Implications of Lipids in Neonatal Body Weight and Fat Mass in Gestational Diabetic Mothers and Non-Diabetic Controls

Purpose of Review

Maternal lipid metabolism greatly changes during pregnancy and we review in this article how they influence fetal adiposity and growth under non-diabetic and gestational diabetic conditions.

Recent Findings

In pregnant women without diabetes (control), maternal glycemia correlates with neonatal glycemia, neonatal body weight and fat mass. In pregnant women with gestational diabetes mellitus (GDM), maternal glucose correlates with neither neonatal glycemia, neonatal birth weight nor fat mass, but maternal triacylglycerols (TAG), non-esterified fatty acids (NEFA) and glycerol do correlate with birth weight and neonatal adiposity. The proportions of maternal plasma arachidonic (AA) and docosahexaenoic (DHA) acids decrease from the first to the third trimester of pregnancy, and at term these long-chain polyunsaturated fatty acids are higher in cord blood plasma than in mothers, indicating efficient placental transfer. In control or pregnant women with GDM at term, the maternal concentration of individual fatty acids does not correlate with neonatal body weight or fat mass, but cord blood fatty acid levels correlate with birth weight and neonatal adiposity—positively in controls, but negatively in GDM. The proportion of AA and DHA in umbilical artery plasma in GDM is lower than in controls but not in umbilical vein plasma. Therefore, an increased utilization of those two fatty acids by fetal tissues, rather than impaired placental transfer, is responsible for their smaller proportion in plasma of GDM newborns.

Summary

In control pregnant women, maternal glycemia controls neonatal body weight and fat mass, whereas in mothers with GDM—even with good glycemic control—maternal lipids and their greater utilization by the fetus play a critical role in neonatal body weight and fat mass. We propose that altered lipid metabolism rather than hyperglycemia constitutes a risk for macrosomia in GDM.

     

Fetal erythrocyte membrane lipids modification: preliminary observation of an early sign of compromised insulin sensitivity in offspring of gestational diabetic women.

AIMS: Intrauterine exposure to diabetes is a significant determinant of the development of obesity and early onset of Type 2 diabetes mellitus in the offspring. Both conditions are characterized by insulin resistance and the latter is associated with reduced membrane arachidonic and docosahexaenoic acids. Hence, we investigated if the membrane arachidonic and docosahexaenoic acids are depressed in the cord blood of babies born to women with gestational diabetes. METHODS: Cord (fetal) and maternal blood were obtained at delivery from control subjects (n = 33) and women with gestational diabetes (n = 40) and analysed for plasma triglycerides and cholinephosphoglycerides, and erythrocyte choline- and ethanolaminephosphoglycerides fatty acids. RESULTS: Babies of gestational diabetic mothers had reduced docosahexaenoic acid in the plasma (5.9 +/- 1.4 vs. 7.1 +/- 2.0, P < 0.01) and erythrocyte (4.0 +/- 2.2 vs. 5.4 +/- 2.9, P < 0.05) cholinephosphoglycerides. Moreover, the total omega-6 and omega-3 fatty acids of the erythrocyte cholinephosphoglycerides were significantly lower (P < 0.05) in these babies. A similar trend was observed in plasma triglycerides and erythrocyte ethanolaminephosphoglycerides. The maternal plasma triglycerides and erythrocyte ethanolaminephosphoglycerides fatty acids profile were not different between the two groups. However, there was a reduction in arachidonic acid and total omega-6 fatty acids in the erythrocyte cholinephosphoglycerides of the gestational diabetic women. CONCLUSION: The altered plasma and erythrocyte fatty acids in the cord blood of babies born to women with gestational diabetes suggests a perturbation in the maternal-fetal nutrient transport and/or fetal lipid metabolism.     

Relationship between circulating n-3 fatty acid concentrations and endothelial function in early adulthood.

AIMS: Fish consumption is inversely associated with cardiovascular mortality, presumably because of n-3 fatty acids in fish. Whether the protection of n-3 fatty acids extends beyond clinical coronary disease to influence the early vascular biology of atherosclerosis remains unclear. This study determined whether circulating levels of n-3 fatty acids are associated with vascular endothelial function in early adulthood. METHODS AND RESULTS: Three hundred and twenty-six adults (157 males, 169 females, aged 20 to 28 years) had high-resolution ultrasound measurements of flow-mediated brachial artery dilatation (FMD) (endothelium-dependent) and arterial response to glyceryl trinitrate (endothelium-independent). Levels of the n-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid in plasma and erythrocyte membranes of subjects were measured. n-3 Fatty acid levels were not related to vascular function in the whole group. In smokers, however, n-3 fatty acids were positively related to flow-mediated dilatation (plasma DHA vs. FMD: 0.045 mm. %(-1), 95% CI 0.011 to 0.079, P=0.01). Flow-mediated dilatation was also associated with n-3 fatty acid levels in subjects in the top third of the insulin, glucose and triglyceride distributions. CONCLUSION: In young smokers and those with higher fasting insulin, glucose or triglyceride concentrations (factors associated with endothelial dysfunction), n-3 fatty acid levels were positively associated with flow-mediated dilatation. This raises the possibility that physiological levels of circulating n-3 fatty acids may protect the endothelium from early adulthood.     

Preeclampsia is associated with compromised maternal synthesis of long-chain polyunsaturated Fatty acids, leading to offspring deficiency

Obesity and excessive lipolysis are implicated in preeclampsia (PE). Intrauterine growth restriction is associated with low maternal body mass index and decreased lipolysis. Our aim was to assess how maternal and offspring fatty acid metabolism is altered in mothers in the third trimester of pregnancy with PE (n=62) or intrauterine growth restriction (n=23) compared with healthy pregnancies (n=164). Markers of lipid metabolism and erythrocyte fatty acid concentrations were measured. Maternal adipose tissue fatty acid composition and mRNA expression of adipose tissue fatty acid-metabolizing enzymes and placental fatty acid transporters were compared. Mothers with PE had higher plasma triglyceride (21%, P<0.001) and nonesterified fatty acid (50%, P<0.001) concentrations than controls. Concentrations of major n-6 and n-3 long-chain polyunsaturated fatty acids in erythrocytes were 23% to 60% lower (all P<0.005) in PE and intrauterine growth restriction mothers and offspring compared with controls. Subcutaneous adipose tissue Δ-5 and Δ-6 desaturase and very long-chain fatty acid elongase mRNA expression was lower in PE than controls (respectively, mean [SD] control 3.38 [2.96] versus PE 1.83 [1.91], P=0.030; 3.33 [2.25] versus 1.03 [0.96], P<0.001; 0.40 [0.81] versus 0.00 [0.00], P=0.038 expression relative to control gene [square root]). Low maternal and fetal long-chain polyunsaturated fatty acid concentrations in PE may be the result of decreased maternal synthesis.     

Effects of introducing linseed in livestock diet on blood fatty acid composition of consumers of animal products

Reducing the ratio between essential fatty acids: C18:2 n-6/C18:3 n-3 down to 5 is recommended by Nutritional Guidelines. We studied the fatty acid (FA) changes in consumers' plasma following changes in livestock diet. First, a zootechnical study introduced 5% of extruded linseed into the diet of livestock to replace other oleaginous ingredients, and on an iso-nutritional values basis. The products from linseed-fed animals contained more n-3 fatty acids (precursor alpha-linolenic and derivatives obtained by elongations and desaturations) than control animal products (issued from animals fed without linseed), and more conjugated linoleic acids (CLA). The n-6/n-3 ratio was reduced by 54% in butter, 60% in meat and 86% in eggs. Following this, a double-blind, randomised, cross-over clinical study involving 75 healthy volunteers compared plasma and erythrocyte FA profiles in consumers of animal products (from livestock fed the linseed diet or from livestock fed standard diet). It showed modifications in the FA composition of the experimental human regimen with more C18:3 n-3 (1.65 vs. 0.75 g/day), and more n-3 derivatives. The C18:2 n-6/C18:3 n-3 ratio decreased (7 vs. 15). In volunteers' plasma, C18:3 n-3 increased in the essay group (0.93 vs. 0.44% of the FA), so did n-3 derivatives and CLA. The n-6/n-3 ratio decreased from 14.3 to 10.2. In erythrocytes, C20:5 n-3 increased in the essay group (0.59 vs. 0.45%) and so did C22:6 n-3. The n-6/n-3 ratio decreased in parallel from 4.2 to 3.8. Without any changes in consumers' eating habits, foodstuffs from animals fed linseed diets induced significant modifications of human plasma and erythrocyte fatty acid composition (comparable to that noted under the 'Cretan' diet) and a sharp increase in CLA.     

Lipid metabolism in pregnancy and its consequences in the fetus and newborn

During early pregnancy there is an increase in body fat accumulation, associated with both hyperphagia and increased lipogenesis. During late pregnancy there is an accelerated breakdown of fat depots, which plays a key role in fetal development. Besides using placental transferred fatty acids, the fetus benefits from two other products: glycerol and ketone bodies. Although glycerol crosses the placenta in small proportions, it is a preferential substrate for maternal gluconeogenesis, and maternal glucose is quantitatively the main substrate crossing the placenta. Enhanced ketogenesis under fasting conditions and the easy transfer of ketones to the fetus allow maternal ketone bodies to reach the fetus, where they can be used as fuels for oxidative metabolism as well as lipogenic substrates. Although maternal cholesterol is an important source of cholesterol for the fetus during early gestation, its importance becomes minimal during late pregnancy, owing to the high capacity of fetal tissues to synthesize cholesterol. Maternal hypertriglyceridemia is a characteristic feature during pregnancy and corresponds to an accumulation of triglycerides not only in very low-density lipoprotein but also in low- and high-density lipoprotein. Although triglycerides do not cross the placental barrier, the presence of lipoprotein receptors in the placenta, together with lipoprotein lipase, phospholipase A₂, and intracellular lipase activities, allows the release to the fetus of polyunsaturated fatty acids transported as triglycerides in maternal plasma lipoproteins. Normal fetal development needs the availability of both essential fatty acids and long chain polyunsaturated fatty acids, and the nutritional status of the mother during gestation has been related to fetal growth. However, excessive intake of certain long chain fatty acids may cause both declines in arachidonic acid and enhanced lipid peroxidation, reducing antioxidant capacity.     

Alcohol consumption in pregnant, black women is associated with decreased plasma and erythrocyte docosahexaenoic acid

BACKGROUND: Inner-city, black women are among those groups that are at higher risk for having infants with fetal alcohol spectrum disorders that can include life-long neurobehavioral and cognitive impairments. Chronic alcohol consumption can decrease amounts of docosahexaenoic acid (DHA), a fatty acid that is essential for optimal infant neural and retinal development in a variety of tissues. METHODS: Black women who presented at an inner-city antenatal clinic for their first prenatal visit were recruited into a longitudinal, observational study. Alcohol intake was determined by a structured interview. Participants provided blood specimens and completed food frequency surveys at 24 weeks of gestation, infant delivery, and 3 months postpartum. Fatty acid composition analyses were completed on 307, 260, and 243 for plasma and 278, 261, and 242 erythrocyte specimens at 24 weeks of gestation, delivery, and 3 months postpartum, respectively. RESULTS: Proportion of drinking days at the first prenatal visit was associated with decreased DHA in plasma and erythrocytes throughout the study. This association was the strongest at 24 weeks of gestation. In addition, an interaction between proportion of drinking days at the time of conception and ounces of absolute alcohol per drinking day at the time of conception was detected and demonstrated that, in daily drinkers, high intakes of alcohol are associated with decreased DHA and arachidonic acid (AA) concentrations in plasma. CONCLUSIONS: Frequent and high intakes of alcohol that have been previously associated with fetal alcohol spectrum disorders are also associated with decreased maternal DHA and AA plasma concentrations. The present findings indicate that maternal DHA deficiency is associated with high-risk drinking and may contribute to the mechanism(s) of alcohol-related neurodevelopmental disorders.     

Carbohydrate and lipid metabolism during human labor: Free fatty acids,glucose, insulin,and lactic acid metabolism during normal and oxytocin-induced labor for postmaturity

This investigation was performed to study the metabolism of the major body fuels (viz. glucose and free fatty acids), insulin, and lactic acid during the stress of human labor. In addition, the role of the normal placenta in the transport of these substances between mother and the fetus was evaluated by measuring them in the mother and cord blood at delivery. To study possible alterations of this role in the placenta which had exceeded the normal period of gestation, a second comparable group of women had labor induced with oxytocin 16–18 days beyond the expected date of delivery. A dramatic twofold increase in maternal plasma free fatty acids was observed during labor. There was a lesser but definite increase in blood glucose concentrations. No rise in serum insulin levels was noted which coincided with the changes in blood glucose. Lactic acid concentrations during the course of labor were variable from baseline but at delivery, the concentrations rose to very significant levels. Free fatty acids and blood glucose levels were significantly higher in the maternal than in the fetal side. A significantly positive correlation was noted between the maternal and cord blood values except for free fatty acids in the postmature group. No significant difference, nor a correlation was found between the two compartments in the insulin nor lactic acid levels.These results suggest that during human labor free fatty acids are the principal metabolic fuel. This increase in maternal free fatty acids may serve to spare glucose as a metabolic fuel in the fetus. The mechanism responsible for the increase maternal free fatty acid mobilization remains to be determined. It is not possible to discern any consistant alteration in placental function as a consequence of prolonged gestation.     

Maternal-fetal fat transport versus new fat synthesis in the pregnant diabetic rat

Summary Rats were made diabetic by the injection of streptozotocin on day 12 of pregnancy and were investigated on days 17 and 20 of pregnancy. A significant correlation between both maternal plasma triglyceride and nonesterified fatty acid levels with placental or fetal triglyceride content was found, although fetal weight did not change significantly. In order to investigate the source of the placental and fetal fat the rats received, intragastrically 24 h earlier, 1-¹⁴C-triolein (as a preformed fatty acid tracer) and tritiated water (as a marker of de novo fatty acid synthesis). Several maternal tissues, placenta, and fetuses were extracted and analysed for fatty acid radioactivity. Compared with non-diabetic pregnant rats, maternal ¹⁴C-label storage was reduced. In contrast, the placental and fetal tissues demonstrated a significant rise in ¹⁴C-label, similar in magnitude to the rise in their triglyceride content. The pattern of ³H incorporation also indicated a pronounced decrease in maternal fatty acid synthesis, but no increase in de novo fatty acid synthesis in the fetus or placenta. The findings show that fetal lipids in the pregnant rat originate both from maternal fatty acids and those synthesized in situ. The diabetes-induced increment in fetal triglyceride content is derived, however, from preformed maternal triglycerides or non-esterified fatty acids secondary to the increase in their concentration in the maternal circulation.     

Docosahexaenoic acid status in females of reproductive age with maple syrup urine disease

Individuals with maple syrup urine disease (MSUD) have impaired metabolism of branched-chain amino acids (BCAA) valine, isoleucine, and leucine. Life-long dietary therapy is recommended to restrict BCAA intake and thus prevent poor neurological outcomes and death. To maintain adequate nutritional status, the majority of protein and nutrients are derived from synthetic BCAA-free medical foods with variable fatty acid content. Given the restrictive diet and the importance of omega-3 fatty acids, particularly docosahexaenoic acid (DHA), in neurological development, this study evaluated the dietary and fatty acid status of females of reproductive age with MSUD attending a metabolic camp. Healthy controls of similar age and sex were selected from existing normal laboratory data. Total lipid fatty acid concentration in plasma and erythrocytes was analyzed using gas chromatography–mass spectroscopy. Participants with MSUD had normal to increased concentrations of plasma and erythrocyte alpha linolenic acid (ALA) but significantly lower concentrations of plasma and erythrocyte docosahexaenoic acid (DHA) as percent of total lipid fatty acids compared with controls (plasma DHA: MSUD 1.03 ± 0.35, controls 2.87 ± 1.08; P = 0.001; erythrocyte DHA: MSUD 2.58 ± 0.58, controls 3.66 ± 0.80; P = 0.011). Dietary records reflected negligible or no DHA intake over the 3-day period prior to the blood draw (range 0–2 mg). These results suggest females of reproductive age with MSUD have lower blood DHA concentrations than age-matched controls. In addition, the presence of ALA in medical foods and the background diet may not counter the lack of preformed DHA in the diet. The implications of these results warrant further investigation.     

Changes in erythrocyte membrane fatty acids during a clinical trial of eicosapentaenoic acid (EPA) supplementation in schizophrenia

In a previously reported double-blind, placebo-controlled trial of eicosapentaenoic acid (EPA) as supplemental treatment in 40 patients with schizophrenia, we found significant improvement in symptoms as measured by the Positive and Negative Syndrome Scale (PANSS) compared to placebo (Emsley et al. 2002). Here we report changes in fatty acid composition of erythrocyte membranes in the same sample (n = 16 in each group). After 12 weeks of receiving EPA, levels of several saturated and mono-unsaturated fatty acids decreased significantly while levels of n-3 fatty acids increased significantly compared to the placebo group. Increases of n-3 and n-6 fatty acids in the erythrocyte membranes were greater in subjects who improved more than 20% on overall symptoms. Changes in fatty acids correlated significantly with improvement in PANSS sub-scale scores, more so in females than in males. Docosahexaenoic acid (DHA) (22:6n-3) levels increased less than expected, suggesting a possible defect in synthesis or incorporation of DHA into membranes in schizophrenia. Improvement in dyskinesia correlated significantly with an increase in alpha-linolenic acid (18:3n-3; p = 0.03), and a decrease in 20:1n-9 (p = 0.005).     

The influence of high maternal plasma glucose levels,and maternal blood flow on the placental transfer of glucose in the guinea pig

Summary The relationship between maternal and fetal plasma glucose concentrations and placental glucose transfer has been studied in the anaesthetised guinea pig. The fetal circulation of the placenta, left in situ, was perfused through the umbilical arteries, after removal of the fetus, with a low molecular weight dextran, containing physiological salts and 100 mg/100 ml glucose. The maternal plasma: fetal perfusate concentration ratio of antipyrine, infused at a constant rate into the maternal circulation, was used to monitor the changes in maternal placental blood flow. — As the maternal plasma glucose was increased from 100 to 450 mg/100 ml the perfusate concentration followed, but at a slower rate. No further increases in perfusate concentration occurred after the maternal plasma level exceeded 450 mg/100 ml which suggests a maximum capacity of the placental membrane to transport glucose, analogous to that observed for the renal tubule and blood brain barrier. — The transfer rates of glucose from the fetal to the maternal circulation were similar to those in the opposite direction, with the same linear relationship to the transplacental gradients. Transfer, in either direction across the placental membrane, was reduced when the maternal placental blood flow was impaired, as indicated by a maternal: fetal antipyrine ratio below 0.6.     

Transport and metabolism of amino acids in placenta

In all mammalian species, the 20 amino acids of the genetic code are required for net protein accretion. The nutritional supply of amino acids for growth is defined as the net umbilical uptake of amino acids, representing the net transfer from maternal circulation, through the placenta and then to the fetus, of essential and non-essential amino acids. In considering the primary role of the placenta in the delivery of amino acids to the fetus for metabolism, it is important to consider the multiplicity of factors that may affect these overall delivery rates, including the activity and location of amino acid transporter systems, changes in these systems as gestation advances, effects of changes in placental surface area, uteroplacental blood flows, and maternal concentrations of amino acids. In this review, we discuss placental amino acid transport, the systems and their associated proteins, umbilical uptake data in animal and human studies, and amino acid transport in fetal growth restriction. Additionally, we discuss the current pool of thought concerning the mechanisms of placental amino acid transport as generated through in vitro vesicle studies and how they relate to the in vivo fluxes of animal studies. Finally, we discuss fetoplacental amino acid metabolism and specifically interorgan exchange.     

Influence of different dietary fatty acid sources on erythrocyte lipids and plasma and liver essential fatty acids in hamsters fed ethanol

Hamsters fed ethanol were given three different dietary sources of essential fatty acids; safflower oil, evening primrose oil (both mainly n-6 fatty acids) or linseed oil (mainly n-3 fatty acids). After 7 weeks, plasma, erythrocyte and liver lipids and fatty acids were analyzed. Plasma and liver lipids were not significantly different in the ethanol-fed hamsters compared to the controls. Erythrocyte total phospholipid was increased only in the ethanol-fed groups given n-6 but not n-3 fatty acids. Some fatty acid changes induced by ethanol were predictable, e.g. lower 20:4 n-6 in hamsters fed n-6 fatty acids, but others were not predictable, e.g. higher 22:6 n-3 in all the ethanol-fed groups. The effect of ethanol on hamster lipids and fatty acid composition appears dependent on the predominant class of dietary fatty acids.     

Early pregnancy maternal endocrine insulin-like growth factor I programs the placenta for increased functional capacity throughout gestation

In early pregnancy, the concentrations of IGFs increase in maternal blood. Treatment of pregnant guinea pigs with IGFs in early to midpregnancy enhances placental glucose transport and fetal growth and viability near term. In the current study, we determined whether exogenous IGFs altered placental gene expression, transport, and nutrient partitioning during treatment, which may then persist. Guinea pigs were infused with IGF-I, IGF-II (both 1 mg/kg x d) or vehicle sc from d 20-35 of pregnancy and killed on d 35 (term is 70 d) after administration of [(3)H]methyl-D-glucose (MG) and [(14)C]amino-isobutyric acid (AIB). IGF-I increased placental and fetal weights (+15 and +17%, respectively) and MG and AIB uptake by the placenta (+42 and +68%, respectively) and fetus (+59 and +90%, respectively). IGF-I increased placental mRNA expression of the amino acid transporter gene Slc38a2 (+780%) and reduced that of Igf2 (-51%), without altering the glucose transporter Slc2a1 or Vegf and Igf1 genes. There were modest effects of IGF-I treatment on MG and AIB uptake by individual maternal tissues and no effect on plasma glucose, total amino acids, free fatty acids, triglycerides, and cholesterol concentrations. IGF-II treatment of the mother did not alter any maternal, fetal or placental parameter. In conclusion, exogenous IGF-I, but not IGF-II, in early pregnancy increases placental transport of MG and AIB, enhancing midgestational fetal nutrient uptake and growth. This suggests that early pregnancy rises in maternal circulating IGF-I play a major role in regulating placental growth and functional development and thus fetal growth throughout gestation.     

Comparative changes in the fatty-acid composition of rat cardiac phospholipids after long-term feeding of sunflower seed oil- or tuna fish oil-supplemented diets

The fatty-acid composition of rat heart phospholipids was examined after long-term, i.e. more than 12 months, feeding of diets supplemented with n-6 fatty acids as sunflower seed oil (SSO), or n-3 fatty acids as tuna fish oil (TFO) which is a particularly rich source of docosahexenoic acid (DHA). Although some small changes occurred in the relative proportions of palmitic and stearic acids and in the ratio of total saturates to total unsaturates, the most important changes were in the relative proportions of 18:2 n-6 and 20:4 n-6 to 20:5 n-3 and 22:6 n-3. In general, the n-6/n-3 ratio of phosphatidylcholine (PC), phosphatidylethanolamine (PE) and diphosphatidyl glycerol (DPG) was altered in favour of the family of fatty acids administered, although the proportions of the individual long-chain polyunsaturated fatty acids which contributed to this ratio varied from one class of phospholipids to another. In cardiac PC and PE, feeding TFO supplements reduced the proportions of arachidonic acid (AA) and significantly elevated (p less than 0.01) the proportions of DHA but produced relatively little change in those of eicosapentenoic acid (EPA). In DPG, feeding TFO led to a significant increase in the proportion of AA as well as an increase in DHA. The level of EPA was relatively low in PC, PE and DPG even after TFO feeding and never reached comparable levels with that of either AA or DHA. Nevertheless the n-6/n-3 ratio in all these classes of major cardiac phospholipids was significantly reduced by feeding TFO compared to the SSO diet or the commercial rat chow (CC) reference group. In contrast to the reports of other workers who have studied the fatty-acid composition of platelet membranes after feeding various fish oil supplements, in the rat heart the major effect of tuna fish oil is an increase in the proportion of DHA rather than EPA in the cardiac phospholipids.     

Alcohol consumption in rhesus monkeys depletes tissues of polyunsaturated fatty acids and alters essential fatty acid metabolism

Rhesus monkeys that were maintained on an adequate diet but with low levels of essential fatty acids (1.4 en% linoleic, 18:2n-6, and 0.08 en%, linolenic acid, 18:3n-3) became depleted of 20:4n-6, and 22: 6n-3 in their livers, plasma lipoproteins, and erythrocytes during an 18-month period of alcohol exposure (2.6 g kg(-1) day(-1)). Monkeys that consumed alcohol also had higher plasma concentrations of 4-hydroxynonenal compared to controls. The metabolism of 18:2n-6 and 18:3n-3 were evaluated in both groups of animals using deuterium-labeled substrates over a 9-day period. Alcohol consumption did not appear to have an effect on the absorption of either 2H5-18:2n-6 or 2H5-18:3n-3 ethyl esters into the circulation after a single oral dose. However, there was a greater enrichment of deuterium in the biosynthesized fatty acids, 20:4n-6 and 22:6n-3, in the plasma of the monkeys exposed to alcohol compared to controls. These results suggest that chronic alcohol exposure may lead to a stimulation of the rate at which long-chain polyunsaturated fatty acids are biosynthesized to compensate for an increase in lipid peroxidation.     

Enhanced level of n-3 fatty acid in membrane phospholipids induces lipid peroxidation in rats fed dietary docosahexaenoic acid oil

The effect of dietary docosahexaenoic acid (DHA, 22:6n-3) oil with different lipid types on lipid peroxidation was studied in rats. Each group of male Sprague-Dawley rats was pair fed 15% (w/w) of either DHA-triglycerides (DHA-TG), DHA-ethyl esters (DHA-EE) or DHA-phospholipids (DHA-PL) for up to 3 weeks. The palm oil (supplemented with 20% soybean oil) diet without DHA was fed as the control. Dietary DHA oils lowered plasma triglyceride concentrations in rats fed DHA-TG (by 30%), DHA-EE (by 45%) and DHA-PL (by 27%), compared to control. The incorporation of dietary DHA into plasma and liver phospholipids was more pronounced in the DHA-TG and DHA-EE group than in the DHA-PL group. However, DHA oil intake negatively influenced lipid peroxidation in both plasma and liver. Phospholipid peroxidation in plasma and liver was significantly higher than control in rats fed DHA-TG or DHA-EE, but not DHA-PL. These results are consistent with increased thiobarbituric acid reactive substances (TBARS) and decreased alpha-tocopherol levels in plasma and liver. In addition, liver microsomes from rats of each group were exposed to a mixture of chelated iron (Fe(3+)/ADP) and NADPH to determine the rate of peroxidative damage. During NADPH-dependent peroxidation of microsomes, the accumulation of phospholipid hydroperoxides, as well as TBARS, were elevated and alpha-tocopherol levels were significantly exhausted in DHA-TG and DHA-EE groups. During microsomal lipid peroxidation, there was a greater loss of n-3 fatty acids (mainly DHA) than of n-6 fatty acids, including arachidonic acid (20:4n-6). These results indicate that polyunsaturation of n-3 fatty acids is the most important target for lipid peroxidation. This suggests that the ingestion of large amounts of DHA oil enhances lipid peroxidation in the target membranes where greater amounts of n-3 fatty acids are incorporated, thereby increasing the peroxidizability and possibly accelerating the atherosclerotic process.     

Effects of long-chain polyunsaturated fatty acids on the contraction of neonatal rat cardiac myocytes.

Because of the ability of certain long-chain polyunsaturated fatty acids (PUFAs) to prevent lethal cardiac arrhythmias, we have examined the effects of various long-chain fatty acids on the contraction of spontaneously beating, isolated, neonatal rat cardiac myocytes. The omega 3 PUFA from fish oils, eicosapentaenoic acid [EPA; C20:5 (n-3)] and docosahexaenoic acid [DHA; C22:6 (n-3)], at 2-10 microM profoundly reduced the contraction rate of the cells without a significant change in the amplitude of the contractions. The fatty acid-induced reduction in the beating rate could be readily reversed by cell perfusion with fatty acid-free bovine serum albumin. Addition of either oxygenase inhibitors or antioxidants did not alter the effect of the fatty acids. Arachidonic acid [AA; C20:4 (n-6)] produced two different effects on the beating rate, an increase or a decrease, or it produced no change. In the case of the increased or unchanged beating rate in the presence of AA, addition of AA oxygenase inhibitors subsequently reduced the contraction rate. The nonmetabolizable AA analog eicosatetraynoic acid (ETYA) always reduced the beating rate, as did EPA or DHA. Two other PUFAs, linoleic acid [C18:2 (n-6)] and linolenic acid [C18:3 (n-3)] also exhibited similar but less potent effects compared with EPA or ETYA. In contrast, neither the monounsaturated fatty acid oleic acid [C18:1 (n-9)] nor the saturated fatty acids stearic acid (C18:0), myristic acid (C14:0), and lauric acid (C12:0) affected the contraction rate. The inhibitory effect of these PUFAs on the contraction rate was similar to that produced by the class I antiarrhythmic drug lidocaine. The fatty acids that are able to reduce the beating rate, particularly EPA and DHA, could effectively prevent and terminate lethal tachyarrhythmias (contracture/fibrillation) induced by high extracellular calcium concentrations or ouabain. These results suggest that free PUFAs can suppress the automaticity of cardiac contraction and thereby exert their antiarrhythmic effects.