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1.
J Lipid Res ; 42(5): 743-50, 2001 May.
Article in English | MEDLINE | ID: mdl-11352981

ABSTRACT

Supplementation with n-3 polyunsaturated fatty acids (PUFA) for 6 weeks did not alter plasma leptin concentrations in male smokers. Changes in dietary intake of saturated fatty acids (FA) correlated positively, whereas changes in the intake of PUFA correlated negatively to changes in plasma leptin levels. A 3-week n-3 PUFA-enriched diet, as compared with a 3-week lard-enriched diet, induced lower plasma leptin concentration and reduced leptin mRNA expression in rat epididymal adipose tissue. In the human trophoblast cell line (BeWo), n-3 PUFA had a dose- and time-dependent effect on leptin expression. One mM of eicosapentaenoic acid or docosahexaenoic acid (DHA) reduced leptin expression by 71% and 78%, respectively, as compared with control, after 72 h. There was no effect on expression of the signal transducing form of the leptin receptor. In BeWo cells transfected with the human leptin promoter, we found that n-3 PUFA reduced leptin promoter activity; in contrast saturated and monounsaturated FA had no effect on leptin promoter activity. The transcription factors peroxysomal proliferator activated receptor gamma and sterol regulatory element binding protein-1 mRNAs were reduced after incubation with n-3 PUFA, whereas the expression of CCAAT/enhancer binding protein alpha was unchanged. DHA-reduced leptin expression was abolished in BeWo cells grown in cholesterol-free medium. In conclusion, n-3 FA decreased leptin gene expression both in vivo and in vitro. The direct effects of PUFA on leptin promoter activity indicate a specific regulatory action of FA on leptin expression.


Subject(s)
Adipose Tissue/metabolism , Dietary Fats, Unsaturated/administration & dosage , Fatty Acids/pharmacology , Gene Expression Regulation , Leptin/blood , Leptin/genetics , Receptors, Cell Surface , Adult , Animals , Antioxidants/administration & dosage , Body Weight , CCAAT-Enhancer-Binding Proteins/genetics , CCAAT-Enhancer-Binding Proteins/metabolism , Carrier Proteins/genetics , Carrier Proteins/metabolism , Cell Line , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Dietary Fats, Unsaturated/metabolism , Dietary Fats, Unsaturated/pharmacology , Double-Blind Method , Epididymis , Fatty Acids/metabolism , Humans , Infant , Leptin/metabolism , Male , Middle Aged , Promoter Regions, Genetic , Rats , Rats, Wistar , Receptors, Cytoplasmic and Nuclear/genetics , Receptors, Cytoplasmic and Nuclear/metabolism , Receptors, Leptin , Smoking , Sterol Regulatory Element Binding Protein 1 , Transcription Factors/genetics , Transcription Factors/metabolism , Transfection
2.
Ann Nutr Metab ; 45(1): 30-7, 2001.
Article in English | MEDLINE | ID: mdl-11244185

ABSTRACT

Long-chain n-3 fatty acids and fat fish are reported, among multiple physiological properties, to enhance peroxisomal beta-oxidation and effect triacylglycerol status. Long-chain n-3 and monounsaturated fatty acids are the main portion of fatty acids in fat fish. The individual effect of long-chain monounsaturated fatty acids on beta-oxidation and fatty acid composition was tested and compared to the effect of n-3 polyunsaturated and saturated fatty acids in a 3-week feeding experiment of rats. To explore the contribution from long-chain monounsaturated fatty acids in these aspects, the effect of long-chain n-3 and monounsaturated fatty acids on mitochondrial and peroxisomal beta-oxidation was compared, as well as fatty acid composition of adipose tissue, liver and serum. Fatty acid oxidase, palmitoyltransferase I and II activities, the amount of serum lipids, and the fatty acid composition of lipid fractions from the organs were analysed. The peroxisomal beta-oxidation was enhanced by the n-3 fatty acids, whereas a small, significant increase with the monounsaturated fatty acids was observed. There was a stimulation of the mitochondrial oxidation with the n-3 fatty acids, but monounsaturated fatty acids gave a small, nonsignificant decrease. With n-3 fatty acids there was a considerable decrease in the levels of serum triacylglycerol, phospholipids, free fatty acids and total cholesterol, while there were only minor effects of monounsaturated fatty acids. As judged from the fatty acid composition data, there was a mobilization on n-3 fatty acids from the adipose tissue to liver and plasma with the n-3 diet. This observation was also seen with the monounsaturated fatty acid-enriched diet. In conclusion, monounsaturated fatty acids seemed to stimulate peroxisomal beta-oxidation and to increase plasma triacylglycerol, whereas the mitochondrial oxidation was slightly decreased.


Subject(s)
Adipose Tissue/metabolism , Fatty Acids, Monounsaturated/pharmacology , Fatty Acids, Omega-3/pharmacology , Lipids/blood , Liver/metabolism , 3-Hydroxyacyl CoA Dehydrogenases/metabolism , Acetyl-CoA C-Acyltransferase/metabolism , Animals , Carbon-Carbon Double Bond Isomerases/metabolism , Carnitine O-Palmitoyltransferase/metabolism , Enoyl-CoA Hydratase/metabolism , Fatty Acids, Monounsaturated/administration & dosage , Fatty Acids, Monounsaturated/metabolism , Fatty Acids, Omega-3/administration & dosage , Fatty Acids, Omega-3/metabolism , Lipid Metabolism , Liver/chemistry , Male , Mitochondria, Liver/enzymology , Oxidation-Reduction , Peroxisomes/enzymology , Racemases and Epimerases/metabolism , Rats , Rats, Wistar , Triglycerides/blood
3.
Br J Nutr ; 84(5): 681-8, 2000 Nov.
Article in English | MEDLINE | ID: mdl-11177181

ABSTRACT

Partially hydrogenated fish oil (PHFO) contains a high amount of trans fatty acids (TFA). Total hydrogenation results in a minimal amount of TFA, but a high content of very-long-chain saturated fatty acids (VLCSFA). Absorption and metabolism of VLCSFA from totally hydrogenated fish oil (THFO) were studied in rats. Groups of eight rats were fed one of four diets containing 40 g soyabean oil (SBO)/kg (low-fat diet), 150 g SBO/kg (SBO diet), 40 g PHFO/kg (PHFO diet) or 40 g THFO/kg (THFO diet) for 4 weeks. A lower absorption coefficient of the fat content was found in the THFO group (61 %) compared with the other groups (PHFO 95 %, SBO 99 %, low fat 98 %; which was mainly due to reduced absorption of VLCSFA. A reduced weight gain was found for the THFO group compared with the other groups, but this was only significant when compared with the SBO group Faecal fat excretion (dry weight) was markedly increased in the THFO group (47 %), which was 2.4, 4.8 and 8.3 times higher compared with the groups fed PHFO, SBO and low-fat diets respectively. Serum total cholesterol was reduced for the PHFO and THFO groups whereas serum triacylglycerol was increased for the PHFO group compared with the other groups Animals fed THFO diet had an increased content of 20:0 and 22:0 in the serum triacylglycerol fraction whereas only 20:0 was increased in the serum phospholipid fraction The low absorption coefficient of THFO must be considered if this fat is to be used for consumption by animals or man.


Subject(s)
Fatty Acids/metabolism , Fish Oils/metabolism , Analysis of Variance , Animals , Cholesterol/blood , Cholesterol/metabolism , Feces/chemistry , Fish Oils/administration & dosage , Intestinal Absorption/physiology , Male , Rats , Triglycerides/blood , Triglycerides/metabolism
5.
Biochem J ; 331 ( Pt 3): 743-52, 1998 May 01.
Article in English | MEDLINE | ID: mdl-9560300

ABSTRACT

The murine macrophage cell line J774 was incubated with [35S]sulphate. The cell-associated 35S-labelled macromolecules were shown to be proteoglycans and glycosaminoglycans in similar amounts. The possible presence of cell-surface proteoglycans was investigated by incubating [35S]sulphate-labelled cells with trypsin for 15 min. The released material contained approx. 70% free glycosaminoglycan chains and 30% proteoglycans. The latter component was demonstrated by HNO2 treatment to contain heparan sulphate. In the total cell fraction not treated with trypsin a small but significant portion was shown to be chondroitin sulphate proteoglycan. The cell-associated glycosaminoglycans contained both chondroitin sulphate and heparan sulphate. To investigate possible biological functions of cell-surface proteoglycans in macrophages, cells were incubated with NaClO3 to inhibit sulphation of proteoglycans and beta-d-xyloside to abrogate proteoglycan expression. The uptake of oxidized 125I-tyraminylcellobiose-labelled low-density lipoprotein (125I-TC-LDL) was typically two to three times higher than that of native 125I-TC-LDL in untreated J774 cells. The cellular uptake at 37 degreesC of native 125I-TC-LDL was decreased 25% after both NaClO3 and xyloside treatment, whereas the uptake of oxidized 125I-TC-LDL was decreased 35% after both types of treatment. The mRNA levels for the scavenger receptor A-II and the LDL receptor were not affected by NaClO3 or xyloside treatment. Furthermore, fluid-phase endocytosis, measured as uptake of horseradish peroxidase, and receptor-mediated endocytosis, measured as uptake of 125I-TC-ovalbumin, were not affected by NaClO3 treatment of J774 cells. Removal of cell-surface chondroitin sulphate with chondroitinase ABC decreased only the binding of native 125I-TC-LDL, whereas removal of heparan sulphate with heparitinase decreased the binding of both oxidized and native 125I-TC-LDL. Addition of lipoprotein lipase increased the uptake of oxidized 125I-TC-LDL 1.7 times and the uptake of native 125I-TC-LDL 2.1 times. The binding of the former was more sensitive to NaClO3 treatment than the latter. The results presented support the notion that some of the uptake pathways for lipoproteins in the foam-cell-forming macrophages depend on the presence of cell-surface heparan sulphate and chondroitin sulphate.


Subject(s)
Lipoproteins/pharmacokinetics , Macrophages/physiology , Membrane Proteins , Proteoglycans/chemistry , Receptors, Lipoprotein , Animals , Cell Line , Chlorates/pharmacology , Chondroitin ABC Lyase/metabolism , Chondroitin Sulfates/chemistry , Endocytosis/physiology , Glycosides/pharmacology , Heparitin Sulfate/chemistry , Lipoprotein Lipase , Lipoproteins, LDL/pharmacokinetics , Membrane Glycoproteins/chemistry , Mice , Ovalbumin/pharmacokinetics , Polysaccharide-Lyases/metabolism , RNA, Messenger/metabolism , Receptors, Immunologic/genetics , Receptors, Scavenger , Scavenger Receptors, Class B , Trypsin/metabolism
6.
J Lipid Res ; 37(7): 1591-600, 1996 Jul.
Article in English | MEDLINE | ID: mdl-8827529

ABSTRACT

Homocysteine is an independent risk factor for cardiovascular diseases. The mechanisms by which elevated plasma concentrations of homocysteine are related to the pathogenesis of atherosclerosis are not fully understood. To examine whether homocysteine is implicated in atherogenesis through the modification of low density lipoprotein (LDL), the effect of homocysteine on the oxidation of LDL was studied by three different oxidation systems. Thus, LDL was subjected to Cu(2+)-catalyzed, azo compound-initiated, and peripheral blood mononuclear cell-mediated oxidative modification. The extent of modification was assessed by measuring the formation of conjugated dienes, lipid peroxides, thiobarbituric acid-reactive substances, and the relative electrophoretic mobility. Homocysteine at a normal plasma concentration (6 microM) showed no effect, whereas a concentration corresponding to moderate hyperhomocysteinemia (25 microM) or to concentrations seen in homocystinuria patients (100, 250, and 500 microM) protected LDL from modification of the lipid as well as of the protein moiety. One exception was observed: when the oxidation was initiated by copper ions, homocysteine at concentrations 6 and 25 microM stimulated the lipid peroxidation of LDL to a small, but statistically significant extent. High concentrations of homocysteine showed antioxidative properties as long as the thiol groups were intact, thereby delaying the onset of the oxidation. The 1,1-diphenyl-2-picrylhydracyl radical test demonstrated that homocysteine at concentrations > or = 50 microM possessed marked free radical scavenging capacity. Finally, LDL isolated from two patients with homozygous homocystinuria showed similar extent of Cu(2+)-catalyzed oxidation as LDL from a group of healthy control subjects. Taken together, our data suggest that low concentrations of homocysteine in the presence of copper ions may enhance the lipid peroxidation of LDL, whereas high concentrations of homocysteine may protect LDL against oxidative modification in the lipid as well as in the protein moiety. Thus, homocysteine-induced atherosclerosis may be explained by mechanisms other than oxidative modification of low density lipoprotein.


Subject(s)
Amidines/pharmacology , Homocysteine/pharmacology , Leukocytes, Mononuclear/metabolism , Lipid Peroxidation/drug effects , Lipoproteins, LDL/metabolism , Picrates , Adolescent , Adult , Arteriosclerosis/etiology , Azo Compounds , Bepridil/analogs & derivatives , Bepridil/pharmacology , Biphenyl Compounds , Child , Copper , Female , Free Radical Scavengers/pharmacology , Homocystinuria/blood , Humans , Leukocytes, Mononuclear/drug effects , Male , Middle Aged
7.
Eur J Clin Nutr ; 50(6): 364-70, 1996 Jun.
Article in English | MEDLINE | ID: mdl-8793417

ABSTRACT

OBJECTIVE: To study the effect of partially hydrogenated fish oil (PHFO-diet), partially hydrogenated soybean oil (PHSO-diet) and butterfat (butter-diet) on the susceptibility of low density lipoprotein (LDL) to in vitro oxidative modification. DESIGN: A strictly controlled, randomized, single-blind dietary study with cross-over design. SUBJECTS: Thirty-three healthy men aged from 21 to 46 years entered the study; 29 men completed the study. INTERVENTIONS: Fat provided approximately 35% of the energy intake in all three test diets, and the content of trans-fatty acids was 8.0, 8.5 and 0.9% of energy in the PHFO-, PHSO- and butter-diets, respectively. The subjects consumed all three test diets each during three weeks, in a single-blind, random order. LDL isolated from the participants given the three different diets was subjected to Cu(2+)-induced oxidation. RESULTS: No significant differences were seen on either conjugated dienes, lipid peroxides, uptake by macrophages or relative electrophoretic mobility of LDL. Vitamin E level in serum from subjects on the PHFO-diet was significantly higher compared to the two other diets. Furthermore, no significant differences were found in the composition of the LDL particle between the three diet groups. CONCLUSIONS: Our results indicate that consumption of trans-fatty acids does not alter the susceptibility of LDL to oxidative modification.


Subject(s)
Butter , Dietary Fats/pharmacology , Fish Oils/pharmacology , Lipid Peroxidation , Lipoproteins, LDL/blood , Soybean Oil/pharmacology , Adult , Copper/metabolism , Cross-Over Studies , Energy Intake , Humans , Hydrogenation , Macrophages/metabolism , Male , Oxidation-Reduction , Vitamin E/blood
8.
Scand J Clin Lab Invest ; 55(6): 469-75, 1995 Oct.
Article in English | MEDLINE | ID: mdl-8571076

ABSTRACT

The effects on blood and liver lipids after feeding rats with concentrated fractions from fish oil consisting of mono-unsaturated fatty acids (80% C20:1 and 22:1) or n-3 polyunsaturated fatty acids (85% C20:5 and 22:6 n-3) were examined. Mono-unsaturated fat had no effects on plasma triacylglycerol, total cholesterol phospholipids or unesterified fatty acid as compared to controls (lard). However, n-3 polyunsaturated fatty acid-fed animals showed a significant decrease in plasma triacylglycerol (74%), phospholipids (40%) and unesterified fatty acids (52%). The concentrated fractions had no effects on liver lipids. While the n-3 diet increased peroxisomal beta-oxidation 2.5-fold, there was only a slight increase with the mono-unsaturated diet. The fatty acid composition in plasma and liver phospholipids was changed with the various diets; 20:4 n-6 was significantly reduced in plasma and liver with the mono-unsaturated diet, and with the n-3 diet in liver. The mono-unsaturated diet, and especially the n-3 diet, increased the 20:5 n-3 level in both plasma and liver. Our results indicate that long-chain mono-unsaturated fatty acids in fish oil do not change the levels of plasma lipids. The beneficial role of fish oil on the level of blood lipids, may therefore be mostly attributed to the effects of long-chain n-3 fatty acids. However, the low 20:4 n-6 and high 20:5 n-3 levels in plasma and liver phospholipids with the concentrated mono-unsaturated fatty acid diet may be of importance for a favourable haemostatic balance with regard to cardiovascular diseases.


Subject(s)
Dietary Fats/pharmacology , Fatty Acids, Monounsaturated/pharmacology , Fatty Acids, Omega-3/pharmacology , Lipids/blood , Liver/chemistry , Liver/drug effects , Animals , Dietary Fats/administration & dosage , Dietary Fats/metabolism , Fatty Acids, Monounsaturated/administration & dosage , Fatty Acids, Omega-3/administration & dosage , Lipid Metabolism , Male , Microbodies/drug effects , Microbodies/metabolism , Oxidation-Reduction , Rats , Rats, Wistar
9.
Ann Nutr Metab ; 39(1): 9-15, 1995.
Article in English | MEDLINE | ID: mdl-7872658

ABSTRACT

Children living on plantations in inland districts of the southeastern part of Sri Lanka frequently develop a skin condition on the legs described as mosaic skin or xeroderma. This condition is characterized by atrophic, dry, shining and scaly skin. The etiology is unknown. A food frequency survey indicated a low energy intake, a diet with a low fat content, and anthropometric data have shown a high prevalence of malnutrition within this group. The skin condition brought attention to a possible deficiency of essential nutrients, especially essential fatty acids. In order to investigate the possible association with a deficiency of essential fatty acids, blood samples were collected from both children having signs of xeroderma and controls. The total amount of phospholipids was low, but the fatty acid profile of this lipid class was similar to the controls. A vitamin A deficiency was indicated by low levels of its transport proteins. A multifactorial etiology where vitamin A deficiency may play a role is discussed.


Subject(s)
Ichthyosis/blood , Lipids/blood , Adolescent , Child , Child, Preschool , Diet , Dietary Fats/administration & dosage , Energy Intake , Fatty Acids, Essential/blood , Humans , Ichthyosis/etiology , Phospholipids/blood , Retinol-Binding Proteins/analysis , Sri Lanka , Vitamin A Deficiency/blood , Vitamin A Deficiency/complications
10.
Biochim Biophys Acta ; 1214(2): 109-14, 1994 Sep 15.
Article in English | MEDLINE | ID: mdl-7918589

ABSTRACT

The elongation system for palmitic acid in rat liver microsomes was decreased to 1/3 by fasting, while the elongation of eicosapentaenoic acid was not sensitive to fasting. The rate of eicosapentaenoic acid elongation in the fed state was 50% higher than using palmitic acid as a substrate. The saturated and polyunsaturated fatty acyl-CoA substrates exhibited positive cooperativity on the rate-limiting condensing step in the elongation system, with a Hill constant of approx. 2. An inhibition by CoASH on the total elongation reaction as well as on the condensation step was demonstrated using acyl-CoA substrates, and followed a hyperbolic pattern. The concentrations giving a 50% inhibition (30-70 microM) were in the range found in rat hepatocyte cytosol, indicating that free CoASH has the potential to act as a physiological regulator.


Subject(s)
Coenzyme A/metabolism , Fasting , Fatty Acids/metabolism , Microsomes, Liver/metabolism , Animals , Coenzyme A/isolation & purification , Coenzyme A/pharmacology , Eicosapentaenoic Acid/metabolism , Fatty Acids/chemistry , Male , Microsomes, Liver/enzymology , Palmitic Acid , Palmitic Acids/metabolism , Rats , Rats, Wistar
11.
Biochem J ; 283 ( Pt 2): 333-9, 1992 Apr 15.
Article in English | MEDLINE | ID: mdl-1349473

ABSTRACT

Rats were fed, for 3 weeks, high-fat (20% w/w) diets containing sunflower-seed oil, linseed oil or fish oil. Chow-fed rats were used as a low-fat reference. The high-fat diets markedly reduced non-fasting-rat serum triacylglycerol as compared with the low-fat reference, and the highest reduction (85%) was observed with the fish-oil group, which was significantly lower than that of the other high-fat diets. The serum concentration of phospholipids was significantly reduced (30%) only in the fish-oil-fed animals, whereas serum non-esterified fatty acids were reduced 40-50% by both the fish-oil- and linseed-oil-fed groups. The liver content of triacylglycerol showed a 1.7-fold increase with the fish-oil diet and 2-2.5-fold with the other dietary groups when compared with rats fed a low-fat diet, whereas the hepatic content of phospholipids was unchanged. Peroxisomal fatty acid oxidation (acyl-CoA oxidase) was 2-fold increased for the rats fed fish oil; however this was not significantly higher when comparison was made with rats fed the linseed-oil diet. There was no difference in phosphatidate hydrolysis (microsomal and cytosolic fractions) among animals fed the various diets. Acyl-CoA:diacylglycerol acyltransferase activity was increased by all high-fat diets, but the fish-oil-diet-fed group showed a significantly lower enzyme activity than did rats fed the other high-fat diets. A linear correlation between acyl-CoA:diacylglycerol acyltransferase activity and liver triacylglycerol was observed, and the microsomal enzyme activity was decreased 40-50% by incubation in the presence of eicosapentaenoyl-CoA. CoA derivatives of arachidonic, linolenic and linoleic acid had no inhibitory effect when compared with the control. These results indicate that dietary fish oil may have greater triacylglycerol-lowering effect than other polyunsaturated diets, owing to decreased triacylglycerol synthesis caused by inhibition of acyl-CoA:diacylglycerol acyltransferase. In addition, increased peroxisomal fatty acid oxidation and decreased availability of non-esterified fatty acids could also contribute by decreasing the amounts of fatty acids as substrates for triacylglycerol synthesis and secretion.


Subject(s)
Dietary Fats/pharmacology , Fatty Acids, Omega-3/pharmacology , Fatty Acids, Unsaturated/pharmacology , Fatty Acids/metabolism , Lipids/blood , Liver/metabolism , Microbodies/metabolism , Phospholipids/metabolism , Triglycerides/metabolism , Acyltransferases/metabolism , Animals , Diacylglycerol O-Acyltransferase , Fatty Acids, Nonesterified/blood , Fatty Acids, Omega-6 , Liver/drug effects , Male , Microbodies/drug effects , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Oxidation-Reduction , Palmitoyl-CoA Hydrolase/metabolism , Phosphatidate Phosphatase/metabolism , Phospholipids/blood , Rats , Rats, Inbred Strains
12.
Biochem J ; 282 ( Pt 2): 565-70, 1992 Mar 01.
Article in English | MEDLINE | ID: mdl-1546971

ABSTRACT

The subcellular localization of dihydroxyacetone phosphate acyltransferase (DHAPAT) activity in rat small intestine was investigated by Nycodenz-gradient centrifugation. We found that DHAPAT had a predominant peroxisomal distribution, with a separate enzyme activity located in the microsomal fraction, the same distribution as found in rat liver. The effect of feeding rats on a diet with 20% (w/w) partially hydrogenated fish oil (PHFO) or 0.3% clofibrate on the activity of DHAPAT in rat small intestine and liver was studied. Both 20% PHFO and 0.3% clofibrate gave a 1.8-fold stimulation of the specific activities of DHAPAT in peroxisomes of the small intestine, whereas in the liver 20% PHFO gave a 1.4-fold stimulation and 0.3% clofibrate a 1.6-fold stimulation of the total DHAPAT activities in the postnuclear supernatant. The specific activities of DHAPAT in liver were not affected.


Subject(s)
Acyltransferases/metabolism , Clofibrate/pharmacology , Fish Oils/pharmacology , Intestine, Small/enzymology , Animals , Fatty Acids/metabolism , Intestine, Small/drug effects , Liver/drug effects , Liver/metabolism , Male , Microbodies/drug effects , Microbodies/enzymology , Oxidation-Reduction , Rats , Rats, Inbred Strains , Substrate Specificity
13.
Biochim Biophys Acta ; 1086(3): 349-53, 1991 Nov 27.
Article in English | MEDLINE | ID: mdl-1742327

ABSTRACT

The fatty acid elongation-desaturation ability of 5,8,11,14-eicosatetraenoic (20:4(n-6)) and 5,8,11,14,17-eicosapentaenoic (20:5(n-3)) acids was determined in both liver microsomal and light mitochondrial (rich in peroxisomes) fractions of untreated and clofibrate treated rats. The elongation and the subsequent desaturation steps were performed in the corresponding favorable media. 20:5(n-3) elongation was about 2-times more extensive than that of 20:4(n-6). Clofibrate feeding for 10 days resulted in a marked decrease in the elongation rate with the two substrates, while the delta 4 desaturation rate was increased. There were small differences in the elongation rate between the microsomal and light mitochondrial fractions, however, the relative delta 4 desaturation rate was higher in the light mitochondrial fraction than microsomes.


Subject(s)
Arachidonic Acid/metabolism , Clofibrate/pharmacology , Eicosapentaenoic Acid/metabolism , Liver/metabolism , Animals , Liver/drug effects , Male , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Mitochondria, Liver/drug effects , Mitochondria, Liver/metabolism , Rats
14.
Biochim Biophys Acta ; 1082(1): 57-62, 1991 Feb 26.
Article in English | MEDLINE | ID: mdl-2009302

ABSTRACT

To study the effect of high-fat diets with varying contents of n-3 and n-6 fatty acids on the metabolism of essential fatty acids, the rat liver microsomal fatty acid desaturases were measured. The rats were fed for 3 weeks with diets high in linseed oil (18:3(n-3)), sunflower seed oil (18:2(n-6)) or fish oil (20:5(n-3) and 22:6(n-3)) (20%, w/w) using pellet fed rats as a reference. The delta 6-desaturase using 18:2(n-6) or 18:3(n-3) as substrates was stimulated 1.5-2.5-fold by linseed or sunflower seed oil, compared to the pellet reference. The delta 5-desaturase was stimulated 3.5-fold with linseed oil and 2.5-fold with sunflower seed oil, while the delta 9-desaturase was inhibited by all the high-fat diets. The delta 6-, 5- and 9-desaturase activities were in all cases considerably reduced with fish oil as compared to linseed and sunflower seed oil diets. With pellet fed rats the rates were highest for delta 9-desaturation and in decreasing order lower for delta 5-desaturation, delta 6-desaturation with 18:3 (n-3) as substrate and finally delta 6-Desaturation with 18:2(n-6) as substrate. The content of 20:4(n-6) in liver phospholipids increased with the diets rich in 18:2(n-6), and was reduced for the fish oil diet enriched in 20:5 and 22:6(n-3) fatty acids. The amount of 20:5(n-3) in phospholipids was as high with linseed oil diet as with the fish oil diet, while the 22:6(n-3) content was only increased with the fish oil diet.


Subject(s)
Dietary Fats, Unsaturated/pharmacology , Fatty Acid Desaturases/metabolism , Microsomes, Liver/enzymology , Animals , Dietary Fats, Unsaturated/administration & dosage , Fatty Acids/metabolism , Fish Oils/administration & dosage , Fish Oils/pharmacology , Linolenic Acids/metabolism , Linseed Oil/administration & dosage , Linseed Oil/pharmacology , Liver/metabolism , Male , Phospholipids/metabolism , Plant Oils/administration & dosage , Plant Oils/pharmacology , Rats , Rats, Inbred Strains , Sunflower Oil
15.
Biochem Pharmacol ; 40(9): 2005-12, 1990 Nov 01.
Article in English | MEDLINE | ID: mdl-2242030

ABSTRACT

Treatment of normolipidemic rats by alkylthiopropionic acid (CETTD), resulted in a dose- and time-dependent increase in total dihydroxyacetone phosphate acyltransferase (DHAPAT) activity, in extent comparable to that of 3-thiadicarboxylic acid (BCMTD) and alkylthioacetic acid (CMTTD). Thus, in CETTD- and CMTTD-treated rats, the specific DHAPAT activity increased in the microsomal, peroxisomal and mitochondrial fractions. In contrast, repeated administration of the peroxisome proliferator, BCMTD, decreased the specific DHAPAT activity both in the peroxisomal fraction and in purified peroxisomes. A three-fold increase in specific activity was, however, revealed in the mitochondrial fraction. Whether the variation of the DHAPAT activity in the mitochondrial and microsomal fractions among the feeding groups can be explained by increased number of enlarged and small peroxisomes sedimenting in the fractions, are to be considered. Subcellular fractionation studies confirmed previous findings that rat liver glycerophosphate acyltransferase (GPAT) was located both in mitochondria and the microsomal fraction. BCMTD was considerably more potent than CMTTD in stimulating the microsomal and mitochondrial GPAT activities. Administration of CETTD marginally affected the isoenzymes of GPAT. Diacylglycerol acyltransferase (DGAT) activity was increased by 35% in BCMTD and CMTTD treated rats, but by administration of CETTD the enzyme activity was decreased by more than 80%. The acyl-CoA cholesterol acyltransferase (ACAT) activity was marginally affected in animals treated with BCMTD, CMTTD and CETTD. Thus, the results indicate that the initial steps in the synthesis of triacylglycerols and ether glycerolipids as well as the last step in triacylglycerol synthesis could not be identified as mediating the fat accumulation or the lowering of triacylglycerol content in liver of CETTD, or BCMTD and CMTTD treated rats. On the other hand, CMTTD increased the palmitoyl-CoA oxidation in mitochondria, and CETTD considerably inhibited the activity. Therefore, it is conceivable that the development of fatty liver with CETTD is mostly due to inhibition of mitochondrial beta-oxidation.


Subject(s)
Dicarboxylic Acids/pharmacology , Liver/drug effects , Propionates/pharmacology , Sulfides/pharmacology , Triglycerides/metabolism , Acyltransferases/metabolism , Animals , Liver/anatomy & histology , Liver/enzymology , Male , Microbodies/drug effects , Microbodies/metabolism , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Mitochondria, Liver/drug effects , Mitochondria, Liver/metabolism , Organ Size/drug effects , Oxidation-Reduction , Rats , Rats, Inbred Strains
16.
Ann Nutr Metab ; 34(1): 13-20, 1990.
Article in English | MEDLINE | ID: mdl-2331136

ABSTRACT

Clofibrate treatment was found to increase by a factor of two the activity of malonyl-CoA-dependent palmitic acid chain elongation in crude 'microsomal' fractions isolated from rat small intestine. A slight stimulation was indicated also after feeding a high fat diet containing partially hydrogenated fish oil (PHFO). This effect was, however, not statistically significant. Subcellular localization of this chain elongation activity was studied by Nycodenz gradient centrifugation. Chain elongation of palmitic acid was observed only in fractions containing high esterase activity, suggesting a microsomal localization. Similar distributions were seen after feeding the peroxisomal proliferators clofibrate and PHFO. Chain-shortening activity was found in the fractions containing high catalase activity, confirming our earlier studies suggesting a peroxisomal localization of this activity also in rat small intestine.


Subject(s)
Clofibrate/pharmacology , Fatty Acids/metabolism , Fish Oils/pharmacology , Intestine, Small/drug effects , Acetyltransferases/metabolism , Animals , Clofibrate/administration & dosage , Dietary Fats/administration & dosage , Dietary Fats/pharmacology , Fatty Acid Elongases , Fish Oils/administration & dosage , Intestinal Mucosa/drug effects , Intestinal Mucosa/enzymology , Intestine, Small/enzymology , Intestine, Small/metabolism , Male , Microbodies/enzymology , Microbodies/metabolism , Microsomes/enzymology , Microsomes/metabolism , Palmitic Acids/metabolism , Rats , Rats, Inbred Strains
17.
J Biol Chem ; 264(18): 10347-50, 1989 Jun 25.
Article in English | MEDLINE | ID: mdl-2732225

ABSTRACT

The fate of the acetyl-CoA units released during peroxisomal fatty acid oxidation was studied in isolated hepatocytes from normal and peroxisome-proliferated rats. Ketogenesis and hydrogen peroxide generation were employed as indicators of mitochondrial and peroxisomal fatty acid oxidation, respectively. Butyric and hexanoic acids were employed as mitochondrial substrates, 1, omega-dicarboxylic acids as predominantly peroxisomal substrates, and lauric acid as a substrate for both mitochondria and peroxisomes. Ketogenesis from dicarboxylic acids was either absent or very low in normal and peroxisome-proliferated hepatocytes, but free acetate release was detected at rates that could account for all the acetyl-CoA produced in peroxisomes by dicarboxylic and also by monocarboxylic acids. Mitochondrial fatty acid oxidation also led to free acetate generation but at low rates relative to ketogenesis. The origin of the acetate released was confirmed employing [1-14C]dodecanedioic acid. Thus, the activity of peroxisomes might contribute significantly to the free acetate generation known to occur during fatty acid oxidation in rats and possibly also in humans.


Subject(s)
Acetates/metabolism , Dicarboxylic Acids/metabolism , Fatty Acids/metabolism , Liver/metabolism , Microbodies/metabolism , Animals , Bezafibrate/pharmacology , Cells, Cultured , Hydrogen Peroxide/metabolism , Ketone Bodies/metabolism , Kinetics , Liver/drug effects , Male , Microbodies/drug effects , Oxidation-Reduction , Rats , Rats, Inbred Strains
18.
J Lipid Res ; 29(11): 1417-26, 1988 Nov.
Article in English | MEDLINE | ID: mdl-2853717

ABSTRACT

The mechanism for the reduced hepatic production of triacylglycerol in the presence of eicosapentaenoic acid was explored in short-term experiments using cultured parenchymal cells and microsomes from rat liver. Oleic, palmitic, stearic, and linoleic acids were the most potent stimulators of triacyl[3H]glycerol synthesis and secretion by hepatocytes, whereas erucic, alpha-linolenic, gamma-linolenic, arachidonic, docosahexaenoic, and eicosapentaenoic acids (in decreasing order) were less stimulatory. There was a linear correlation (r = 0.85, P less than 0.01) between synthesis and secretion of triacyl[3H]glycerol for the fatty acids examined. The extreme and opposite effects of eicosapentaenoic and oleic acids on triacylglycerol metabolism were studied in more detail. With increasing number of free fatty acid molecules bound per molecule of albumin, the rate of synthesis and secretion of triacyl[3H]glycerol increased, most markedly for oleic acid. Cellular uptake of the two fatty acids was similar, but more free eicosapentaenoic acid accumulated intracellularly. Eicosapentaenoic acid caused higher incorporation of [3H]water into phospholipid and lower incorporation into triacylglycerol and cholesteryl ester as compared to oleic acid. No difference was observed between the fatty acids on incorporation into cellular free fatty acids, monoacylglycerol and diacylglycerol. The amount of some 16- and 18-carbon fatty acids in triacylglycerol was significantly higher in the presence of oleic acid compared with eicosapentaenoic acid. Rat liver microsomes in the presence of added 1,2-dioleoyl-glycerol incorporated eicosapentaenoic acid and eicosapentaenoyl-CoA into triacylglycerol to a lesser extent than oleic acid and its CoA derivative. Decreased formation of triacylglycerol was also observed when eicosapentaenoyl-CoA was given together with oleoyl-CoA, whereas palmitoyl-CoA, stearoyl-CoA, linoleoyl-CoA, linolenoyl-CoA, and arachi-donoyl-CoA had no inhibitory effect. In conclusion, inhibition of acyl-CoA:1,2-diacylglycerol O-acyltransferase (EC 2.3.1.20) by eicosapentaenoic acid may be important for reduced synthesis and secretion of triacylglycerol from the liver.


Subject(s)
Acyl Coenzyme A/antagonists & inhibitors , Acyltransferases/antagonists & inhibitors , Eicosapentaenoic Acid/pharmacology , Microsomes, Liver/metabolism , Triglycerides/biosynthesis , Animals , Cells, Cultured , Diacylglycerol O-Acyltransferase , Eicosapentaenoic Acid/metabolism , Fatty Acids/metabolism , Fatty Acids/pharmacology , Microsomes, Liver/drug effects , Microsomes, Liver/enzymology , Oleic Acid , Oleic Acids/metabolism , Rats , Triglycerides/metabolism
19.
Biochim Biophys Acta ; 962(1): 122-30, 1988 Sep 02.
Article in English | MEDLINE | ID: mdl-3416002

ABSTRACT

In this paper, we describe the early biochemical changes in liver cells that occur in rats fed a semisynthetic diet containing 20% (w/w) partially hydrogenated fish oil. Within hours the level of ornithine decarboxylase (ODC) increased, peaked at about 24 h (11-fold increase) and returned to subnormal levels within 48 h. The diet evoked a similar rapid increase in the cellular level of mRNA for the bifunctional enzyme of peroxisomal beta-oxidation (enoyl-CoA hydratase: beta-hydroxyacyl-CoA dehydrogenase (HD)) (12-fold), followed by increases in the specific content of HD protein (3-fold) and the capacity for beta-oxidation in peroxisomes (5.3-fold). The cellular level of long-chain acyl-CoA increased 2.1-fold. By contrast, no significant changes were observed in the specific activities of ornithine decarboxylase, peroxisomal beta-oxidation activity and microsomal omega-hydroxylation as well as the level of long-chain acyl-CoA in livers of rats fed (1 week) diets containing 20% (w/w) soybean oil with added 3 or 6% (w/w) of either elaidic acid (18:1(11) (trans)), brassidic acid (22:1(13) (trans)) or erucic acid (22:1(13) (cis)). Expression of normal levels of mRNA for the bifunctional enzyme was also found. Morphometric analyses revealed no proliferation of peroxisomes in these fatty acid-supplemented diets, in contrast to that observed with the partially hydrogenated fish oil diet. These results are consistent with the proposal (Flatmark, T., Christiansen, E.N. and Kryvi, H. (1983) Biochim. Biohys. Acta 753, 460-466) that components in dietary oils, different from C22:1 cis and trans fatty acids, are responsible for the pleiotropic responses evoked in target cells. Thus, the pattern of response induced by partially hydrogenated fish oil mimics those induced by xenobiotic compounds collectively termed peroxisome proliferators.


Subject(s)
Dietary Fats/administration & dosage , Fatty Acids/metabolism , Fish Oils/administration & dosage , Microbodies/enzymology , Microsomes, Liver/metabolism , 3-Hydroxyacyl CoA Dehydrogenases/metabolism , Acyl Coenzyme A/metabolism , Animals , Body Weight/drug effects , Cytochrome P-450 CYP4A , Enoyl-CoA Hydratase/metabolism , Enzyme Induction , Male , Mixed Function Oxygenases/metabolism , Polyamines/metabolism , RNA, Messenger/isolation & purification , Rats , Rats, Inbred Strains
20.
Am J Clin Nutr ; 47(2): 253-5, 1988 Feb.
Article in English | MEDLINE | ID: mdl-3341256

ABSTRACT

Phrynoderma cases were identified in a village close to Colombo in Sri Lanka. The alpha-tocopherol level in plasma was 3.3 +/- 0.6 mumol/L among the phrynoderma patients (n = 11) and 13.0 +/- 2.3 mumol/L among the control subjects (p less than 0.002). A test on glutathione reductase activity in erythrocytes revealed a stronger riboflavin deficiency among patients than among control subjects (p less than 0.005). No significant differences were found between the groups with regard to plasma levels of retinol, retinol-binding protein, vitamin B-12, folic acid, thiamin, selenium, zinc, or essential fatty acid pattern. Primary malnutrition may partly explain the deficiency of alpha-tocopherol and riboflavin observed in phrynoderma cases.


Subject(s)
Darier Disease/etiology , Vitamin E Deficiency/complications , Adult , Darier Disease/blood , Diet Surveys , Female , Humans , Riboflavin/blood , Riboflavin Deficiency/blood , Riboflavin Deficiency/complications , Rural Population , Socioeconomic Factors , Sri Lanka , Vitamin E/blood , Vitamin E Deficiency/blood
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