalization of the anti-apoptotic nuclear transcription factor-kappaB (NF-kappaB). In conclusion, here we demonstrate that: a) breast cancer cells retain dependence on endogenous fatty acid synthesis and sensitivity to FAS inhibition in the presence of supraphysiological levels of dietary fatty acids, supporting the notion that FAS inhibition may be useful in treFAS inhibition may be useful in treating breast cancer in vivo; b) endogenous fatty acid synthesis is functional in breast cancer cells and is vital since its pharmacological inhibition is cytotoxic by promoting apoptosis, and c) specific blockade of FAS activity induces the accumulation, activation, and/or cellular relocalization of multiple and diverse pro- and anti-apoptotic signaling pathways, suggesting that p53-p21WAF1/CIP1, ERK1/2 MAPK, p27KIP1, BRCA1, and NF-kappaB play a novel role in the breast cancer cell response to a metabolic stress after perturbation of FAS-dependent de novo fatty acid biosynthesis.

Active Transport, Cell Nucleus↗
PubMed2002

The role of n-3 polyunsaturated fatty acids in brain: modulation of rat brain gene expression by dietary n-3 fatty acids.

Rats were fed either a high linolenic acid (perilla oil) or high eicosapentaenoic + docosahexaenoic acid (fish oil) diet (8%), and the fatty acid and molecular species composition of ethanolamine phosphoglycerides was determined. Gene expression pattern resulting from the feeding of n-3 fatty acids also was studied. Perilla oil feeding, in contrast to fish oil feeding, was not reflected in total fatty acid composition of ethanolamine phosphoglycerides. Levels of the alkenylacyl subclass of ethanolamine phosphoglycerides increased in response to feeding. Similarly, levels of diacyl phosphatidylethanolamine molecular species containing docosahexaenoic acid (18:0/22:6) were higher in perilla-fed or fish oil-fed rat brains whereas those in ethanolamine plasmalogens remained unchanged. Because plasmalogen levels in the brains of rats fed a n-3 fatty acid-enriched diet increased, it is plausible, however, that docosahexaenoic acid taken up from the food or formed from linolenic acid was deposited in this phospholipid subclass. Using cDNA microarrays, 55 genes were found to be overexpressed and 47 were suppressed relative to controls by both dietary regimens. The altered genes included those controlling synaptic plasticity, cytosceleton and membrane association, signal transduction, ion channel formation, energy metabolism, and regulatory proteins. This effect seems to be independent of the chain length of fatty acids, but the n-3 structure appears to be important. Because n-3 polyunsaturated fatty acids have been shown to play an important role in maintaining normal mental functions and docosahexaenoic acid-containing ethanolamine phosphoglyceride (18:0/22:6) molecular species accumulated in response to n-3 fatty acid feeding, a casual relationship between the two events can be surmised.

Animals↗
PubMed1974

Mitogenic activity of sterculic acid, a cyclopropenoid fatty acid.

Hepatocytes in rainbow trout and rat are stimulated to augmented DNA synthesis and cell division by low concentrations of cyclopropenoid fatty acids in the diet. Sterculic acid isolated as the methyl ester from Sterculia foetida oil has been identified as one of the mitogenic principles.

Animals↗
PubMed2001

Effect of diets containing n-3 fatty acids on muscle long-chain n-3 fatty acid content in lambs fed low- and medium-quality roughage diets.

In two experiments, each with 32 cross-bred ([Merino x Border Leicester] x Poll Dorset) wether lambs (26 to 33 kg weight range), animals were randomly assigned to one of four treatments. A mixture of lucerne chaff:oaten chaff was used as a basal diet, offered in different ratios. Animals were allowed to consume on a free-access basis in Exp. 1 or 90% of ad libitum intake in Exp. 2 in order to provide a low- (6.5 MJ ME/d) and medium- (9.5 MJ ME/d) quality basal diet, respectively. Isoenergetic amounts of lipid supplements, fish meal (80 g DM), canola meal (84 g DM), and soy meal (75 g DM) were tested in Exp. 1. In Exp. 2, fish meal (9% DM), unprotected rapeseed (7% DM), and protected canola seed (6% DM) were fed as supplements. At the end of 53-d (Exp. 1) or 46-d (Exp. 2) experimental periods, lambs were slaughtered at a commercial abattoir and at 24 h postmortem longissimus thoracis (LT) muscle was collected for the analysis of fatty acid (FA) composition of structural phospholipid and storage triglyceride fractions. Fish meal diet increased LT muscle long-chain n-3 FA content by 27% (P < 0.02) in Exp. 1 and 30% (P < 0.001) in Exp. 2 compared with lambs fed the basal diet, but fish meal decreased (P < 0.01) the n-6 FA content only in Exp. 1. Soy meal and protected canola seed diets increased (P < 0.01) LT muscle n-6 FA content but did not affect long-chain n-3 FA content. Longissimus thoracis muscle long-chain n-3 FA were mainly deposited in structural phospholipid, rather than in storage triglyceride. In both Exp. 1 and Exp. 2, the ratio of n-6:n-3 FA in LT muscle was lowest (P < 0.01) in lambs fed fish meal supplement compared with all other treatments. Protected canola seed diet increased the ratio of n-6:n-3 FA (P < 0.01) and PUFA:saturated fatty acid (P < 0.03) content from those animals fed the basal, fish meal, and unprotected rapeseed diets in Exp. 2. This was due to an increase in muscle n-6 FA content, mainly linoleic acid, of both phospholipid (P < 0.001) and triglyceride (P < 0.01) fractions and not to an increase in muscle n-3 FA content. The results indicate that by feeding fish meal supplement, the essential n-3 FA can be increased while lowering the ratio of n-6:n-3 content in lamb meat to an extent that could affect nutritional value, attractiveness, and the economic value of meat.

Animal Feed↗
PubMed2005

Influence of extended-release nicotinic acid on nonesterified fatty acid flux in the metabolic syndrome with atherogenic dyslipidemia.

Nicotinic acid has favorable effects on atherogenic dyslipidemia. However, in some patients who have diabetes, crystalline nicotinic acid decreases glycemic control; this effect could be due to a marked rebound of nonesterified fatty acids (NEFAs) observed after nicotinic acid suppression of lipolysis in adipose tissue. Recent reports have indicated that small doses of extended-release nicotinic acid do not cause a substantial decrease in glucose levels. Therefore, in this study, we examined whether 2 g/day of extended-release nicotinic acid abolishes the NEFA rebound that is reported with crystalline nicotinic acid. Seventeen men who had the metabolic syndrome (8 did not have type 2 diabetes and 9 did) were treated for 4 months. At baseline and at 4 months, measurements were made of plasma glucose, insulin, and NEFA during an oral glucose tolerance test. At 3 months, effects of extended-release nicotinic acid on NEFA levels and flux rates were determined on 3 separate days at 3 separate intervals after the final dose of nicotinic acid (4, 9, and 28 hours). Values obtained at 28 hours were taken as baseline (i.e., no nicotinic acid remaining in the circulation). After 4 hours (percent baseline), NEFA levels were -30% without diabetes and -37% with diabetes, and flux rates were -21% without diabetes and -25% with diabetes; after 9 hours, NEFA levels were 43% without diabetes and 50% with diabetes, and flux rates were 38% without diabetes and 70% with diabetes. Extended-release nicotinic acid did not abolish NEFA rebound. Nonetheless, the rebound was much less than previously reported for crystalline nicotinic acid. Moreover, after 4 months of nicotinic acid therapy, levels of NEFA, glucose, and insulin during the oral glucose tolerance test were not significantly different from those before institution of nicotinic acid therapy, suggesting minimal changes in insulin sensitivity.

Adult↗
PubMed2007

Deposition of dietary fatty acids, de novo synthesis and anatomical partitioning of fatty acids in finishing pigs.

Predicting aspects of pork quality becomes increasingly important from both a nutritional and technological point of view. The aim of the present study was to provide quantitative information on the relation between nutrient intake and whole-body fatty acid (FA) depositions. This information is essential to develop mechanistic models predicting the FA content of tissues. A serial slaughter study was carried out in which thirty pigs were slaughtered between 90 and 150 kg. The diet included 15 g/kg soyabean oil and contained 44 g/kg fat. Only 0.31 and 0.40 of the digested n-6 and n-3 FA were deposited, respectively. Approximately one-third of the n-3 supply that was deposited resulted from the conversion of 18:3 to other metabolites (i.e. EPA, docosapentaenoic acid and DHA). This proportion was affected by the pig genotype. De novo-synthesised FA represented 0.86 of the total non-essential FA deposition, and its average composition corresponded to 0.017, 0.286, 0.025, 0.217 and 0.454 for 14:0, 16:0, 16:1, 18:0 and 18:1, respectively. Although the average whole-body FA composition was relatively constant during the finishing period, this was not so for the tissues. In the carcass (without backfat), the content of 18:1 increased during the finishing period, whereas that of 16:0 and 18:0 decreased. Backfat captured a proportionally greater fraction of 18:2 than did the carcass of the residual tissues. In contrast, a proportionally greater fraction of the dietary 18:3 supply was deposited in the carcass compared to other tissues.

Adipose Tissue↗
PubMed2003

Long-chain polyunsaturated fatty acids and chemically induced diabetes mellitus. Effect of omega-3 fatty acids.

In a previous study, we showed that prior oral feeding of oils rich in omega-3 eicosapentaenoic acid and docosahexaenoic acid and omega-6 gamma-linolenic acid and arachidonic acid prevent the development of alloxan-induced diabetes mellitus in experimental animals. We also observed that 99% pure omega-6 fatty acids gamma-linolenic acid and arachidonic acid protect against chemically induced diabetes mellitus. Here we report the results of our studies with omega-3 fatty acids. Alloxan-induced in vitro cytotoxicity and apoptosis in an insulin-secreting rat insulinoma cell line, RIN, was prevented by prior exposure of these cells to alpha-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid. Prior oral supplementation with alpha-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid prevented alloxan-induced diabetes mellitus. alpha-Linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid not only attenuated chemical-induced diabetes mellitus but also restored the anti-oxidant status to normal range in various tissues. These results suggested that omega-3 fatty acids can abrogate chemically induced diabetes in experimental animals and attenuate the oxidant stress that occurs in diabetes mellitus.

Administration, Oral↗
PubMed2003

Identification of a free fatty acid receptor, FFA2R, expressed on leukocytes and activated by short-chain fatty acids.

Short-chain fatty acids (SCFAs) have long been known to exert cellular effects on blood leukocytes. Acetate, propionate, and butyrate represent the most capable SCFA, inducing calcium mobilization which subsequently regulates leukocyte function in the immune system. We have cloned the previously described putative orphan G-protein coupled receptor, GPR43, and have functionally identified SCFA as the activating ligands. Acetate and propionate were found to be the two most potent ligands, although butyrate, formate, and valerate (in this order of potency) also were able to induce receptor activation. Both the human and mouse receptor homologues were found to share the same pattern of ligand activation. This finding, together with a high degree of amino acid sequence similarity between the mouse and human homologues, indicates an evolutionary conserved function. Upon ligand stimulation, the receptor mobilized intracellular calcium in both a recombinant system as well as in human granulocytes. We found the human gene to be predominantly expressed in peripheral blood leukocytes and, to a lesser extent, in spleen. We suggest the designation FFA(2)R to this second receptor activated by free fatty acids. The first-described FFAR, now named FFA(1)R, is activated by medium- to long-chain free fatty acids.

Amino Acid Sequence↗
PubMed2004

The alpha-helical domain of liver fatty acid binding protein is responsible for the diffusion-mediated transfer of fatty acids to phospholipid membranes.

Intestinal fatty acid binding protein (IFABP) and liver FABP (LFABP), homologous proteins expressed at high levels in intestinal absorptive cells, employ markedly different mechanisms for the transfer of fatty acids (FAs) to acceptor membranes. Transfer from IFABP occurs during protein-membrane collisional interactions, while for LFABP, transfer occurs by diffusion through the aqueous phase. Earlier, we had shown that the helical domain of IFABP is critical in determining its collisional FA transfer mechanism. In the study presented here, we have engineered a pair of chimeric proteins, one with the "body" (ligand binding domain) of IFABP and the alpha-helical region of LFABP (alphaLbetaIFABP) and the other with the ligand binding pocket of LFABP and the helical domain of IFABP (alphaIbetaLFABP). The objective of this work was to determine whether the change in the alpha-helical domain of each FABP would alter the rate and mechanism of transfer of FA from the chimeric proteins in comparison with those of the wild-type proteins. The fatty acid transfer properties of the FABP chimeras were examined using a fluorescence resonance transfer assay. The results showed a significant modification of the absolute rate of FA transfer from the chimeric proteins compared to that of the wild type, indicating that the slower rate of FA transfer observed for wild-type LFABP relative to that of wild-type IFABP is, in part, determined by the helical domain of the proteins. In addition to these quantitative changes, it was of great interest to observe that the apparent mechanism of FA transfer also changed when the alpha-helical domain was exchanged, with transfer from alphaLbetaIFABP occurring by aqueous diffusion and transfer from alphaIbetaLFABP occurring via protein-membrane collisional interactions. These results demonstrate that the alpha-helical region of LFABP is responsible for its diffusional mechanism of fatty acid transfer to membranes.

Animals↗
PubMed2000

Dietary n-3 fatty acid restriction during gestation in rats: neuronal cell body and growth-cone fatty acids.

Growth cones are membrane-rich structures found at the distal end of growing axons and are the predecessors of the synaptic membranes of nerve endings. This study examined whether n-3 fatty acid restriction during gestation in rats alters the composition of growth cone and neuronal cell body membrane fatty acids in newborns. Female rats were fed a standard control diet containing soy oil (8% of fatty acids as 18:3n-3 by wt) or a semisynthetic n-3 fatty acid-deficient diet with safflower oil (0.3% of fatty acids as 18:3n-3 by wt) throughout normal pregnancy. Experiments were conducted on postnatal day 2 to minimize the potential for contamination from synaptic membranes and glial cells. Dietary n-3 fatty acid restriction resulted in lower docosahexaenoic acid (DHA) concentrations and a corresponding higher docosapentaenoic acid concentration in neuronal growth cones, but had no effects on neuronal cell body fatty acid concentrations. These studies suggest that accretion of DHA in growth cones, but not neuronal cell bodies, is affected by n-3 fatty acid restriction during gestation. Differences in other fatty acids or components between the semisynthetic and the standard diet, however, could have been involved in the effects on growth-cone DHA content. The results also provide evidence to suggest that the addition of new membrane fatty acids to neurons during development occurs along the shaft of the axon or at the growth cone, rather than originating at the cell body.

Animals↗
PubMed1998

Assessment of trans-fatty acid intake with a food frequency questionnaire and validation with adipose tissue levels of trans-fatty acids.

Past studies of the association of trans-fatty acid intake with coronary heart disease have been hindered by the lack of a database on the trans-fatty acid content of various foods. The authors used new data from the US Department of Agriculture to estimate trans-fatty acid intake using a self-administered food frequency questionnaire (FFQ), and they assessed the validity of the FFQ by comparing the dietary estimates with trans-fatty acid concentrations in adipose tissue. The 1996 study included 27 women and 24 men aged 51-78 years. The mean consumption of total trans-fatty acids estimated from the FFQ was 2.24 g per day and 5% of total dietary fat. The mean concentration of total trans-fatty acids in buttock adipose tissue was 4.7% of total fatty acids. Pearson correlations between total dietary intake of trans-fatty acids and total trans-fatty acid levels in adipose tissue were 0.67 (95% confidence interval (CI) 0.36-0.84) among men and 0.58 (95% CI 0.26-0.79) among women. After adjustment for energy intake, age, and body mass index, the correlation coefficients were 0.76 (95% CI 0.51-0.89) among men and 0.52 (95% CI 0.17-0.75) among women. The FFQ validated in this study is an important new tool for assessing usual intake of trans-fatty acids.

Adipose Tissue↗