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PubMed1992

Hydrogenation alternatives: effects of trans fatty acids and stearic acid versus linoleic acid on serum lipids and lipoproteins in humans.

The objective of this study was to compare the effects of linoleic acid (cis,cis-C18:2(n-6)) and its hydrogenation products elaidic (trans-C18:1(n-9)) and stearic acid (C18:0) on serum lipoprotein levels in humans. Twenty-six men and 30 women, all normolipemic and apparently healthy, completed the trial. Three experimental diets were supplied to every subject for 3 weeks each, in random order (multiple cross-over). The Linoleate-diet provided 12.0% of total energy intake as linoleic acid, 2.8% as stearic acid, and 0.1% as trans fatty acids. The Stearate-diet supplied 3.9 energy % as linoleic acid, 11.8% stearic acid, and 0.3% trans fatty acids. The Trans-diet provided 3.8 energy % as linoleic acid, 3.0% stearic acid, and 7.7% as monounsaturated trans fatty acids, largely elaidic acid (trans-C18:1(n-9)). Other nutrients were constant. Fasting blood was sampled at the end of each dietary period. Mean (+/- SD) serum LDL cholesterol was 109 +/- 24 mg/dl (2.83 +/- 0.63 mmol/l) on the Linoleate-diet. It rose to 116 +/- 27 mg/dl (3.00 +/- 0.71 mmol/l) on the Stearate-diet (change, 7 mg/dl or 0.17 mmol/l, P = 0.0008) and to 119 +/- 25 mg/dl (3.07 +/- 0.65 mmol/l) on the Trans-diet (change, 9 mg/dl or 0.24 mmol/l, P less than 0.0001). High density lipoprotein (HDL) cholesterol decreased by 2 mg/dl (0.06 mmol/l, P less than 0.0001) on the Stearate-diet and by 4 mg/dl (0.10 mmol/l, P less than 0.0001) on the Trans-diet, both relative to linoleic acid. Our findings show that 7.7% of energy (mean, 24 g/day) of trans fatty acids in the diet significantly lowered HDL cholesterol and raised LDL cholesterol relative to linoleic acid. Combination with earlier results (Mensink, R. P., and M. B. Katan. 1990. N. Engl. J. Med. 323: 439-445) suggests a linear dose-response relation. Replacement of linoleic acid by stearic acid also caused somewhat lower HDL cholesterol and higher LDL cholesterol levels. Hydrogenation of linoleic acid to either stearic or trans fatty acids produces fatty acids that may increase LDL and decrease HDL cholesterol relative to linoleic acid itself.

Adolescent↗

PubMed1993

Effect of ursodeoxycholic acid on the kinetics of cholic acid and chenodeoxycholic acid in patients with primary sclerosing cholangitis.

Treatment of patients with cholestatic liver diseases with ursodeoxycholic acid has been shown to have beneficial effects that may be related to a shift in the balance between hydrophilic and hydrophobic bile acids in favor of hydrophilic bile acids. During treatment of patients with primary sclerosing cholangitis with ursodeoxycholic acid, plasma concentrations of some endogenous bile acids decrease. To test whether the changes in plasma bile acids are due to decreases of their pool sizes or synthesis rates, we determined bile acid kinetics of cholic and chenodeoxycholic acid in six patients with primary sclerosing cholangitis, of whom four also had ulcerative colitis. All patients were studied before and 3 mo after the start of ursodeoxycholic acid treatment. Six healthy subjects served as controls. In patients with primary sclerosing cholangitis, pool sizes of cholic and chenodeoxycholic acid were considerably smaller than those in healthy controls; after ursodeoxycholic acid treatment they were unchanged. Fractional turnover and synthesis of cholic acid increased significantly after ursodeoxycholic acid administration. Fractional turnover of chenodeoxycholic acid also increased significantly, whereas synthesis of this bile acid was unchanged. Our data indicate that in patients with primary sclerosing cholangitis, pool sizes of bile acids are reduced. The decrease of levels of endogenous bile acids in plasma under ursodeoxycholic acid treatment despite unchanged bile acid pool sizes indicates redistribution of the bile acids into the enterohepatic circulation, probably because of improved hepatic clearance after ursodeoxycholic acid treatment.

Adult↗

PubMed2002

Fatty acid signalling in a mouse enteroendocrine cell line involves fatty acid aggregates rather than free fatty acids.

Fatty acids induce cholecystokinin (CCK) secretion both in humans and from murine enteroendocrine cell lines. In both cases, only fatty acids above a critical acyl chain length (C(10)) are capable of inducing a response. Using the enteroendocrine cell line STC-1, the aim of this study was to determine whether this acyl chain length dependency is related to the fact that longer chain fatty acids are relatively insoluble in aqueous solutions and, if so, whether it is insoluble aggregates of fatty acids rather than free fatty acids which evoke CCK secretion. Solutions of fatty acids (chain length C(8)-C(14)), which were judged by filtration and Zeta sizer measurement to contain no fatty acid aggregates, never evoked CCK secretion from STC-1 cells. Filtering fatty acid solutions (of chain length C(10), C(12) and C(14)) through polytetrafluoroethylene (PTFE) filters (0.45 microm pore size) revealed a narrow concentration range for each acid over which the amount of fatty acid removed from the solution increased sharply due to the formation of fatty acid aggregates. Filtration experiments, in which suspensions of C(10), C(12) and C(14) fatty acids were passed through pore sizes of 0.2, 0.45 or 1.2 microm, suggested that STC-1 cells did not respond to fatty acid aggregates of greater than 1.2 microm, while at least 50 % of the CCK response was mediated by aggregates which were smaller than 0.45 microm. Fatty acids induce CCK secretion from STC-1 cells by elevating intracellular Ca(2+) concentration ([Ca(2+)](i)). We therefore measured the effects on [Ca(2+)](i) of filtered C(10), C(12) and C(14) fatty acids. In all cases, [Ca(2+)](i) responses were closely correlated with CCK secretion. Interestingly, while filtrates of fatty acid solutions evoked CCK secretion and elevated [Ca(2+)](i), freshly prepared solutions of fatty acids at the same concentration as the filtrates did not. This suggested that fatty acid aggregates were not in equilibrium with the solvent after filtration. The observation that the ability of C(10), C(12) and C(14) filtrates to elevate [Ca(2+)](i) decayed with time was consistent with this hypothesis. Furthermore, sonication of the filtrates abolished their ability to elevate [Ca(2+)](i). These data further suggest that it is a physical property of the fatty acid solution (the presence of insoluble fatty aggregates) which is responsible for the observed cellular responses. We conclude that Ca(2+) mobilisation and CCK secretion in STC-1 cells is driven by a signal transduction mechanism that senses insoluble fatty acid aggregates, rather than free fatty acids in solution.

Animals↗

PubMed2001

Sensitivity of acid-adapted and acid-shocked Shigella flexneri to reduced pH achieved with acetic, lactic, and propionic acids.

Survival and growth characteristics of unadapted, acid-adapted, and acid-shocked Shigella flexneri 2a cells in acidified (pH 3.5 to 5.5) tryptic soy broth with 0.25% glucose (TSB) and tryptic soy agar (TSA) were determined. S. flexneri was grown at 37 degrees C for 18 h in tryptic soy broth without glucose (TSBNG) (unadapted) and TSBNG supplemented with 1% glucose (TSBG) (acid-adapted). Cells grown in TSBNG were acid shocked by adjusting 16-h cultures to pH 5.05 +/- 0.05 with lactic acid. Cells were then inoculated into TSB acidified with acetic, lactic, or propionic acids to pH 5.5, 4.5, or 3.5 and incubated at 37 degrees C for 6 h. The order of lethality at a given pH was lactic acid < acetic acid < propionic acid. Significantly (P < or = 0.05) higher numbers of acid-adapted cells, compared to acid-shocked and unadapted cells, were recovered from TSB acidified (pH 3.5) with lactic or acetic acids. None of the cells survived a 30-min exposure in TSB acidified with propionic acid to pH 3.5. When the three cell types were plated on TSA acidified with lactic, acetic, or propionic acids at pH < or = 4.5, < or = 5.5, and < or = 5.5, respectively, visible colonies were not detected. Viable unadapted, acid-adapted, and acid-shocked cells were, however, recovered from TSA acidified with all three acids at pH > or = 4.5. Acid-adapted and, to a lesser extent, acid-shocked cells survived at lower pH than did unadapted cells, indicating that prior exposure to mild acidic environment results in increased acid resistance. Survival of S. flexneri at a given pH was influenced by the type of acidulant used, a response characteristic exhibited by other gram-negative enteric pathogens.

Acetic Acid↗

PubMed1972

Properties of maedi nucleic acid and the presence of ribonucleic acid- and deoxyribonucleic acid-dependent deoxyribonucleic acid polymerase in the virions.

Maedi virus contains a ribonucleic acid (RNA) which can be resolved into three major components, namely, 62S, 33S, and 13S, by sucrose gradient centrifugation. The presence of RNA- and deoxyribonucleic acid (DNA)-dependent DNA polymerase in virions of maedi virus was demonstrated. The enzyme product could be converted into acid-soluble form by pancreatic deoxyribonuclease, but was resistant to digestion by pancreatic ribonuclease and to hydrolysis by NaOH.

Animals↗

PubMed1998

Monounsaturated trans fatty acids, elaidic acid and trans-vaccenic acid, metabolism and incorporation in phospholipid molecular species in hepatocytes.

The incorporation of [14C]elaidic acid (trans18:1(n-9)) in phosphatidylcholine and phosphatidylethanolamine molecular species in isolated rat liver cells has been studied, and the results compared with the incorporation, previously published (B. Woldseth et al. Biochim Biophys Acta 1993; 1167: 296-302), of [14C]palmitic acid (16:0) and [14C]stearic acid (18:0) and with that of [14C]oleic acid (cis18:1(n-9)). The pattern of incorporation in phospholipid molecular species is similar to that of [14C]stearic acid and different from that of [14C]palmitic acid. In phosphatidylcholine [14C]trans18:1-18:2 and [14C]trans18:1-20:4 were the most abundant species, and in phosphatidylethanolamine [14C]trans18:1-20:4 was the predominant species. With increasing concentration of [14C]elaidic acid increasing amounts of [14C]trans18:1-[14C]trans18:1 were found. The total incorporation in phospholipids was less than that of [14C]stearic acid, but more than that of [14C]palmitic acid. The distribution in percent of [14C]elaidic acid in phospholipid classes was 8.8% in phosphatidylinositol, 1.8% in phosphatidylserine, 59.1% in phosphatidylcholine and 30.3% in phosphatidylethanolamine with 0.1 mmol l-1 substrate concentration. More [14C]elaidic acid than [14C]palmitic acid or [14C]stearic acid was oxidized. The incorporation in phospholipids of [14C]elaidic acid was very different from that of [14C]oleic acid. The main species with [14C]oleic acid were 16:0-[14C]cis18:1 in phosphatidylcholine, and [14C]cis18:1-20:4 in phosphatidylethanolamine. In some experiments [14C]18:2(n-6) was incubated together with unlabelled elaidic or unlabelled trans-vaccenic acid (trans18:1(n-7)). In these experiments, more trans18:1-18:2 was formed from elaidic acid than from trans-vaccenic acid, especially in phosphatidylethanolamine.

Animals↗

PubMed1980

Metabolism of linoleic and arachidonic acids in VX2 carcinoma tissue: identification of monohydroxy octadecadienoic acids and monohydroxy eicosatetraenoic acids.

The metabolism of arachidonic and linoleic acids by VX2 carcinoma tissue in vitro was determined. Prostaglandin E2 was the major metabolic product of arachidonic acid in the neoplastic tissue. Minor products accounting for 3- 8% of arachidonic acid metabolism were II-hydroxy-5, 8, 12, 14-eicosatetraenoic acid (II-HETE) and 15-hydroxy-5, 8, 11, 13-eicosatetraenoic acid (15-HETE). Linoleic acid was converted to a mixture of 9-hydroxy-10, 12-octadecadienoic acid (9-HODD) and 13-hydroxy-9, 11-octadecadienoic acid (13-HODD). The conversion of linoleic acid to monohydroxy C-18 fatty acids varied from 40-80% 9-HODD and 20-60% 13-HODD in tumor tissue harvested from different animals. The quantity of monohydroxy C-18 fatty acids biosynthesized by VX2 carcinoma tissue from endogenous linoleic acid equals or exceeds that of prostaglandin E2 biosynthesis from endogenous arachidonic acid. The presence of a hydroxyl group adjacent to a conjugated diene suggest that the monohydroxy C-18 and monohydroxy C-20 fatty acids were formed via the action of lipoxygenase-like enzymes. These lipoxygenase-like reactions are inhibited by indomethacin in a concentration-dependent fashion similar to the inhibition of prostaglandin E2 biosynthesis. The enzymes catalyzing the lipoxygenase-like reactions of linoleic and arachidonic acids are localized in the microsomal fraction of VX2 carcinoma tissue. These data suggest that the lipoxygenase-like reactions are catalyzed by fatty acid cyclooxygenase and that there are two major pathways of fatty acid cyclooxygenase metabolism of polyenoic fatty acids in the neoplastic tissue. One pathway involves the formation of prostaglandin E2 via cyclic endoperoxy intermediates. The second pathway involves the formation of monohydroxy C-18 fatty acids from linoleic acid via lipoxygenase-like reactions.

Animals↗

PubMed1999

In contrast with docosahexaenoic acid, eicosapentaenoic acid and hypolipidaemic derivatives decrease hepatic synthesis and secretion of triacylglycerol by decreased diacylglycerol acyltransferase activity and stimulation of fatty acid oxidation.

Hypolipidaemic fatty acid derivatives and polyunsaturated fatty acids decrease concentrations of plasma triacylglycerol by mechanisms that are not fully understood. Because poor susceptibility to beta- and/or omega-oxidation is apparently a determinant of the peroxisome proliferating and hypolipidaemic capacity of fatty acids and derivatives, the relative importance of activation of the peroxisome-proliferator-activated receptor alpha (PPARalpha), fatty acid oxidation and triacylglycerol synthesis were examined. We have compared the effects of differentially beta-oxidizable fatty acids on these parameters in primary cultures of rat hepatocytes. Tetradecylthioacetic acid (TTA), 2-methyleicosapentaenoic acid and 3-thia-octadecatetraenoic acid, which are non-beta-oxidizable fatty acid derivatives, were potent activators of a glucocorticoid receptor (GR)-PPARalpha chimaera. This activation was paradoxically reflected in an substantially increased oxidation of [1-(14)C]palmitic acid and/or oleic acid. The incorporation of [1-(14)C]palmitic acid and/or oleic acid into cell-associated and secreted triacylglycerol was decreased by 15-20% and 30% respectively with these non-beta-oxidizable fatty acid derivatives. The CoA ester of TTA inhibited the esterification of 1, 2-diacylglycerol in rat liver microsomes. Both eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) activated GR-PPARalpha. EPA increased the oxidation of [1-(14)C]palmitic acid but DHA had no effect. The CoA ester of EPA inhibited the esterification of 1, 2-diacylglycerol, whereas DHA-CoA had no effect. The ratio between synthesized triacylglycerol and diacylglycerol was lower in hepatocytes cultured with EPA in the medium compared with DHA or oleic acid, indicating a decreased conversion of diacylglycerol to triacylglycerol. Indeed, the incorporation of [1-(14)C]oleic acid into secreted triacylglycerol was decreased by 20% in the presence of EPA. In conclusion, a decreased availability of fatty acids for triacylglycerol synthesis by increased mitochondrial beta-oxidation and decreased triacylglycerol formation caused by inhibition of diacylglycerol acyltransferase might explain the hypolipidaemic effect of TTA and EPA.

Acyltransferases↗

PubMed2000

Dietary marine fatty acids (fish oil) for asthma.

BACKGROUND: Epidemiological studies suggest that a diet high in marine fatty acids (fish oil) may have beneficial effects on inflammatory conditions such as rheumatoid arthritis and possibly asthma. OBJECTIVES: 1. To determine the effect of marine n-3 fatty acid (fish oil) supplementation in asthma. 2. To determine the effect of a diet high in fish oil in asthma. SEARCH STRATEGY: The Cochrane Airways Review Group register was search using the terms: marine fatty acids OR diet OR nutrition OR fish oil OR eicosapentaenoic acid OR EPA. Bibliographies of retrieved trials were searched and fish oil manufacturers contacted. SELECTION CRITERIA: Randomised controlled trials in patients with asthma more than two years of age were included. The study duration had to be in excess of 4 weeks. Double blind trials were preferred, but single-blind and open trials were also reviewed for possible inclusion. Three reviewers read each paper, blind to its identity. Decisions concerning inclusion were made by simple majority. Quality assessment was performed by all three reviewers independently. DATA COLLECTION AND ANALYSIS: The only comparison possible was between marine n-3 fatty acid supplementation and placebo. There were insufficient trials to examine dietary manipulation alone. MAIN RESULTS: Eight randomised controlled trials conducted between 1986 and 1998 satisfied the inclusion criteria. Six were of parallel design and two were cross-over studies. Seven compared fish oil with placebo whilst one compared high dose vs low dose marine n-3 fatty acid supplementation. None of the included studies reported asthma exacerbations, health status or hospital admissions. There was no consistent effect on any of the analyzable outcomes: FEV1, peak flow rate, asthma symptoms, asthma medication use or bronchial hyper reactivity. The single study performed in children also combined dietary manipulation with fish oil supplementation and showed improved peak flow and reduced asthma medication use. There were no adverse events associated with fish oil supplements. REVIEWER'S CONCLUSIONS: There is little evidence to recommend that people with asthma supplement or modify their dietary intake of marine n-3 fatty acids (fish oil) in order to improve their asthma control. Equally, there is no evidence that they are at risk if they do so.

Adult↗

PubMed1997

Up-regulated delta 9-desaturase gene expression by hypolipidemic peroxisome-proliferating fatty acids results in increased oleic acid content in liver and VLDL: accumulation of a delta 9-desaturated metabolite of tetradecylthioacetic acid.

In the liver of rats, monocarboxylic 3-thia fatty acids, tridecylthioacetic acid (C13-S-acetic acid) and tetradecylthioacetic acid (C14-S-acetic acid), increase the mRNA levels of delta 9-desaturase both in a time- and dose-dependent manner. The increased delta 9-desaturase mRNA levels were accompanied by increased delta 9-desaturase activity and increased amounts of oleic acid (18:1 n-9) and delta 9-desaturated C14-S-acetic acid. delta 9-Desaturated C14-S-acetic acid was only detected in phospholipid and cholesterolester species after C14-S-acetic acid treatment. In contrast, C14-S-acetic acid was detected in all the different hepatic lipid fractions, but mainly in the phospholipids. Moreover, C13-S-acetic acid and C14-S-acetic acid were detected in both liver and very low density lipoprotein (VLDL). No delta 9-desaturated 3-thia fatty acid products, however, were found in VLDL. Administration of mono- and dicarboxylic 3-thia fatty acids to rats induced liver expression of the fatty acyl-CoA oxidase gene. After 1 week of C14-S-acetic acid treatment, the levels of fatty acyl-CoA oxidase mRNA increased 5-fold, whereas the delta 9-desaturase mRNA was increased about 1.8-fold. Both fatty acyl-CoA oxidase and delta 9-desaturase mRNA increased about 8-fold after 12 weeks of treatment with C14-S-acetic acid. In conclusion, this study demonstrates that C14-S-acetic acid increases rat delta 9-desaturase gene expression and activity and that changes in hepatic lipids, e.g., 18:1 n-9, are reflected in the VLDL. The peroxisome-proliferating monocarboxylic thia fatty acids are good substrates for desaturases, as delta 9-desaturated metabolites of monocarboxylated thia acids were formed in the liver. Modification of delta 9-desaturation, however, appears not to be related to peroxisome proliferation.

Acyl-CoA Oxidase↗

PubMed1979

Pattern of aliphatic dicarboxylic acids in uremic serum including a new organic acid, 2,4-dimethyladipic acid.

(1) 2,4-Dimethyladipic acid was first identified in normal human urine using gas chromatography-mass spectrometry. Urinary excretion of 2,4-dimethyladipic acid in 7 healthy adults ranged from 4.9 mumol to 14 mumol per 24 h. (2) Succinic acid, adipic acid, 3-methyladipic acid, 2,4-dimethyladipic acid, pimelic acid and azelaic acid were identified in the ultrafiltrate of the blood obtained from a chronic uremic patient using a hemodialyzer. (3) Levels of succinic acid, adipic acid, 3-methyladipic acid, 2,4-dimethyladipic acid, pimelic acid and azelaic acid in uremic serum were determined using a mass fragmentographic technique. Concentration of succinic acid in uremic serum was comparable to that in normal serum, whereas concentrations of adipic acid, 3-methyladipic acid, 2,4-dimethyladipic acid, pimelic acid and azelaic acid were highly elevated in uremic serum.

Adipates↗

PubMed1985

Synthesis of potential cholelitholytic agents: 3 alpha,7 alpha,12 alpha-trihydroxy-7 beta-methyl-5 beta-cholanoic acid, 3 alpha,7 beta,12 alpha-trihydroxy-7 alpha-methyl-5 beta-cholanoic acid, and 3 alpha,12 alpha-dihydroxy-7 xi-methyl-5 beta-cholanoic acid.

This report describes the chemical synthesis of six new bile acid analogs, namely, 3 alpha,7 alpha,12 alpha-trihydroxy-7 beta-methyl-5 beta-cholanoic acid (7 beta-methyl-cholic acid), 3 alpha,7 beta,12 alpha-trihydroxy-7 alpha-methyl-5 beta-cholanoic acid (7 alpha-methyl-ursocholic acid), 3 alpha,12 alpha-dihydroxy-7 xi-methyl-5 beta-cholanoic acid (7 xi-methyl-deoxycholic acid), 3 alpha,12 alpha-dihydroxy-7-methyl-5 beta-chol-7-en-24-oic acid, 3 alpha,12 alpha-dihydroxy-7-methyl-5 beta-chol-6-en-24-oic acid, and 3 alpha,12 alpha-dihydroxy-7-methylene-5 beta-cholan-24-oic acid. The carboxyl group of the starting material 3 alpha,12 alpha-dihydroxy-7-oxo-5 beta-cholanoic acid was protected by conversion to its oxazoline derivative. A Grignard reaction of the bile acid oxazoline with CH3MgI followed by acid hydrolysis gave two epimeric trihydroxy-7-methyl-cholanoic acids and three dehydration products. The latter were purified by silica gel column chromatography and silica gel-AgNO3 column chromatography of their methyl ester derivatives. Catalytic hydrogenation of 3 alpha,12 alpha-dihydroxy-7-methyl-5 beta-chol-6-en-24-oic acid and 3 alpha,12 alpha-dihydroxy-7-methylene-5 beta-cholan-24-oic acid gave 3 alpha,12 alpha-dihydroxy-7 xi-methyl-5 beta-cholanoic acid. The configuration of the 7-methyl groups and the position of the double bonds were assigned by proton nuclear magnetic resonance spectroscopy and the chromatographic and mass spectrometric properties of the new compounds. These compounds were synthesized for the purpose of exploring new and potentially more effective cholelitholytic agents. The hydrophilic bile acids 7 beta-methyl-cholic acid and 7 alpha-methyl-ursocholic acid are of particular interest because they should be resistant to bacterial 7-dehydroxylation.

Cholelithiasis↗

PubMed1990

High branched-chain alpha-keto acid intake, branched-chain alpha-keto acid dehydrogenase activity, and plasma and brain amino acid and plasma keto acid concentrations in rats.

Diets containing high quantities of individual branched-chain alpha-keto acids (BCKAs) or a combination of BCKAs as used for treatment of renal disease were fed to rats. When the diet contained a single BCKA, its concentration was high in plasma and the concentration of its corresponding amino acid was high in plasma and brain. Liver BCKA dehydrogenase (BCKD) was 42% active in control rats. Consumption of diets containing 0.38 mol/kg diet of alpha-ketoisocaproate (KIC), alpha-keto-beta-methylvalerate (KMV), or alpha-ketoisovalerate (KIV) resulted in complete activation of liver BCKD. Consumption of the diet containing the combination of BCKAs increased basal BCKD activity of liver twofold. Muscle BCKD was activated after feeding the KIV diet (2-fold), the KIC diet (3-fold), and the KMV diet (15-fold). Total BCKD activity of liver and muscle was unaffected by dietary treatments. Activation of liver and muscle BCKD by dietary BCKA is consistent with their ability to inhibit BCKD kinase in vitro.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗

PubMed1998

Postprandial decrease in plasma unesterified fatty acids during n-3 fatty acid feeding is not caused by accumulation of fatty acids in adipose tissue.

Dietary supplementation of very long-chain n-3 fatty acids to rats reduces postprandial plasma concentrations of triacylglycerol, unesterified fatty acids and glycerol after long-term feeding by unknown mechanisms [Rustan et al., J. Lipid Res. 34 (1993) 1299-1309]. In the present study we examine the role of adipose tissues in metabolism of fatty acids. Postprandial plasma concentrations of triacylglycerol, unesterified fatty acids and glycerol were reduced by 75%, 50% and 30%, respectively, during 49 days of feeding high-fat diets containing n-3 fatty acids (6.5% n-3 fatty acid concentrate, 13% lard) as compared to lard (19.5% lard). These differences were observed already after two days of feeding. Plasma concentration of unesterified very long-chain n-3 fatty acids increased to 50 microM in n-3 fatty acid-supplemented rats, whereas these fatty acids were undetectable in lard-fed animals. The n-3 fatty acid-enriched diet limited cell volumes of perirenal and epididymal adipocytes by 40% and 30%, respectively, after 49 days, as compared to lard feeding. This reduction in cell volume was not due to reduced synthesis of glycerolipids in epididymal adipocytes. Acute incubation of perirenal and epididymal adipocytes with oleic acid or eicosapentaenoic acid, caused similar increase in synthesis of triacylglycerol. Dietary supplementation with n-3 fatty acids decreased basal and total lipolysis (isoprenalin-stimulated) in perirenal adipocytes. Basal lipolysis in epididymal adipocytes was reduced by n-3 fatty acids only after 49 days. n-3 fatty acids increased total lipolysis in mesenteric and subcutaneous fat cells compared to adipocytes derived from lard-fed animals, whereas basal lipolysis was unchanged. These results suggest that the reduced postprandial plasma concentration of unesterified fatty acids after n-3 fatty acid-supplementation is not caused by accumulation of fatty acids in adipose tissue. The reduced trophic growth of adipocytes might be due to decreased supply of unesterified fatty acids for triacylglycerol storage. (c) 1998 Elsevier Science B.V.

Adipose Tissue↗

PubMed1991

Physiological occurrence, biosynthesis and metabolism of retinoic acid: evidence for roles of cellular retinol-binding protein (CRBP) and cellular retinoic acid-binding protein (CRABP) in the pathway of retinoic acid homeostasis.

This article will address recent work on the physiological occurrence, biogenesis and metabolism of retinoic acid and summarize the data that retinoic acid is synthesized in situ in multiple tissues and cell types via enzymes or enzyme complexes that are distinct from the alcohol dehydrogenases. There is now considerable evidence that retinoic acid is an activated metabolite of retinol that supports the systemic functions of vitamin A in vivo. Many studies in vitro, for example, have shown that retinoic acid is the most potent naturally-occurring retinoid with an ED-50 in the range of 1 pM to 10 nM, depending on the assay system. This is below the tissue concentrations of retinoic acid which range from approximately 20-600 nM. Retinoic acid synthesis from retinol in the dog kidney cell line MDCK maintained in serum-free medium is inhibited by the prostanoid, PGE, and the phorbol ester, TPA. In tissues, one pathway of retinoic acid synthesis begins with apo-CRBP stimulating retinyl ester hydrolysis by a microsomal, cholate-independent retinyl ester hydrolase to form holo-CRBP. The holo-CRBP itself is used as substrate by an NADP-dependent, microsomal retinol dehydrogenase to generate retinal, which is converted into retinoic acid by a cytosolic NAD-dependent retinal dehydrogenase. Therefore, cellular retinol-binding protein (CRBP) apparently has at least 2 functions in retinoic acid synthesis: the apo form stimulates retinol mobilization from retinyl ester stores; the holo form delivers the retinol via direct transfer to dehydrogenase(s). Retinoic acid is converted into a mixture of at least 4 metabolites by testes microsomes which migrate closely on reverse-phase HPLC with 4-hydroxyretinoic acid, and may be mistaken for either 4-hydroxy or 4-oxo-retinoic acid. More rigorous analysis, however, shows that only one of them is 4-hydroxyretinoic acid, and another is 18-hydroxyretinoic acid. Two others remain unidentified. These metabolites are also formed in the presence of excess cellular retinoic acid-binding protein (CRABP), which increases the elimination half-life of retinoic acid, but does not prevent retinoic acid catabolism, suggesting that holo-CRABP may be a substrate for retinoic acid catabolism that modulates the steady-state concentrations of retinoic acid. Thus, both retinoid binding proteins, CRBP and CRABP, may each have direct roles as substrate in the biosynthesis and metabolism of retinoic acid, respectively.

Carrier Proteins↗

PubMed1988

Localization of quinolinic acid metabolizing enzymes in the rat brain. Immunohistochemical studies using antibodies to 3-hydroxyanthranilic acid oxygenase and quinolinic acid phosphoribosyltransferase.

Specific antibodies raised in rabbits against 3-hydroxyanthranilic acid oxygenase (EC 1.13.11.6) and quinolinic acid phosphoribosyltransferase (EC 1.13.11.6) and quinolinic acid phosphoribosyltransferase (EC 2.4.2.19) were used in immunohistochemical studies to map the cellular localization of the quinolinic acid metabolizing enzymes in the adult male rat brain. 3-Hydroxyanthranilic acid oxygenase immunoreactivity was found to be present in glial cells of presumed astroglial identity, as judged by co-localization with glial fibrillary acidic protein. 3-Hydroxyanthranilic acid oxygenase-immunoreactive glial cells were present in all brain regions and within major fiber tracts. The density of 3-hydroxyanthranilic acid oxygenase-immunoreactive glial cells as well as the intensity of staining of these cells differed among brain regions. In general, telencephalic acid diencephalic areas harbored a larger number of 3-hydroxyanthranilic acid oxygenase-positive cells than did mesencephalic regions. In the former regions the caudate nucleus, septum, nucleus accumbens, neocortex and hippocampus were particularly enriched in 3-hydroxyanthranilic acid oxygenase-immunoreactive cells. In the thalamus, regional differences were noted with regard to the intensity of staining among glial cells with high densities of 3-hydroxyanthranilic acid oxygenase cells in the anteroventral, reticular and ventromedial nuclei. In the inferior and superior colliculi, numerous 3-hydroxyanthranilic acid oxygenase-positive glial cells were found in all layers. In the hypothalamus, 3-hydroxyanthranilic acid oxygenase-immunoreactive glial cells were encountered in the zona incerta, the lateral hypothalamic area, the caudal preoptic region and in the dorsomedial nucleus. In the mesencephalon, the substantia nigra contained numerous, moderately stained cells. At caudal levels of the brain-stem, a relatively large number of cells was detected in the nucleus of the solitary tract, the pontine nucleus and in the fascial nerve nucleus, while other nuclei, such as the reticular formation and the area postrema were relatively poor in 3-hydroxyanthranilic acid oxygenase-immunoreactive cells. In addition to staining of glial cells, neuronal cell bodies containing 3-hydroxyanthranilic acid oxygenase immunoreactivity were detected in the main and in the accessory olfactory bulb, as well as in the ventromedial nucleus of the hypothalamus. Quinolinic acid phosphoribosyltransferase immunoreactivity was observed within glial cells and in association with neuronal cell bodies. Some, but not all, quinolinic acid phosphoribosyltransferase positive glial cells contained glial fibrillary acidic protein (Köhl

3-Hydroxyanthranilate 3,4-Dioxygenase↗

PubMed2000

Intracellular accumulation of ascorbic acid is inhibited by flavonoids via blocking of dehydroascorbic acid and ascorbic acid uptakes in HL-60, U937 and Jurkat cells.

In HL-60, U937 and Jurkat cells, the intracellular accumulation of ascorbic acid occurred via uptakes of both dehydroascorbic acid (an oxidized metabolite of ascorbic acid) and ascorbic acid (vitamin C). Dehydroascorbic acid and ascorbic acid were transported into cells by sodium-independent glucose transporters (GLUT 1 and GLUT 3) and sodium-dependent ascorbic acid transporters, respectively. Flavonoids inhibited the intracellular accumulation of ascorbic acid by blocking dehydroascorbic acid and ascorbic acid uptakes in the transformed cells. At flavonoid concentrations of 10-70 micromol/L, approximately 50% of dehydroascorbic acid uptake was inhibited in the cells. In Jurkat cells, two potent flavonoids (myricetin and quercetin) competitively inhibited dehydroascorbic acid uptake, and K(i) values were approximately 14 and 15 micromol/L, respectively. Because GLUT 1 and GLUT 3 transport dehydroascorbic acid, the inhibition of dehydroascorbic acid uptake by flavonoids was investigated by using Chinese hamster ovary cells overexpressing rat GLUT 1 or human GLUT 3. Myricetin at concentrations of 22 and 18 micromol/L, respectively, inhibited half of dehydroascorbic acid uptake in the cells overexpressing GLUT 1 and GLUT 3. Myricetin also inhibited ascorbic acid uptake; inhibition was noncompetitive with K(i) = 14 micromol/L in Jurkat cells. These data indicate that flavonoids inhibit both ascorbic acid and dehydroascorbic acid uptake but do so by different mechanisms. These data may contribute to new understanding of the biological effect of flavonoids on the intracellular accumulation of ascorbic acid in human cells.

Animals↗

PubMed1987

Simultaneous determination of pool sizes and fractional turnover rates, of deoxycholic acid, cholic acid and chenodeoxycholic acid in man by isotope dilution with 2H and 13C labels and serum sampling.

This paper describes a method for simultaneous determination of the kinetics of the three major bile acids in man using (2,2,4,4-2H4) deoxycholic acid, (24-13C) cholic acid and (24-13C) chenodeoxycholic acid. The gas chromatographic/mass spectrometric-selected ion monitoring technique used provided complete separation of deoxycholic acid, cholic acid and chenodeoxycholic acid, which permitted simultaneous measurement of isotope ratios for all three bile acids. Since measurement of all three pool sizes and fractional turnover rates in a single experiment requires different isotopic labels for deoxycholic acid and cholic acid, we investigated the in vivo stability and applicability of (2,2,4,4-2H4) deoxycholic acid as a stable isotope marker for isotope dilution studies in man. No consistent differences were observed between deoxycholic acid pool sizes and fractional turnover rates determined in serum samples after administration of (2,2,4,4-2H4) deoxycholic acid and (24-13C) deoxycholic acid. Simultaneous administration of (2,2,4,4-2H4) deoxycholic acid, (24-13C) cholic acid and (24-13C) chenodeoxycholic acid and isotope ratio measurements in serum permitted determination of pool sizes and fractional turnover rates of the three major bile acid and the 7 alpha-dehydroxylation fraction. Pool sizes, fractional turnover rates and synthesis rates (input rates) agreed well with data obtained previously with (24-13C) labels in independent studies.

Carbon Isotopes↗