Dietary n-3 polyunsaturated fatty acids decrease hepatic triglycerides in Fischer 344 rats

Dietary fatty acid composition modifies hepatic lipid metabolism. To determine the effects of fatty acids on hepatic triglyceride storage, rats were fed diets enriched in carbohydrates (control), fish oil, or lard. After 4 weeks, the animals were fasted overnight. In the morning, the animals were either sacrificed or fed 8 g of their respective diets before sacrifice. Animals ingested more food calories with diets containing fish oil than with other diets. However, fish oil-fed animals weighed less and had less body fat. In fish oil-fed animals, liver triglyceride was lower by 27% (P <.05) and 73% (P <.01) than in control- and lard-fed animals, respectively. Fish oil altered the postprandial gene expression of hepatic regulators of fatty acid degradation and synthesis. Fish oil feeding blunted the normal postprandial decline in fatty acid degradation genes (PPARalpha, CPT1, and ACO) and blunted the normal postprandial rise in triglyceride synthesis genes (SREBP1-c, FAS, SCD-1). Therefore, the direct postprandial effect of fish oil ingestion decreases the propensity for hepatic triglyceride storage. In conclusion, n-3 polyunsaturated fatty acids decrease total body weight, total body fat, and hepatic steatosis.     

n-3多不饱和脂肪酸与心房颤动

多不饱和脂肪酸(polyunsaturated fatty acid,PUFA)又称多烯酸.是指分子结构中含有2个或2个以上不饱和双键的脂肪酸.PUFA按照n编号系统(也叫ω,编号系统),即从甲基端开始第1个双键的位置,可分为n-3组、n-6组、n-7组、n-9组,每一组成员都可转化为多不饱和或链更长的脂肪酸.     

A high-cholesterol, n-3 polyunsaturated fatty acid diet causes different responses in rats and hamsters

This study was designed to investigate the response to a high-cholesterol, n-3 polyunsaturated fatty acid (PUFA) or n-6 PUFA diet in rats and hamsters. Animals were fed n-3 or n-6 PUFA with a cholesterol-free diet, or with a diet enriched with cholesterol (0.5%, w/w) for 2 weeks. In rats and hamsters fed a cholesterol-free diet, plasma cholesterol, triglycerides and very-low-density lipoprotein (VLDL)-triglyceride levels in n-3 PUFA group were significantly lower than those in n-6 PUFA group. In contrast, when diets were supplemented with 0.5% cholesterol, the plasma cholesterol- and triglyceride-lowering effect of dietary n-3 PUFA disappeared. In hamsters fed with the atherogenic diet (0.5% dietary cholesterol) for 2 weeks, n-3 PUFA induced hypercholesterolemia more than n-6 PUFA, the increase being in the VLDL and low-density lipoprotein (LDL) fractions. Our data thus indicate that elevation of VLDL- and LDL-cholesterol in hamsters by n-3 PUFA, compared with n-6 PUFA, is dependent on 0.5% dietary cholesterol supplementation. In rats, on the other hand, dietary n-3 PUFA did not induce hypercholesterolemia more than n-6 PUFA when 0.5% cholesterol was supplemented. Although the effects of n-3 PUFA on plasma cholesterol, triglycerides and VLDL-triglycerides were similar in hamsters and rats, the interactive effects of n-3 PUFA and cholesterol on plasma and lipoprotein cholesterol levels differed in the two species. It was also found that plasma triglycerides, cholesterol and lipoprotein cholesterol levels in hamsters are higher than in rats in the presence and absence of dietary cholesterol. In addition, cholesterol feeding induces hypertriglyceridemia and hypercholesterolemia only in hamsters. Moreover, liver triglyceride concentrations increased in rats fed a cholesterol-rich diet and hepatic triglyceride levels of the n-3 PUFA-fed rats were significantly lower than those in the n-6 PUFA-fed rats in the presence and absence of dietary cholesterol. However, triglycerides did not accumulate in the liver in hamsters fed a cholesterol-rich diet and hepatic triglyceride levels of the n-3 PUFA-fed hamsters were not significantly different from those in the n-6 PUFA-fed hamsters in the presence and absence of dietary cholesterol. Therefore, these studies confirm marked species differences in response to the interactive effects of dietary n-3 PUFA and cholesterol.     

Fatty acid and enzymatic compositional changes in the pancreas of rats fed dietary n-3 and n-6 polyunsaturated fatty acids

The influence of n-3 and n-6 PUFA on the fatty acid composition and the enzyme content of zymogen granules of the normal exocrine pancreas was tested on rats. The animals were fed on different diets comprising 5% fish oil (FO), safflower oil (SFO), and evening primrose oil (EPO) used singly or in combination as dietary fats. The results were compared with those from animals fed 5% hydrogenated beef tallow (HBT). The fatty acid composition and digestive enzyme content were analyzed after a 6-wk feeding period. Differences in the pancreatic fatty acid profiles were related to the fatty acid composition of the ingested fats. Equivalent levels of n-3 fatty acids and 20:3n-6 were obtained with either EPO or FO fed singly or in combination. Similar results were observed with SFO/FO. Higher C20:3n-6/C20:4n-6 ratios were obtained with the oil mixtures. An increase in amylase levels, but a decrease in serine protease (Band 21 kdalton) levels, was associated with EPO. An elevation in procarboxypeptidase levels paralleled an increase in 18:0 levels, whereas the proportion of lipase (Band 49 kdalton) varied inversely with the proportion of C20:3n-6. The SFO/FO mixture elevated the proportions of protease II and proelastase. These results suggest that specific fatty acids influence the proportion of specific digestive enzymes in the zymogen granules.     

Identification and characterization of an enzyme involved in the elongation of n-6 and n-3 polyunsaturated fatty acids

The enzymes that are involved in the elongation of fatty acids differ in terms of the substrates on which they act. To date, the enzymes specifically involved in the biosynthesis of polyunsaturated fatty acids have not yet been identified. In an attempt to identify a gene(s) encoding an enzyme(s) specific for the elongation of gamma-linolenic acid (GLA) (18:3n-6), a cDNA expression library was made from the fungus Mortierella alpina. The cDNA library constructed in a yeast expression vector was screened by measuring the expressed elongase activity [conversion of GLA to dihomo-GLA (20:3n-6)] from an individual yeast clone. In this report, we demonstrate the isolation of a cDNA (GLELO) whose encoded protein (GLELOp) was involved in the conversion of GLA to dihomo-GLA in an efficient manner (60% conversion). This cDNA contains a 957-nucleotide ORF that encodes a protein of 318 amino acids. Substrate specificity analysis revealed that this fungal enzyme acted also on stearidonic acid (18:4n-3). This report identifies and characterizes an elongase subunit that acts specifically on the two Delta6-desaturation products, 18:3n-6 and 18:4n-3. When this GLELO cDNA was coexpressed with M. alpina Delta5-desaturase cDNA in yeast, it resulted in the conversion of GLA to arachidonic acid (20:4n-6) as well as the conversion of stearidonic acid to eicosopentaenoic acid (20:5n-3). Thus, this GLELO gene may play an critical role in the bio-production of both n-6 and n-3 polyunsaturated fatty acids.     

Dietary polyunsaturated fatty acid prevents hyperlipidemia and hepatic oxidant status in pregnant diabetic rats and their macrosomic offspring

A considerable amount of clinical and experimental evidence now exists and suggests the involvement of fatty acids and free radical-mediated oxidative processes in the pathogenesis of diabetic complications. Fetuses from diabetic mothers are at increased risk of developing neonatal macrosomia and oxidative stress. We investigated the modulation of antioxidant status and liver biochemical parameters in normal and diabetic pregnant rats and their offspring. Animals were randomly allocated into three groups of six rats each: a control group, a diabetic group and diabetic rats fed with flax and sesame seeds mixture group. The time course of changes in lipid metabolism and antioxidant status by dietary rich in ω3- and ω6-polyunsaturated fatty acids in alloxan-induced diabetic pregnant rats and their macrosomic offspring was studied. Glucose and insulin levels were also assessed in order to characterize the diabetic state of dams and their offspring. The diabetic rats presented a significant increase in glycemia, plasma and liver lipid parameters compared with those of control group. In addition, liver malonaldialdehyde levels significantly increased. Antioxidant enzyme activities such as catalase and superoxide dismutase and reduced glutathione levels significantly decreased in the liver of diabetic rats when compared with controls. Diet supplemented with flax and sesame seeds mixture in pregnant diabetic rats ameliorated lipid parameters, antioxidant enzyme activities, level of reduced glutathione and significantly decreased malonaldialdehyde levels. These ameliorations were also observed in pups whose pregnant diabetic mothers were fed seeds mixture. Our results suggested that flax and sesame seeds mixture supplemented to diet of pregnant diabetic rats might be helpful in preventing diabetic complications in adult dams and their offspring.     

n-3多聚不饱和脂肪酸与心血管疾病

在发达国家,心血管疾病为其主要死亡原因,在发展中国家,心血管疾病的发病率逐年增加。根据2000年中国卫生年鉴公布的资料显示,心血管（包括脑血管）病的死亡率无论在城市还是农村均居于首位。如何预防心血管疾病,控制其病情,改善其预后为当代医学的主要研究课题之一。在西方国家的研究中,鱼油被认为具有心血管保护作用。     

Dietary n-3 polyunsaturated fatty acids and endothelium dysfunction induced by lysophosphatidylcholine in Syrian hamster aorta

This study investigated the influence of an eicosapentaenoic acid (EPA)- or a docosahexaenoic acid (DHA)-supplemented diet on the deleterious effects of lysophosphatidylcholine (LPC) on endothelium-dependent vasorelaxation of Golden Syrian hamster thoracic aorta. In a second step, LPC-modulated phospholipase A(2) (PLA(2))-derived ways of relaxation were investigated. Golden Syrian hamsters were fed for 6 weeks with a control diet or an EPA- or DHA-supplemented diet. Aortic fatty acid composition was analyzed by gas chromatography. Aortic rings were incubated for 20 minutes with LPC before constructing cumulative concentration-response curves for acetylcholine (ACh; 3 nmol/L-30 micromol/L) or sodium nitroprusside (3 nmol/L-30 micromol/L). The EPA- or DHA-supplemented diet increased n-3 polyunsaturated fatty acids in aortic fatty acids content because of the increase of EPA or DHA content, respectively, and decreased arachidonic acid aortic content. Lysophosphatidylcholine (1, 10, 15, and 20 micromol/L) induced a concentration-dependent inhibition of ACh-induced relaxation of preconstricted aortic rings in the control group, but did not influence sodium nitroprusside-induced aortic relaxation. The DHA- or EPA-supplemented diet worsened LPC (20 micromol/L) inhibitory effects on ACh-induced vasorelaxation. In the control diet group, ACh-induced relaxation was abolished by the nitric oxide synthase inhibitor (l-N(G)-nitro-arginine methyl ester; 100 micromol/L), whether LPC was added or not. The ACh-induced vasorelaxation was partially inhibited by PLA(2) inhibitors methyl arachidonyl fluorophosphonate (25 micromol/L) and arachidonyl trifluoromethyl ketone (20 micromol/L) as well as by the combination of 2 Ca(2+)-dependent potassium (K(Ca)) channel inhibitors charybdotoxin (0.1 micromol/L) plus apamin (0.3 micromol/L). In the presence of LPC (20 micromol/L), ACh-induced vasorelaxation was abolished by these inhibitors. These effects were not influenced by DHA or EPA diet. Our results suggested that EPA- or DHA-supplemented diet did not exhibit any beneficial effect against LPC-induced inhibition of endothelium-dependent aortic relaxation in Golden Syrian hamsters. These LPC effects were associated in our study not only with an inhibition of nitric oxide-dependent vasorelaxation, but also with a concomitant activation of a compensatory vasorelaxant pathway depending both on PLA(2) metabolites and on K(Ca) channel opening.     

Effects of n-3 polyunsaturated fatty acid on upper limit of vulnerability shocks

BACKGROUND: Ventricular fibrillation (VF) can be induced when a strong shock is delivered during the vulnerable period of a cardiac cycle. VF, however, cannot be induced if the shock strength is increased to the "upper limit of vulnerability" (ULV) level. Docosahexaenoic acid (DHA) has been shown to prevent the occurrence of VF after coronary occlusion. However, its effects on the ULV have not been verified. We tested the hypothesis that ULV shock strength is decreased after DHA administration. METHODS: In 10 pigs, 10 S1s (square, 5-ms) were delivered from the RV apex electrode at 300 ms cycle length. Shocks (S2, biphasic) were delivered from the RV-SVC electrodes after the last S1. The ULV was determined using an up/down protocol. In group 1 (n = 5), after the control ULV was determined at the beginning of the study, a solution containing 1.0 gm of DHA was infused intravenously within 90 min. The ULV (DHA-ULV) was determined again after the end of infusion. In group 2 (n = 5), the vehicle for DHA was infused instead of DHA to confirm that the vehicle did not have an effect on the ULV. RESULTS: DHA-ULV (412 +/- 58 V, 12 +/- 3 J) was significantly decreased (P < 0.04) compared to the control ULV (478 +/- 32 V, 16 +/- 3 J). The ULV before (483 +/- 28 V, 16 +/- 1 J) and after (463 +/- 28 V, 15 +/- 2 J) the vehicle infusion was not different (P = 0.4). There was no change in the systolic blood pressure as well as heart rate in both groups. CONCLUSION: DHA significantly decreases the ULV (13% by voltage and 25% by energy), suggesting that DHA can help to prevent VF induced by a strong stimulus delivered during the vulnerable period.     

Dietary n-3 polyunsaturated fatty acids reduce disease and colonic proinflammatory cytokines in a mouse model of colitis

BACKGROUND: n-3 polyunsaturated fatty acids (PUFAs) reduce the severity of chronic inflammatory bowel disease, probably by means of reduction of immune cell activation or enhancement of the epithelial barrier. Using the severe combined immunodeficient (SCID) mouse model of colitis, this study examined the effect of dietary n-3 PUFAs on development of colitis and on immunologic, epithelial, and matrix parameters in the intestines of control and colitic animals. METHODS: SCID mice were fed n-3-enriched or control diet for 3 weeks before colitis induction by transplantation of CD45RB T cells and maintained on the same diet for 4 to 8 weeks. Phenotype of infiltrating cells, epithelial ZO-1 protein, and mucosal type I collagen were assessed by immunohistology and tissue cytokines by ELISA. RESULTS: Transplanted n-3-fed animals had significantly reduced pathology scores, colonic tumor necrosis factor-alpha, interleukin-12, and interleukin-1beta compared with animals fed standard diet. Proinflammatory cytokines were reduced despite a similar level of immune cell infiltration by T cells, CD11c cells, and CD11b cells. Neutrophil infiltration was significantly reduced in n-3-fed control and colitic mice, and other myeloid populations were reduced in mice on the n-3 diet. Epithelial ZO-1 expression was increased, and myofibroblast activation significantly decreased in transplanted n-3-fed animals compared with standard diet mice. Submucosal collagen synthesis was enhanced in n-3-fed mice. CONCLUSIONS: Dietary n-3 PUFAs reduced clinical colitis and colonic immunopathology in this model of colonic inflammation by decreasing proinflammatory cytokine synthesis, reducing myeloid cell recruitment and activation, and enhancing epithelial barrier function and mucosal wound healing mechanisms.     

Protective effect of n-3 polyunsaturated fatty acid on primary culture of rat hepatocytes

BACKGROUND AND AIM: Recently, we reported on the beneficial clinical effects of eicosapentaenoic acid (EPA) in patients with primary biliary cirrhosis (PBC) who were unresponsive to ursodeoxycholic acid (UDCA). In this study we examined the effect of EPA on rat hepatocytes in primary culture. METHODS: Hepatocytes were isolated from rat liver by perfusion of collagenase and cultured with or without EPA. Cell damage induced by chenodeoxycholic acid (CDCA) was assessed by WST-8 assay and lactate dehydrogenase (LDH) release. PGE(2) and LTB(4) concentrations in the culture medium were measured by enzyme-linked immunosorbent assay (ELISA). cDNA was made from total RNA that was extracted from hepatocytes, and TaqMan polymerase chain reaction (PCR) was performed to assess the expression of CuZn and Mn superoxide dismutase (SOD) mRNA. RESULTS: When rat hepatocytes were cultured in the presence of EPA, the damage caused by CDCA was significantly decreased compared with cells cultured without EPA. Cytotoxicity significantly decreased in the presence of EPA. Furthermore, SOD mRNA expression was increased by adding EPA. These findings indicated that EPA protects cells by scavenging superoxide radicals ((*)O(2-)) mediated by SOD production. CONCLUSION: EPA has a direct protective effect on rat hepatocytes, which is in agreement with the clinical efficacy of EPA in PBC patients.     

Biosynthesis of polyunsaturated fatty acids of (n-6) and (n-3) series in isolated adrenocortical cells of rats. Effect of ACTH

Both the capacity of isolated adrenocortical cells to incorporate and transform [1-14C]linoleic and [1-14C]alpha-linolenic acids and the effect of ACTH on the biosynthesis of polyunsaturated fatty acids from [1-14C]alpha-linolenic acid were investigated. The cells were able to incorporate both labeled precursor acids and convert them into higher homologs. This transformation increases along the incubation time tested. When linoleic acid was the precursor, the biosynthesis of higher homologs was carried out following the desaturating-elongating route. Both pathways, the desaturating-elongating and the elongating, were detected when the substrate was alpha-linolenic acid. The results proved the existence of delta 6, delta 5 and delta 4-desaturases in this type of cells. Isolated adrenocortical cells obtained from rats treated with ACTH showed an increase in the amount of [1-14C]alpha-18:3 that remained in the cells without metabolization and, consequently, a decrease in the last product formed (20:5 n-3) was evident compared to the controls. Simultaneously, the desaturation-elongation products decreased significantly. Similar results were obtained when cells isolated from untreated rats were incubated for 3 h in the presence of ACTH. In this case, the values obtained returned to normal levels 6 h after incubation. These results were mimicked by dibutyryl-cyclic AMP. It can be concluded that the effect of ACTH on the biosynthesis of polyunsaturated fatty acids from alpha-linolenic acid was mediated through an enhancement of the intracellular levels of cAMP.     

Dietary fish and n-3 fatty acid intake and cardiac electrocardiographic parameters in humans.

OBJECTIVES: We evaluated the association between dietary fish intake and several cardiac electrocardiographic parameters in humans relevant to arrhythmic risk. BACKGROUND: Fish consumption may reduce the incidence of sudden death and atrial fibrillation, possibly related to anti-arrhythmic effects. METHODS: In a population-based study of 5,096 men and women, we evaluated cross-sectional associations between usual dietary fish intake and electrocardiographic measures of heart rate, atrioventricular conduction (PR interval), ventricular repolarization (QT interval), and ventricular conduction (QRS interval). Multivariate models were adjusted for age, gender, race, education, smoking, body mass index, diabetes, coronary heart disease, physical activity, and intakes of beef or pork, fried fish, fruits, vegetables, alcohol, and total calories. RESULTS: Consumption of tuna or other broiled or baked fish (comparing the highest to the lowest category of intake) was associated with lower heart rate (-3.2 beats/min, 95% confidence interval [CI] = 1.3 to 5.1; p trend <0.001), slower atrioventricular conduction (PR interval +7.2 ms, 95% CI = 1.4 to 12.9; p trend = 0.03), and substantially lower likelihood of prolonged QT (relative risk = 0.50, 95% CI = 0.27 to 0.95; p trend = 0.03). Tuna/other fish intake was not associated with ventricular conduction (p = 0.60). Findings were similar for estimated intake of marine n-3 fatty acids: a 1 g/day higher intake was associated with 2.3 beats/min lower heart rate (95% CI = 0.9 to 3.7), 7.6 ms longer PR interval (95% CI = 3.3 to 11.9), and 46% lower likelihood of prolonged QT (relative risk = 0.54, 95% CI = 0.33 to 0.88). CONCLUSIONS: These findings in this large, population-based study suggest that dietary fish intake is associated with cardiac electrophysiology in humans, including heart rate, atrioventricular conduction, and ventricular repolarization, with potential implications for arrhythmic risk.     

Serum enriched with n-3 polyunsaturated fatty acids inhibits procoagulant activity in endothelial cells.

Nine healthy male volunteers (mean age 24.3 years, range 21-27 years) ingested 25 ml cod liver oil (CLO) daily for 8 weeks. Blood samples were collected before and after the intervention period. A slight increase in total serum cholesterol (+ 12.2%, P less than 0.01) and high density lipoprotein cholesterol (+ 16.9%, P less than 0.01) were calculated to have a non-significant effect on the high/low density lipoprotein ratio. Polyunsaturated fatty acids in serum were displaced from the n-6 family to the n-3 family, reflected by an eight-fold increase of the eicosapentaenoic (20:5 n-3)/arachidonic (20:4n-6) acid ratio. Human umbilical vein endothelial cells were grown in a medium to which 30% sterile filtered serum, collected before and after CLO supplementation for 72 h, was added. After 2 h exposure to lipopolysaccharides the thromboplastin activity in endothelial cultures incubated with serum enriched with n-3 fatty acids was 43% lower than in cultures containing serum collected before the intervention (1.86 +/- 0.48 10(-3)/10(6) cells vs 3.26 +/- 0.85 10(-3)/10(6) cells). It is suggested that serum prepared from subjects given n-3 fatty acids may support the thromboresistence of endothelial cells.     

Competition of n-3 and n-6 polyunsaturated fatty acids in the isolated perfused rat heart

When perfused with exogenous arachidonic acid (AA) or eicosapentaenoic acid (EPA), the rat heart incorporated these fatty acids into phospholipids, chiefly as phosphatidylcholine. The pattern of fatty acid incorporation at any given concentration of fatty acid in the perfusate was not different between n-3 and n-6 polyenoates. When rat hearts were perfused with the same amounts but different mixtures of EPA and AA, the incorporation of EPA showed a marked increase proportional to the EPA/AA ratio present in the perfusate. Results indicated that cardiac muscle phospholipids incorporate n-3 and n-6 polyenoates equally effectively and hence enrichment of n-3 polyenoate can displace AA in the cardiac phospholipid pool.