The hypolipidaemic effect of EPA is potentiated by 2- and 3-methylation.
Explore the source record for details and available documents.
Acyl-CoA Oxidase↗
Biomedical subjects
N Willumsen
Publications and source records attributed to N Willumsen.
Inward rectifying endogenous chloride channels in the Drosophila foetal cell line, S2.
Explore the source record for details and available documents.
Journal Article↗
On the effect of 2-deuterium- and 2-methyl-eicosapentaenoic acid derivatives on triglycerides, peroxisomal beta-oxidation and platelet aggregation in rats.
A series of 2-substituted eicosapentaenoic acid (EPA) derivatives (as ethyl esters) have been synthesized and evaluated as hypolipidemic and antithrombotic agents in feeding experiments in rats. Repeated administration of purified 2-methyl-eicosapentaenoic acid and its deuterium analogues (all as ethyl esters) to rats resulted in a decrease in plasma triglycerides and high density lipoprotein cholesterol. The 2-methyl-EPA analogues were, apparently, four times more potent than EPA in inducing the triglyceride lowering effect. The 2-deuterium-2-methyl-EPA decreased plasma cholesterol level to approximately 40%. A moderate enlargement of the liver was observed in 2-methyl-EPA treated rats. This was accompanied with an acute reduction in the liver content of triglycerides and a stimulation of peroxisomal beta-oxidation and fatty acyl-CoA oxidase activity. The results suggest that the triglyceride-lowering effect of 2-methyl-EPA may be due to a reduced supply of fatty acids for hepatic triglyceride biosynthesis because of increased fatty acid oxidation. Platelet aggregation with ADP and A23187 was performed ex vivo in platelet-rich plasma, after administration of different doses of the EPA-derivatives for five days. EPA and 2,2-dideuterium EPA had no effect on ADP-induced aggregation, while 2-deuterium-, 2-methyl- and 2-deuterium-2-methyl EPA produced a biphasic effect, i.e. potentiation and inhibition at low (250 mg/day kg body weight) and higher doses (600-1300 mg/day kg body weight), respectively. A23187-induced platelet aggregation was affected in a similar way by feeding the 2-substituted EPA derivatives, except that 2-deuterium-2-methyl EPA had no effect relative to EPA itself and that the inhibition was far greater than that for ADP-induced aggregation (approximately 100% inhibition with 600 mg 2-methyl-EPA/day kg body weight). The ranking order of the EPA-derivatives to affect platelet aggregation and to cause hypolipidemia was different, suggesting different mechanisms. Our observations suggest that the effects of the EPA derivatives on platelet aggregation could be related to the degree of bulkiness around C2 and that an asymmetric substitution at C2 caused inhibition of platelet aggregation while a symmetric substitution did not. It is suggested that the bulky, asymmetric derivatives inhibit platelet aggregation by altering platelet membrane phospholipid packing.
Animals↗
Enhanced hepatic fatty acid oxidation and upregulated carnitine palmitoyltransferase II gene expression by methyl 3-thiaoctadeca-6,9,12,15-tetraenoate in rats.
This study reports the effects of a novel polyunsaturated 3-thia fatty acid, methyl 3-thiaoctadeca-6,9,12,15-tetraenoate on serum lipids and key enzymes in hepatic fatty acid metabolism compared to a saturated 3-thia fatty acid, tetradecylthioacetic acid. Palmitic acid treated rats served as controls. Fatty acids were administered by gavage in daily doses of 150 mg/kg body weight for 10 days. The aim of the present study was: (a) To investigate the effect of a polyunsaturated 3-thia fatty acid ester, methyl 3-thiaoctadeca-6,9,12,15-tetraenoate on plasma lipids in normolipidemic rats: (b) to verify whether the lipid-lowering effect could be consistent with enhanced fatty acid oxidation: and (c) to study whether decreased activity of esterifying enzymes and diversion to phospholipid synthesis is a concerted mechanism in limiting the availability of free fatty acid as a substrate for hepatic triglyceride formation. Repeated administration of the polyunsaturated 3-thia fatty acid ester for 10 days resulted in a reduction of plasma triglycerides (40%), cholesterol (33%) and phospholipids (20%) compared to controls. Administration of polyunsaturated and saturated 3-thia fatty acids (daily doses of 150 mg/kg body weight) reduced levels of lipids to a similar extent and followed about the same time-course. Both mitochondrial and peroxisomal fatty acid oxidation increased (1.4-fold- and 4.2-fold, respectively) and significantly increased activities of carnitine palmitoyltransferase (CPT) (1.6-fold), 2,4-dienoyl-CoA reductase (1.2-fold) and fatty acyl-CoA oxidase (3.0-fold) were observed in polyunsaturated 3-thia fatty acid treated animals. This was accompanied by increased CPT-II mRNA (1.7-fold). 2,4-dienoyl-CoA reductase mRNA (2.9-fold) and fatty acyl-CoA oxidase mRNA (1.7-fold). Compared to controls, the hepatic triglyceride biosynthesis was retarded as indicated by a decrease in liver triglyceride content (40%). The activities of glycerophosphate acyltransferase, acyl-CoA: 1,2-diacylglycerol acyltransferase and CTP:phosphocholine cytidylyltransferase were increased. The cholesterol lowering effect was accompanied by a reduction in HMG-CoA reductase activity (80%) and acyl-CoA:cholesterol acyltransferase activity (33%). In hepatocytes treated with methyl 3-thiaoctadeca-6,9,12,15-tetraenoate, fatty acid oxidation was increased 1.8-fold compared to controls. The results suggest that treatment with methyl 3-thiaoctadeca-6,9,12,15-tetraenoate reduces plasma triglycerides by a decrease in the availability of fatty acid substrate for triglyceride biosynthesis via enhanced fatty acid oxidation, most likely attributed to the mitochondrial fatty acid oxidation. It is hypothesized that decreased phosphatidate phosphohydrolase activity may be an additive mechanism which contribute whereby 3-thia fatty acids reduce triglyceride formation in the liver. The cholesterol-lowering effect of the polyunsaturated 3-thia fatty acid ester may be due to changes in cholesterol/cholesterol ester synthesis as 60% of this acid was observed in the hepatic cholesterol ester fraction.
Alkenes↗
Eicosapentaenoic acid, but not docosahexaenoic acid, increases mitochondrial fatty acid oxidation and upregulates 2,4-dienoyl-CoA reductase gene expression in rats.
The aim of the present study was to investigate whether eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) was responsible for the triglyceride-lowering effect of fish oil. In rats fed a single dose of EPA as ethyl ester (EPA-EE), the plasma concentration of triglycerides was decreased at 8 h after acute administration. This was accompanied by an increased hepatic fatty acid oxidation and mitochondrial 2,4-dienoyl-CoA reductase activity. The steady-state level of 2,4-dienoyl-CoA reductase mRNA increased in parallel with the enzyme activity. An increased hepatic long-chain acyl-CoA content, but a reduced amount of hepatic malonyl-CoA, was obtained at 8 h after acute EPA-EE treatment. On EPA-EE supplementation, both EPA (20:5n-3) and docosapentaenoic acid (DPA, 22:5n-3) increased in the liver, whereas the hepatic DHA (22:6n-3) concentration was unchanged. On DHA-EE supplementation retroconversion to EPA occurred. No statistically significant differences were found, however, for mitochondrial enzyme activities, malonyl-CoA, long-chain acyl-CoA, plasma lipid levels, and the amount of cellular fatty acids between DHA-EE treated rats and their controls at any time point studied. In cultured rat hepatocytes, the oxidation of [1-14C]palmitic acid was reduced by DHA, whereas it was stimulated by EPA. In the in vivo studies, the activities of phosphatidate phosphohydrolase and acetyl-CoA carboxylase were unaffected after acute EPA-EE and DHA-EE administration, but the fatty acyl-CoA oxidase, the rate-limiting enzyme in peroxisomal fatty acid oxidation, was increased after feeding these n-3 fatty acids. The hypocholesterolemic properties of EPA-EE may be due to decreased 3-hydroxy-3-methylglutaryl-CoA reductase activity. Furthermore, replacement of the ordinary fatty acids, i.e., the monoenes (16:1n-7, 18:1n-7, and 18:1n-9) with EPA and some conversion to DPA concomitant with increased fatty acid oxidation is probably the mechanism leading to changed fatty acid composition. In contrast, DHA does not stimulate fatty acid oxidation and, consequently, no such displacement mechanism operates. In conclusion, we have obtained evidence that EPA, and not DHA, is the fatty acid primarily responsible for the triglyceride-lowering effect of fish oil in rats.
Acyl-CoA Dehydrogenase, Long-Chain↗
Eicosapentaenoic acid causes transient accumulation of lipids in rat myocardium.
Rats were given eicosapentaenoic acid (EPA) or palmitic acid (PALM) up to 15 days, and control animals were given carboxymethylcellulose. All suspensions which were given by gastric intubation contained tocopherol. Heart triacylglycerols, heart cholesterol and heart phospholipids significantly increased after one day of EPA treatment, but they were normalized within 15 days. Both after 2 and 10 days of treatment with palmitic acid the heart triacylglycerols were significantly greater than control. The heart cholesterol and heart phospholipids were significantly greater than control after 10 days of treatment with palmitic acid. Total carnitine palmitoyltransferase (CPT) activity in heart was significantly greater in rats treated with EPA for 15 days compared to control, but treatment with palmitic acid had no effect. The fatty acyl-CoA oxidase activity was greater in rats treated with EPA for 15 days and palmitic acid for 10 days compared to control. The fractional volume of lipid droplets in myocardial cells was calculated from electronmicrographs and was 0.112 +/- 0.016% after 1 day of EPA treatment compared to 0.035 +/- 0.016% in the control group. After 5 and 15 days the fractional volume was the same as control. The fractional volume of lipid droplets in rats treated with palmitic acid for 10 days was 0.120 +/- 0.023%. Treatment with EPA caused an immediate accumulation of lipids and lipid droplets in the rat heart which after few days normalized in parallel with an increased activity of total CPT in the heart.
Acyl-CoA Oxidase↗
A study on lipid metabolism in heart and liver of cholesterol- and pectin-fed rats.
Pectin is known as a cholesterol-reducing dietary fibre, and in the present study we addressed the question whether pectin affected the quantity of lipid in droplets in the myocardial cells and of lipid in the liver cells. Male Wistar rats received either a diet containing cholesterol or a standard diet without cholesterol with 0, 50 or 100 g pectin/kg incorporated for 10 d. The fractional volume of lipid droplets in the myocardial cells decreased as a function of pectin dose in both the standard-fed and the cholesterol-fed rats. Serum cholesterol was significantly reduced in both groups after addition of 100 g pectin/kg diet. The cholesterol diet increased the liver cholesterol level, and 100 g pectin/kg diet resulted in a lower concentration of liver cholesterol in the cholesterol-fed animals, but the influence on standard-fed rats was modest. Hydroxymethylglutaryl-CoA reductase (EC 1.1.1.88; HMG-CoA reductase) activity increased when pectin was given in the standard diet. Liver triacylglycerol level increased after cholesterol and pectin feeding. Mitochondrial fatty acid oxidation and phosphatidate phosphohydrolase (EC 3.1.3.4) activity tended to decrease, whereas the peroxisomal fatty acid oxidation and acyl-CoA oxidase activity were unchanged. Increased hepatic triacylglycerol content by cholesterol and pectin treatment may be due to inhibited mitochondrial fatty acid oxidation along with increased availability of fatty acid for esterification and triacylglycerol synthesis. The presence of pectin in the diets of cholesterol-fed rats resulted in increased hepatic concentration of triacylglycerols and increased mitochondrial fatty acid oxidation. In this case the hepatic accumulation of triacylglycerol may be mediated by a reduced efflux of triacylglycerols from the liver.
Animals↗
Docosahexaenoic acid induces lipid accumulation in myocardial cells of rats.
The aim of the study was to explore whether treatment with highly purified docosahexaenoic acid (DHA) over a short period affects the amount of lipid droplets in myocardial cells of rats, and whether heart peroxisomal enzyme activity is changed. Fifteen rats were fed a standard diet for 10 days and 15 rats were fed a cholesterol diet (2% of cholesterol) for 10 days. In each experiment six rats served as control, and three rats in each treatment group were given one of the following treatments by gastric intubation: DHA at 500, 1000, or 1500 mg day-1 kg-1 body weight. The fractional volume of lipid droplets in myocardial cells was calculated by morphometric methods. The heart triglycerides and the volume fraction of lipid droplets in the myocardium were greater in the standard diet rats treated with DHA compared with controls. There was no such increase caused by DHA treatment in the cholesterol diet rats. The heart fatty acyl-CoA oxidase tended to increase with DHA treatment in both standard and cholesterol diet rats, but this was significantly increased only after treatment with DHA 1500 mg day-1 kg-1 in the cholesterol diet rats. We conclude that treatment with highly purified DHA for 10 days results in cardiac lipidosis, assessed both by biochemical and morphological methods in standard diet rats, whereas DHA treatment has no additive effect on lipid accumulation in cholesterol fed rats.
Acyl-CoA Oxidase↗
Early effects on mitochondrial and peroxisomal beta-oxidation by the hypolipidemic 3-thia-fatty acids in rat livers.
A single administration of 3-thiadicarboxylic and tetradecylthioacetic acids stimulates both mitochondrial and peroxisomal beta-oxidation and lowers plasma triacylglycerol levels. An increased rate of mitochondrial beta-oxidation and carnitine palmitoyl-transferase activity was established after 3 h and this was accompanied by a lowering of plasma triacylglycerol. Peroxisomal beta-oxidation, however, remained unchanged up to 8 h and was significantly increased after 12 h. These results suggest that after a single administration of 3-thia fatty acids mitochondrial beta-oxidation precedes peroxisomal beta-oxidation. Furthermore, they show that the observed tricylglycerol-lowering effect, which is established early (3-4 h) after the administration of 3-thia fatty acids, is initially due to an increased mitochondrial beta-oxidation.
Animals↗
The hypotriglyceridemic effect of eicosapentaenoic acid in rats is reflected in increased mitochondrial fatty acid oxidation followed by diminished lipogenesis.
The effect of eicosapentaenoic acid (EPA) on fatty acid oxidation and on key enzymes of triglyceride metabolism and lipogenesis was investigated in the liver of rats. Repeated administration of EPA to normolipidemic rats resulted in a time-dependent decrease in plasma triglycerides, phospholipids and cholesterol. The triglyceride-lowering effect was observed after one day of feeding whereas lowering of plasma cholesterol and phospholipids was observed after five days of treatment. The triglyceride content of liver was reduced after two-day treatment. At that time, increased mitochondrial fatty acid oxidation occurred whereas mitochondrial and microsomal glycerophosphate acyltransferase was inhibited. The phosphatidate phosphohydrolase activity was unchanged. Adenosine triphosphate:citrate lyase, acetyl-CoA carboxylase, fatty acid synthetase and glucose-6-phosphate dehydrogenase were inhibited during the 15 d of EPA treatment whereas peroxisomal beta-oxidation was increased. At one day of feeding, however, when the hypotriglyceridemic effect was established, the lipogenic enzyme activities were reduced to the same extent in palmitic acid-treated animals as in EPA-treated rats. In cultured rat hepatocytes, the oxidation of [14C]palmitic acid to carbon dioxide and acid-soluble products was stimulated in the presence of EPA. These results suggest that the instant hypolipidemia in rats given EPA could be explained at least in part by a sudden increase in mitochondrial fatty acid oxidation, thereby reducing the availability of fatty acids for lipid synthesis in the liver for export, e.g., in the form of very low density lipoproteins, even before EPA induced peroxisomal fatty acid oxidation, reduced triglyceride biosynthesis and diminished lipogenesis.
Animals↗
Cholesterol induced lipid accumulation in myocardial cells of rats.
OBJECTIVE: The aim was to investigate whether cholesterol feeding of rats for only 10 d would result in lipid accumulation in myocardial cells and a change in the peroxisomal beta oxidation in the heart compared to the hearts of rats on standard feeds. METHODS: Eight rats received a cholesterol diet (2%) and eight rats received a standard diet for 10 d. Lipids were measured in serum, liver, and heart. Palmitoyl-CoA hydrolase and fatty acyl-CoA oxidase were determined in total homogenate of hearts. The fractional volume of lipid droplets in myocardial cells was calculated from micrographs at a magnification of x9600 obtained by electron microscopy. RESULTS: The fractional volume of lipid droplets in the cardiomyocytes increased from 0.109(SEM 0.019)% to 0.259(0.037)%, (p < 0.003), as a result of cholesterol feeding. Cholesterol and triglycerides in the heart measured by biochemical methods increased by 13% and 24%, respectively. There was no difference in palmitoyl-CoA hydrolase or fatty acyl-CoA oxidase in the hearts of the cholesterol fed group compared to the control group, suggesting an unaltered peroxisomal beta oxidation of fatty acids in the myocardium. The serum triglycerides and serum phospholipids were reduced in the cholesterol fed rats (p < 0.05 and p < 0.001, respectively). Rats fed cholesterol diet showed a reduced ratio of HDL cholesterol to total cholesterol in serum, together with an increased liver weight and relative liver weight compared to the control rats. The addition of cholesterol to the diet increased liver cholesterol to 21.0(1.6) mumol.g-1 wet weight compared to 5.87(0.93) mumol.g-1 in the controls on standard diet (p < 0.0001). Cholesterol feeding had no effect on the hepatic level of phospholipids, but the liver triglycerides tended to increase from 23.3(9.5) mumol.g-1 wet weight to 53.3(6.3) mumol.g-1. CONCLUSIONS: Lipid accumulation in the myocardial cells was shown by morphometry after 10 d of cholesterol feeding, without any visible damage to the tissue.
Acyl-CoA Oxidase↗
Docosahexaenoic acid shows no triglyceride-lowering effects but increases the peroxisomal fatty acid oxidation in liver of rats.
The effect of docosahexaenoic acid (DHA) on mitochondrial and peroxisomal fatty acid oxidation and on key enzymes in triglyceride metabolism was investigated in the liver of rats fed a standard diet, a cholesterol diet, and a pelleted chow diet. Unexpectedly, in all three rat models repeated administration of highly purified DHA (92% pure) at different doses and times, at a dose of 1000 mg/day per kg body weight, resulted in no significant decrease of hepatic and plasma concentration of triglycerides. The serum concentrations of cholesterol and phospholipids showed an increase in a time-dependent manner in rats fed the pelleted chow diet. The hepatic concentration of cholesterol was increased in rats fed the cholesterol diet and pelleted chow diet after administration of DHA compared to palmitic acid. In all rat models, treatment with DHA tended to increase the peroxisomal beta-oxidation. This was accompanied with a significant increase (1.5-fold) of fatty acyl-CoA oxidase activity. The mitochondrial fatty acid oxidation system and carnitine palmitoyl-transferase activity, however, were almost unchanged. Moreover, palmitoyl-CoA synthetase activity was increased, whereas the palmitoyl-CoA hydrolase activity was decreased. Neither microsomal phosphatidate phosphohydrolase activity nor cytosolic phosphatidate phosphohydrolase activity was affected by DHA feeding in the three rat models. Acyl-CoA:1,2-diacylglycerol acyltransferase activity was also unaffected. In contrast to docosahexanoic acid feeding, eicosapentaenoic acid (EPA) administration possessed a hypotriglyceridemic effect and resulted in an increase of mitochondrial and peroxisomal oxidation of fatty acids. Carnitine palmitoyltransferase activity was also stimulated. Phosphatidate phosphohydrolase activity was unaffected whereas diacylglycerol acyltransferase activity was increased by EPA treatment compared with palmitic acid feeding. The results indicate that docosahexaenoic acid, in contrast to eicosapentaenoic acid, does not inhibit the synthesis and secretion of triglycerides in the liver. In addition, the results emphasize the importance that stimulation of peroxisomal beta-oxidation by these n-3 fatty acids is not sufficient to decrease the serum levels of triglycerides. In addition, increased mitochondrial beta-oxidation of fatty acids and thereby decreased availability of nonesterified fatty acids may be a mechanism by which EPA inhibits triglyceride, and subsequently very low density lipoprotein-triglyceride, production. Whether DHA and EPA possess different metabolic properties should be considered.
Animals↗
Eicosapentaenoic acid at hypotriglyceridemic dose enhances the hepatic antioxidant defense in mice.
The effect of oral administration of purified (95%) eicosapentaenoic acid on serum lipids, hepatic peroxisomal enzymes, antioxidant enzymes and lipid peroxidation was compared with that of palmitic acid fed mice and corresponding controls. After 10 d, a dose of 1000 mg eicosapentaenoic acid per day/kg body weight lowered serum triglycerides by 45%, while no significant change in serum cholesterol level was noted in comparison to palmitic acid fed mice and controls. Hepatic acyl-CoA oxidase and catalase activities increased by 50% and 30%, respectively, in the eicosapentaenoic acid fed group. In addition, the hepatic reduced glutathione content and the activities of glutathione transferase, glutathione peroxidase and glutathione reductase, increased significantly during eicosapentaenoic acid treatment. The levels of hepatic lipid peroxides were lower after eicosapentaenoic acid feeding, while no significant change was noted in the palmitic acid fed mice when compared to the controls. Taken together, the present data demonstrate for the first time that at hypolipidemic doses eicosapentaenoic acid feeding i) enhances the hepatic antioxidant defense, and ii) does not cause a significant differential induction of the two peroxisomal enzymes, acyl-CoA oxidase and catalase, as was noted after administration of hypolipidemic peroxisome proliferating compounds, such as clofibrate in rodents.
Acyl-CoA Oxidase↗
Relationship between translocation of long-chain acyl-CoA hydrolase, phosphatidate phosphohydrolase and CTP:phosphocholine cytidylyltransferase and the synthesis of triglycerides and phosphatidylcholine in rat liver.
Translocation of long-chain acyl-coenzyme A hydrolase from the microsomal fraction to the cytosolic fraction was promoted in cell-free extracts of rat liver by palmitic acid, oleic acid, tetradecylthioacetic acid, and tetradecylthiopropionic acid, and by their CoA esters. The CoA esters were more effective than the non-esterified acids in the translocation of the enzyme. Treatment of normolipidemic rats with sulfur-substituted non-beta-oxidizable fatty acid analogues resulted in a transitory increase in hepatic concentration of long-chain acyl-CoA. Longer feeding times almost normalized the hepatic long-chain acyl-CoA content. Microsomal long-chain acyl-CoA hydrolase activity was inhibited, whereas the activity of the cytosolic form was stimulated. The rise in enzyme activity coincided with a reduction in liver content of triglyceride and an increase in hepatic phospholipid content. The results suggest that the activity of long-chain acyl-CoA hydrolase in the cytosol may control the amount of acyl-CoA thioesters in the liver. Esterified and non-esterified fatty acids caused in vitro translocation of phosphatidate phosphohydrolase and cytidine 5'-triphosphate (CTP):phosphocholine cytidylyltransferase from the cytosolic fraction to the microsomal fraction. However, the translocation of these two enzyme systems was not obtained in vivo. The activity of phosphatidate phosphohydrolase decreased in microsomal and cytosolic fractions while the activity of cytidylyltransferase in these fractions increased. The activities of soluble phosphatidate phosphohydrolase and long-chain acyl-CoA hydrolase appeared to be inversely correlated.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Ion transport in normal and CF airway epithelia.
Explore the source record for details and available documents.
Biological Transport, Active↗
3. Epithelial injury. Mechanisms and cell biology of airway epithelial injury.
Injury of airway epithelia involves selective interactions of toxins with the cellular and paracellular components of the epithelial barrier. Repair of epithelial injury appears to involve mitogenic and differentiating factors that function in autocrine and paracrine modes. Fruitful techniques for future study of airway epithelial injury and repair will include combinations of cell culture and modulation of gene expression.
Cell Division↗