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PubMed2005

Probing conformational changes of human serum albumin due to unsaturated fatty acid binding by chemical cross-linking and mass spectrometry.

Mass spectrometry with chemical cross-linking was used to probe the conformational changes of HSA (human serum albumin) in solution on interaction with monounsaturated OA (oleic acid) or polyunsaturated AA (arachidonic acid) or DHA (docosahexaenoic acid). Fatty acid-free or -bound HSA was modified with lysine-specific cross-linkers and digested with trypsin. Cross-linked peptides were analysed by nano-electrospray ionization MS to localize the sites of cross-linking. Our data indicated that a local conformational change involving movement of the side chains of Lys-402 of subdomain IIIA or Lys-541 of subdomain IIIB occurred upon binding of all three fatty acids. Our data also indicated that the side chains of Lys-205 (IIA) and Lys-466 (IIIA) moved closer towards each other upon binding AA or DHA, but not OA, suggesting that the conformations of HSA when bound to mono- and poly-unsaturated fatty acids are distinctively different. While these observations agreed with previous X-ray crystallographic studies, the distances between epsilon-amino groups of most cross-linked lysine pairs were shorter than the crystal structure predicted, possibly reflecting a discrepancy between the solution and crystal structures. This method can serve as a useful complement to X-ray crystallography, particularly in probing the structure of a protein in solution.

Amino Acid Sequence↗
PubMed2003

Docosahexaenoic acid and other fatty acids induce a decrease in pHi in Jurkat T-cells.

1. Docosahexaenoic acid (DHA) induced rapid (t1/2=33 s) and dose-dependent decreases in pHi in BCECF-loaded human (Jurkat) T-cells. Addition of 5-(N,N-dimethyl)-amiloride, an inhibitor of Na+/H+ exchanger, prolonged DHA-induced acidification as a function of time, indicating that the exchanger is implicated in pHi recovery. 2. Other fatty acids like oleic acid, arachidonic acid, eicosapentaenoic acid, but not palmitic acid, also induced a fall in pHi in these cells. 3. To assess the role of calcium in the DHA-induced acidification, we conducted experiments in Ca2+-free (0% Ca2+) and Ca2+-containing (100% Ca2+) buffer. We observed that there was no difference in the degree of DHA-induced transient acidification in both the experimental conditions, though pHi recovery was faster in 0% Ca2+ medium than that in 100% Ca2+ medium. 4. In the presence of BAPTA, a calcium chelator, a rapid recovery of DHA-induced acidosis was observed. Furthermore, addition of CaCl2 into 0% Ca2+ medium curtailed DHA-evoked rapid pHi recovery. In 0% Ca2+ medium, containing BAPTA, DHA did not evoke increases in [Ca2+]i, though this fatty acid still induced a rapid acidification in these cells. These observations suggest that calcium is implicated in the long-lasting DHA-induced acidosis. 5. DHA-induced rapid acidification may be due to its deprotonation in the plasma membrane (flip-flop model), as suggested by the following observations: (1) DHA with a -COOH group induced intracellular acidification, but this fatty acid with a -COOCH3 group failed to do so, and (2) DHA, but not propionic acid, -induced acidification was completely reversed by addition of fatty acid-free bovine serum albumin in these cells. 6. These results suggest that DHA induces acidosis via deprotonation and Ca2+ mobilization in human T-cells.

Docosahexaenoic Acids↗
PubMed1997

Fatty acid composition of adipose tissue, an indication of dietary fatty acids, and breast cancer prognosis.

PURPOSE: Fatty acid composition of adipose tissue is an indicator of the long-term ingestion pattern of several specific fatty acids. There is good correlation of antecedent diet with the essential fatty acids, and there is reflection of the diet with the fatty acids that can be synthesized. The relationship between the fatty acid levels and lymph node status and clinical outcome was examined. METHODS: At the time of diagnostic surgery, 161 women with clinical stage T1NO breast cancer had subcutaneous adipose tissue (breast and abdominal) aspirated. The concentrations of 35 fatty acids, seven summed classes, and six fatty acid groups were measured by capillary gas chromatography. Lymph node status was determined with axillary dissection, and patients were followed-up (mean, 7.3 years) for clinical outcome. RESULTS: There was no significant association of any adipose tissue fatty acids with overall survival, although few (16 of 161 women) died of breast cancer. However, the odds of having positive lymph nodes (57 of 161 women) were significantly higher for women with a greater adipose tissue proportion of oleic acid (odds ratio [OR], 7.56; 95% confidence interval [CI], 1.78 to 32.1) or total saturated acids (OR, 8.43; 95% CI, 1.48 to 40.0) and significantly lower with a higher proportion of trans fatty acids (OR, 0.24; 95% CI, 0.07 to 0.77), as assessed by multivariate logistic regression. CONCLUSION: These data support previous research with dietary questionnaire methodology, suggesting that specific dietary fatty acids may be associated with breast cancer promotion. Further research with long-term clinical follow-up is necessary to investigate these observations in large, diverse populations before dietary recommendations can be envisioned.

Abdomen↗
PubMed2006

Malonyl CoA control of fatty acid oxidation in the newborn heart in response to increased fatty acid supply.

The concentration of fatty acids in the blood or perfusate is a major determinant of the extent of myocardial fatty acid oxidation. Increasing fatty acid supply in adult rat increases myocardial fatty acid oxidation. Plasma levels of fatty acids increase post-surgery in infants undergoing cardiac bypass operation to correct congenital heart defects. How a newborn heart responds to increased fatty acid supply remains to be determined. In this study, we examined whether the tissue levels of malonyl CoA decrease to relieve the inhibition on carnitine palmitoyltransferase (CPT) I when the myocardium is exposed to higher concentrations of long-chain fatty acids in newborn rabbit heart. We then tested the contribution of the enzymes that regulate tissue levels of malonyl CoA, acetyl CoA carboxylase (ACC), and malonyl CoA decarboxylase (MCD). Our results showed that increasing fatty acid supply from 0.4 mmol/L (physiological) to 1.2 mmol/L (pathological) resulted in an increase in cardiac fatty acid oxidation rates and this was accompanied by a decrease in tissue malonyl CoA levels. The decrease in malonyl CoA was not related to any alterations in total and phosphorylated acetyl CoA carboxylase protein or the activities of acetyl CoA carboxylase and malonyl CoA decarboxylase. Our results suggest that the regulatory role of malonyl CoA remained when the hearts were exposed to high levels of fatty acids.

AMP-Activated Protein Kinases↗
PubMed2003

Effect of n-3 fatty acid ratio and dose on clinical manifestations, plasma fatty acids and inflammatory mediators in dogs with pruritus.

The use of n-3 fatty acids is often recommended to manage pruritus. The purpose of this study was to determine the effect of various doses of n-3 fatty acids at different n-6:n-3 ratios on plasma fatty acids, clinical response and inflammatory mediators in pruritic dogs. After baseline assessment, dogs were randomly assigned to receive diets varying in both total n-3 and n-6 fatty acid dose and n-6:n-3 ratio. The total clinical score decreased significantly in all four diet groups after 8 weeks with no difference between groups. Plasma fatty acid changes generally mirrored the fatty acid content of the test diets, although alterations appeared to depend on both the dose of n-3 fatty acids and the n-6:n-3 ratio. In this clinical trial, which controlled dietary intake of fatty acids, n-3 fatty acid supplementation did not appear to have an added benefit on clinical signs over thorough clinical management.

Animals↗
PubMed2001

Dietary fatty acid composition in pregnancy alters neurite membrane fatty acids and dopamine in newborn rat brain.

The importance of maternal dietary fatty acids on arachidonic acid [AA; 20:4(n-6)] and docosahexaenoic acid [DHA; 22:6(n-3)] in fetal brain nerve growth cone membranes and monoaminergic neurotransmitters was investigated. Rats were fed purified diets containing 20 g/100 g safflower oil with 74.3% 18:2(n-6), 0.2% 18:3(n-3), soybean oil with 55.4% 18:2(n-6), 7.7% 18:3(n-3) or high fish oil with 24.6% 22:6(n-3) through gestation. Tissue for rats within a litter were pooled at birth, brain growth cone membranes prepared and phosphatidylcholine (PC), phosphatidylserine (PS), phosphatidylethanolamine (PE) and phosphatidylinositol (PI) fatty acids quantified by gas-liquid chromatography. Dopamine, serotonin, and the metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid, and 5-hydroxyindolacetic acid were quantified by HPLC. Growth cone membranes from offspring of rats fed safflower oil had significantly lower, and offspring of rats fed high 22:6(n-3) fish oil had significantly higher 22:6(n-3) in PE, PS and PI than the soybean oil group. The growth cone membrane PC, PE and PS 20:4(n-6) was significantly lower in the fish oil than in the soybean or safflower oil groups. Serotonin concentration was significantly higher in brain of offspring in the safflower oil compared with the soybean oil group. The newborn brain dopamine was inversely related to PE DHA and PS DHA (P < 0.001), but positively related to PC AA (P < 0.05). These studies show that maternal dietary fatty acids may alter fetal brain growth cone (n-6) and (n-3) fatty acids, and neurotransmitters involved in neurite extension, target finding and synaptogenesis. The functional importance, however, is not known at this time.

Animals↗
PubMed1997

Effect of dietary n-3/n-6 fatty acid ratio on the total count, fatty acid composition, and histamine and leukotriene concentrations of mast cells in tunica mucosa bronchiorum of type I allergic guinea pig.

To search for the most effective dietary n-3/n-6 ratio to suppress the type I allergic response, we performed basic experiments that applied parameters, associated with the type I allergy. Guinea pigs fed on diets containing lipids with the n-3/n-6 ratio at different levels and the polyunsaturated fatty acid/saturated fatty acid ratio of a fixed level were sensitized with ovalbumin and reared for two weeks. The lowest or critical level of the n-3/n-6 ratio which produced a significant difference in the parameters was as follows: about 2.0 for the response of mast cells and eosinophils; 0.5 and 1.0, respectively, for the uptake of n-3 and n-6 polyunsaturated fatty acids and decreased histamine production; and 0.2 for decreased leukotriene B4 and total leukotrienes 4, and increased leukotrienes 5/leukotrienes 4. The critical level of the n-3/n-6 ratio thus differed widely according to the parameter. Overall, the upper limit for the dietary n-3/n-6 ratio to suppress antigen-induced type I allergic responses is suggested to be around 1.0.

Animals↗
PubMed2006

Effects of dietary n-6:n-3 fatty acid ratio on feed intake, digestibility, and fatty acid profiles of the ruminal contents, liver, and muscle of growing lambs.

This study investigated the effect of modifying the n-6:n-3 fatty acid ratio (FAR) of diets using linseed, soybean, and cottonseed oils on apparent digestibility, ruminal fermentation characteristics, growth performance, key circulating hormones, and the fatty acid profile of ruminal digesta, liver, and fore-shank muscle of growing lambs fed a high concentrate diet. Forty individually housed Katadhin Dorper lambs (average of 20.0 kg of BW) were fed Bermudagrass hay in ad libitum amounts and concentrates at 3.7% of BW daily. The concentrate contained 68.9% corn, 23.8% soybean meal, 3.3% limestone, and 4.0% oil supplements (DM basis). The treatments consisted of dietary n-6:n-3 FAR of 2.3:1, 8.8:1, 12.8:1, and 15.6:1. After feeding for 35 d in metabolism crates, lambs were slaughtered 15 h after feeding, and samples of ruminal digesta, blood, liver, and foreshank tissue were collected. Increasing dietary n-6:n-3 FAR did not affect the intake of DM nor the apparent digestibility of DM, ether extract, NDF, or ADF, but did increase apparent digestibility of CP (linear, P < 0.05). Concentrations of ruminal butyrate increased linearly (P < 0.05) with increasing dietary n-6:n-3 FAR, whereas the valerate concentration decreased linearly (P < 0.001). Concentrations of plasma insulin and IGF-I were not affected by dietary n-6:n-3 FAR. Concentrations of C18:3n-3 increased linearly (P < 0.001), whereas that of C18:2n-6 decreased linearly (P < 0.001) in ruminal digesta with decreasing dietary n-6:n-3 FAR. Concentrations of transisomers of fatty acids in ruminal digesta did not change. Proportions of C18:0 in liver and foreshank muscle were unchanged by diet. The proportion of trans11 C18:1 and cis-9 trans11 CLA decreased (P < 0.05) in liver but increased (P < 0.05) in foreshank muscle as dietary n-6:n-3 FAR decreased. Proportions of all measured n-3 fatty acids were greater in liver when diets contained more C18:3n-3 from linseed oil. By decreasing the dietary n-6:n-3 FAR, the proportions of n-6 fatty acids in foreshank muscle decreased dramatically; specifically, C18:2n-6 decreased linearly (P < 0.001) from 28.0 to 16.5% and C20:4n-6 decreased linearly (P < 0.001) from 14.7 to 8.6%. Although feeding a diet that contained more n-3 fatty acids increased the n-3 fatty acid concentration of muscle, the ratio of PUFA to SFA was decreased.

Ammonia↗
PubMed1973

Biochemical effects of the hypoglycaemic compound pent-4-enoic acid and related non-hypoglycaemic fatty acids. Effects of their coenzyme A esters on enzymes of fatty acid oxidation.

1. Pent-4-enoyl-CoA and its metabolites penta-2,4-dienoyl-CoA and acryloyl-CoA, as well as n-pentanoyl-CoA, cyclopropanecarbonyl-CoA and cyclobutanecarbonyl-CoA, were examined as substrates or inhibitors of purified enzymes of beta-oxidation in an investigation to locate the site of inhibition of fatty acid oxidation by pent-4-enoate. 2. The reactions of various acyl-CoA derivatives with l-carnitine and of various acyl-l-carnitine derivatives with CoA, catalysed by carnitine acetyltransferase, were investigated and V(max.) and K(m) values were determined. Pent-4-enoyl-CoA and n-pentanoyl-CoA were good substrates, whereas cyclobutanecarbonyl-CoA, cyclopropanecarbonyl-CoA and acryloyl-CoA reacted more slowly. A very slow rate with penta-2,4-dienoyl-CoA was detected. Pent-4-enoyl-l-carnitine, n-pentanoyl-l-carnitine and cyclobutanecarbonyl-l-carnitine were good substrates and cyclopropanecarbonyl-l-carnitine reacted more slowly. 3. Pent-4-enoyl-CoA and n-pentanoyl-CoA were substrates for butyryl-CoA dehydrogenase and for octanoyl-CoA dehydrogenase, and both compounds were equally effective competitive inhibitors of these enzymes with butyryl-CoA or palmitoyl-CoA respectively as substrates. V(max.), K(m) and K(i) values were determined. 4. None of the acyl-CoA derivatives inhibited enoyl-CoA hydratase or 3-hydroxybutyryl-CoA dehydrogenase. Penta-2,4-dienoyl-CoA was a substrate for enoyl-CoA hydratase when the reaction was coupled to that catalysed by 3-hydroxybutyryl-CoA dehydrogenase. 5. In a reconstituted sequence with purified enzymes crotonoyl-CoA was largely converted into acetyl-CoA, and pent-2-enoyl-CoA into acetyl-CoA and propionyl-CoA. Penta-2,4-dienoyl-CoA was slowly converted into acetyl-CoA and acryloyl-CoA. 6. Penta-2,4-dienoyl-CoA, a unique metabolite of pent-4-enoate, was the only compound that specifically inhibited an enzyme of the beta-oxidation sequence, 3-oxoacyl-CoA thiolase. The formation of penta-2,4-dienoyl-CoA could explain the strong inhibition of fatty acid oxidation in intact mitochondria by pent-4-enoate.

Acetyltransferases↗
PubMed1992

Inhibition of phospholipase A2 by cis-unsaturated fatty acids: evidence for the binding of fatty acid to enzyme.

Calcium-dependent phospholipases A2 are markedly inhibited in vitro by cis-unsaturated fatty acids (CUFAs) and to a much lesser extent by trans-unsaturated or saturated fatty acids. Thus, CUFAs may function as endogenous suppressors of lipolysis. To better understand the mechanism of inhibition, kinetic analysis, fluorescence spectroscopy and gel permeation chromatography were employed to demonstrate that CUFAs interact with a highly purified Ca(2+)-dependent phospholipase A2 from Naja mossambica mossambica venom. Arachidonate inhibited hydrolysis of both [1-14C]oleate-labelled, autoclaved Escherichia coli and [1-14C]linoleate-labelled phosphatidylethanolamine in an apparent competitive manner. When subjected to gel permeation chromatography, [3H]arachidonate, but not [3H]palmitate, comigrated with the enzyme. Arachidonic and other CUFAs increased the fluorescence intensity of the enzyme almost 2-fold in a dose-dependent fashion (50 microM = 180% of control); methyl arachidonate was without effect. Saturated fatty acids had only a modest effect on enzyme fluorescence (50 microM = 122% of control). Concentrations of arachidonate that inhibited in vitro enzymatic activity by almost 80% did not alter binding of phospholipase A2 to the E. coli substrate. Collectively, these data demonstrate that, while CUFAs selectively bind to the enzyme, they do not influence phospholipase A2-substrate interaction. Inhibition of in vitro phospholipase A2 activity by CUFAs may be mediated by the formation of an enzymatically inactive enzyme-substrate-inhibitor complex.

Arachidonic Acid↗
PubMed1996

Dietary fatty acid composition induces comparable changes in cardiolipin fatty acid profile of heart and brain mitochondria.

The fatty acid profile of cardiolipin (CL) from brain and cardiac mitochondria was measured to determine whether CL isolated from these two tissue sources responded similarly to alterations in dietary fat composition. Male Wistar rats were fed 20% (w/w) diets containing 2 to 12% (w/w) 18:2n-6 for four weeks. Despite higher baseline levels of CL 18:2n-6 in cardiac (54 +/- 1% of total fatty acids) compared to brain (13 +/- 1%) mitochondria, CL 18:2n-6 levels increased in proportion to dietary 18:2 levels. The degree of change in 18:2n-6 was comparable with both tissues showing an approximate 1.5- to 2-fold increase. The time course of changes in CL fatty acid profile was examined in a subsequent experiment in which animals were fed 20% (w/w) fat diets containing either 3 or 15% alpha-linoleate. Changes in cardiac CL 18:1, 18:2n-6, and 22:6n-3 levels were observed within one week of feeding. While statistically significant differences were not observed in brain CL until the second week of feeding, the time course did not differ substantively from that observed in heart. The results from this study suggest that while baseline fatty acid profile of cardiac and neural CL differ, mitochondria from both tissues show comparable sensitivity to changes in dietary fat composition. Furthermore, it would appear that the turnover rate of fatty acids in CL is similar in both tissues.

Animals↗
PubMed2004

The influence of different combinations of gamma-linolenic, stearidonic and eicosapentaenoic acids on the fatty acid composition of blood lipids and mononuclear cells in human volunteers.

This study set out to identify whether stearidonic acid (18:4n-3; STA) can be used to increase the eicosapentaenoic acid (20:5n-3; EPA) content of plasma lipids and cells in humans and to understand more about the effects of increased consumption of gamma-linolenic acid (18:3n-3; GLA), STA and EPA in humans. Healthy young males were randomised to consume one of seven oil blends for a period of 12 weeks (9g oil/day) (n = 8-12 subjects/group). Palm oil, sunflower oil, an EPA-rich oil, borage oil (rich in GLA), and Echium oil (rich in STA) were blended in various combinations to generate a placebo oil and oils providing approximately 2g GLA + STA + EPA per day, but in different combinations. Blood was collected at 0, 4, 8 and 12 weeks and the fatty acid compositions of plasma triacylglycerols, cholesteryl esters and phospholipids and of peripheral blood mononuclear cells (PBMCs) determined. Significant effects were observed with each lipid fraction. Neither STA nor its derivative 20:4n-3 appeared in any of the lipid fractions studied when STA (up to 1g/day) was consumed. However, STA (1g/day), in combination with GLA (0.9 g/day), increased the proportion of EPA in some lipid fractions, suggesting that STA-rich plant oils may offer a novel means of increasing EPA status. Furthermore, this combination tended to increase the dihomo-gamma-linolenic acid (20:3n-6; DGLA) content of PBMCs, without an increase in arachidonic acid (AA) (20:4n-6) content. EPA consumption increased the EPA content of all lipid fractions studied. Consumption of GLA (2g/day), in the absence of STA or EPA, increased DGLA content with a tendency to increase AA content in some fractions. This effect was prevented by inclusion of EPA in combination with GLA. Thus, this study indicates that STA may be used as a precursor to increase the EPA content of human lipids and that combinations of GLA, STA and EPA can be used to manipulate the fatty acid compositions of lipid pools in subtle ways. Such effects may offer new strategies for manipulation of cell composition in order to influence cellular responses and functions in desirable ways.

Adult↗
PubMed2004

Role of group VIA calcium-independent phospholipase A2 in arachidonic acid release, phospholipid fatty acid incorporation, and apoptosis in U937 cells responding to hydrogen peroxide.

Group VIA calcium-independent phospholipase A2 (iPLA2) has been shown to play a major role in regulating basal phospholipid deacylation reactions in certain cell types. More recently, roles for this enzyme have also been suggested in the destruction of membrane phospholipid during apoptosis and after oxidant injury. Proposed iPLA2 roles have rested heavily on the use of bromoenol lactone as an iPLA2-specific inhibitor, but this compound actually inhibits other enzymes and lipid pathways unrelated to PLA2, which makes it difficult to define the contribution of iPLA2 to specific functions. In previous work, we pioneered the use of antisense technology to decrease cellular iPLA2 activity as an alternative approach to study iPLA2 functions. In the present study, we followed the opposite strategy and prepared U937 cells that exhibited enhanced iPLA activity by stably expressing a plasmid containing iPLA2 cDNA. Compared with control cells, the iPLA2 -overexpressing U937 cells showed elevated responses to hydrogen peroxide with regard to both arachidonic acid mobilization and incorporation of the fatty acid into phospholipids, thus providing additional evidence for the key role that iPLA2 plays in these events. Long-term exposure of the cells to hydrogen peroxide resulted in cell death by apoptosis, and this process was accelerated in the iPLA2-overexpressing cells. Increased phospholipid hydrolysis and fatty acid release also occurred in these cells. Unexpectedly, however, abrogation of U937 cell iPLA2 activity by either methyl arachidonyl fluorophosphonate or an antisense oligonucleotide did not delay or decrease the extent of apoptosis induced by hydrogen peroxide. These results indicate that, although iPLA2-mediated phospholipid hydrolysis occurs during apoptosis, iPLA2 may actually be dispensable for the apoptotic process to occur. Thus, beyond a mere destructive role, iPLA2 may play other roles during apoptosis.

Apoptosis↗
PubMed1989

Arachidonic acid and other fatty acids directly activate potassium channels in smooth muscle cells.

Arachidonic acid, as well as fatty acids that are not substrates for cyclooxygenase and lipoxygenase enzymes, activated a specific type of potassium channel in freshly dissociated smooth muscle cells. Activation occurred in excised membrane patches in the absence of calcium and all nucleotides. Therefore signal transduction pathways that require such soluble factors, including the NADPH-dependent cytochrome P450 pathway, do not mediate the response. Thus, fatty acids directly activate potassium channels and so may constitute a class of signal molecules that regulate ion channels.

Animals↗
PubMedDate not supplied

[Long-term effect of polyenic-fatty-acids-enriched diet on the relations of fatty acids and glycerophospholipids in 50- to 60-year-old HLP patients].

Seventy-seven patients (twenty-nine males and forty-eight females aged fifty to sixty) with primary HLP type IIa, IIb, IV were treated for eight months with polyenic fatty acids enriched metabolic basis diet. Gas chromatographic analyses of the fatty acid pattern of glycerophospholipids were carried out in 4-monthly intervals. It was found an increase of polyenic fatty acids and a decrease of saturated and monoenic fatty acids in all three types of HLP. Polyenic fatty acids enriched metabolic basis diet influences favourable atherogenic fatty acids constellations of the glycerophospholipids.

Age Factors↗
PubMed1990

Effects of dietary supplementation with n-3 fatty acids on kidney morphology and the fatty acid composition of phospholipids and triglycerides from mice with polycystic kidney disease.

The DBA/2FG-pcy strain of mouse has been developed as an animal model for adult polycystic kidney disease and we have determined the effects of feeding an n-3 fatty acid-enriched diet on kidney morphology and the fatty acid compositions of the constituent phospholipid and triglyceride fractions in this strain. Twelve male and female DBA/2FG-pcy mice were fed lab chow or semi-purified diets containing sunflower seed oil (SO) or a n-3 fatty acid-enriched concentrate (MaxEPA) for 60 days. At necropsy, blood and urine samples were taken and the kidneys processed for examination by light microscopy. Gas-liquid chromatography of the fatty acids in the kidney lipids was also performed. Male and female mice fed the MaxEPA-based diet tended to have lower mean kidney weights. Hematocrits, blood urea, and serum creatinine levels were similar among the lab chow-, SO- and MaxEPA-fed groups. All the groups exhibited a moderate hematuria; the incidence of this symptom was lowest in the MaxEPA-fed male animals. Extensive tubular dilatation was apparent in the cortices and medullae from the lab chow-fed animals; these lesions were slightly less severe in the SO-fed group and least severe in kidneys from the MaxEPA-fed animals. By morphometry, the renal area occupied by cysts was also lowest in the male Max-EPA-fed group; females fed the MaxEPA-based diet did not show a marked decrease in the proportion of kidney area occupied by cysts. Fatty acid compositions of the total phospholipid and triglyceride fractions from kidneys of male mice fed the MaxEPA-based diet showed a reciprocal replacement of the n-6 fatty acids with the n-3 fatty acids compared to kidneys from males fed the SO-based diet.

Animals↗
PubMed1999

Methylated eicosapentaenoic acid and tetradecylthioacetic acid: effects on fatty acid metabolism.

We introduced methyl or ethyl groups to the 2- or 3-position of the eicosapentaenoic acid (EPA) molecule to investigate whether the branching of EPA could influence its hypolipidemic effect in rats. The most effective branching involved two methyl groups in the 2-position and one methyl group in the 3-position. These EPA derivatives increased hepatic mitochondrial and peroxisomal beta-oxidation and decreased plasma lipids concomitant with suppressed acetyl-coenzyme A (CoA) carboxylase (EC 6.4.1.2) and fatty acid synthase (EC 2.3.1.85) activities. This was followed by elevated activities of camitine O-palmitoyltransferase (EC 2.3.1.21) and possibly 2,4-dienoyl-CoA reductase (EC 1.3.1.34), as well as induced mRNA levels of these enzymes and fatty acyl-CoA oxidase. The fatty acid composition in liver changed, with an increased 18:1 n-9 content, whereas the expression of delta9-desaturase remained unchanged. We investigated the flux of fatty acids in cultured hepatocytes, and found that oxidation of [1-14C]-labeled palmitic acid increased but the secretion of palmitic acid-labeled triglycerides decreased after addition of 2-methyl-EPA. The fatty acyl-CoA oxidase (EC 1.3.3.6) activity in these cells remained unchanged. A significant negative correlation was obtained between palmitic acid oxidation and palmitic acid-labeled synthesized triglycerides. To investigate whether the hypolipidemic effect occurred independently of induced peroxisomal beta-oxidation, we fed rats 2-methyl-tetradecylthioacetic acid. This compound increased the peroxisomal but not the mitochondrial beta-oxidation, and the plasma lipid levels were unchanged. In conclusion, EPA methylated in the 2- or 3-position renders it more potent as a hypolipidemic agent. Furthermore, this study supports the hypothesis that the mitochondrion is the primary site for the hypolipidemic effect.

Animals↗