Decreased fatty acit Â-oxidation in riboflavin-responsive, multiple acylocoenzyme a dehydrogenase-deficient patients is associated with an increase in uncoupling protein-3

Riboflavin-responsive, multiple acylcoenzyme A dehydrogenase deficiency (RR-MAD), a lipid storage myopathy, is characterized by, among others, a decrease in fatty acid (FA) ß-oxidation capacity. Muscle uncoupling protein 3 (UCP3) is up-regulated under conditions that either increase the levels of circulating free FA and/or decrease FA ß-oxidation. Using a relatively large cohort of seven RR-MAD patients, we aimed to better characterize the metabolic disturbances of this disease and to explore the possibility that it might increase UCP3 expression. A battery of biochemical and molecular tests were performed, which demonstrated decreases in FA ß-oxidation and in the activities of respiratory chain complexes I and II. These metabolic alterations were associated with increases of 3.1- and 1.7-fold in UCP3 mRNA and protein expression, respectively. All parameters were restored to control values after riboflavin treatment. We postulate that the up-regulation of UCP3 in RR-MAD is due to the accumulation of muscle FA/acylCoA. RR-MAD is an optimal model to support the hypothesis that UCP3 is involved in the outward translocation of an excess of FA from the mitochondria and to show that, in humans, the effects of FA on UCP3 expression are direct and independent of fatty acid ß-oxidation.

A stearic acid-rich diet improves thrombogenic and atherogenic risk factor profiles in healthy males

Objective: To determine whether healthy males who consumed increased amounts of dietary stearic acid compared with increased dietary palmitic acid exhibited any changes in their platelet aggregability, platelet fatty acid profiles, platelet morphology, or haemostatic factors.

Design: A randomized cross-over dietary intervention.

Subjects and interventions: Thirteen free-living healthy males consumed two experimental diets for 4 weeks with a 7 week washout between the two dietary periods. The diets consisted of ~30% of energy as fat (66% of which was the treatment fat) providing ~6.6% of energy as stearic acid (diet S) or ~7.8% of energy as palmitic acid (diet P). On days 0 and 28 of each dietary period, blood samples were collected and anthropometric and physiological measurements were recorded.

Results: Stearic acid was increased significantly in platelet phospholipids on diet S (by 22%), while on diet P palmitic acid levels in platelet phospholipids also increased significantly (8%). Mean platelet volume, coagulation factor FVII activity and plasma lipid concentrations were significantly decreased on diet S, while platelet aggregation was significantly increased on diet P.

Conclusion: Results from this study indicate that stearic acid (19 g/day) in the diet has beneficial effects on thrombogenic and atherogenic risk factors in males. The food industry might wish to consider the enrichment of foods with stearic acid in place of palmitic acid and trans fatty acids.

Validation of a FFQ to estimate the intake of PUFA using plasma phospholipid fatty acids and weighed foods records

Due to the growing knowledge about the role of specific fatty acids in health and disease, dietary intake measurements of individual fatty acids or classes of fatty acids are becoming increasingly important. The objective of this study was to evaluate the ability of the Nambour FFQ to estimate intakes of specific fatty acids, particularly PUFA. The study population was a sub-sample of adult participants in a randomised controlled trial of [beta]-carotene and sunscreen in the prevention of skin cancer (n 43). Dietary intake was assessed by a self-administered FFQ and a weighed food record (WFR). Non-fasting blood samples were collected and analysed for plasma phospholipid fatty acids. Median intakes on the FFQ were generally higher than the WFR except for the n-3 PUFA groups, where the FFQ estimated higher intakes. Correlations between the FFQ and WFR were moderate (r 0–32-0-59) except for trans fatty acids (r 0–03). Correlations between each of the dietary assessment methods and the plasma phospholipids were poor for all fatty acids other than the PUFA. Using the methods of triads approach, the FFQ validity coefficients for total n-3 fatty acids, total long chain n-3 fatty acids, EPA, arachidonic acid, docosapentaenoic acid and DHA were 0–50, 0–63, 0–45 and 0–62 and 0–62, respectively. For most fatty acids, the FFQ adequately estimates group mean fatty acid intakes and can adequately rank individuals; however, the ability of this FFQ to estimate trans fatty acids was poor.

Failure of conjugated linoleic acid supplementation to enhance biosynthesis of docosahexaenoic acid from α-linolenic acid in healthy human volunteers

A rate-limiting step in docosahexaenoic acid (DHA) formation from α-linolenic acid (ALA) involves peroxisomal oxidation of 24:6n-3 to DHA. The aim of the study was to determine whether conjugated linoleic acid (CLA) would enhance conversion of ALA to DHA in humans on an ALA-supplemented diet. The subjects (n=8 per group) received daily supplementation of ALA (11g) and either CLA (3.2g) or placebo for 8 weeks. At baseline, 4 and 8 weeks, blood was collected for plasma fatty acid analysis and a number of physiological measures were examined. The ALA-supplemented diet increased plasma levels of ALA and eicosapentaenoic acid (EPA). The addition of CLA to the ALA diet resulted in increased plasma levels of CLA, as well as ALA and EPA. Plasma level of DHA was not increased with either the ALA alone or ALA plus CLA supplementation. The results demonstrated that CLA was not effective in enhancing DHA levels in plasma in healthy volunteers.

Dietary omega 3 fatty acids decrease intraocular pressure with age by increasing Aqueous outflow

Purpose: To determine whether there is an association between dietary omega-3 (ω-3) fatty acid intake, age, and intraocular pressure (IOP) caused by altered aqueous outflow. Methods: Sprague–Dawley rats were fed either ω-3–sufficient (ω-3⁺) or ω-3–deficient (ω-3^–) diets from conception. The diets had 7% lipid content. The ω-3⁺ diet contained safflower, flaxseed, and tuna oils (5.5:1.0:0.5), and the ω-3^– diet contained safflower oil only. Intraocular pressure was measured at 5 to 40 weeks of age under light anesthesia (ω-3⁺, n = 39; ω-3^–, n = 48). Aqueous outflow was determined at 45 weeks in a subgroup of animals (ω-3⁺, n = 15;ω-3^–, n = 22) using pulsed infusion. Ciliary body tissues (n = 6 per group) were assayed for fatty acid content by thin-layer and gas-liquid chromatography in both diet groups. Results: Animals raised on ω-3⁺ diets had a 13% decrease in IOP at 40 weeks of age (13.48 ± 0.32 mm Hg vs. 15.46 ± 0.29 mm Hg; P < 0.01). When considered as a change in IOP relative to 5 weeks of age, the ω-3⁺ group showed a 23% decrease (P < 0.001). This lower IOP in the ω-3⁺ diet group was associated with a significant increase (+56%; P < 0.001) in outflow facility and a decrease in ocular rigidity (–59%; P < 0.001). The ω-3⁺ group showed a 3.3 times increase in ciliary body docosahexaenoic acid (P < 0.001). Conclusions: Increasing dietary ω-3 reduces IOP with age because of increased outflow facility, likely resulting from an increase in docosanoids. This indicates that dietary manipulation may provide a modifiable factor for IOP regulation. However, further studies are needed to consider whether this can modify the risk for glaucoma and can play a role in treatment of the disease.

Omega 3 fatty acids and the brain : review of studies in depression

The brain is a lipid-rich organ containing mostly complex polar  phospholipids, sphingolipids, gangliosides and cholesterol. These lipids are involved in the structure and function of cell membranes in the brain. The glycerophospholipids in the brain contain a high proportion of  polyunsaturated fatty acids (PUFA) derived from the essential fatty acids, linoleic acid and alpha-linolenic acid. The main PUFA in the brain are docosahexaenoic acid (DHA, all cis 4,7,10,13,16,19-22:6) derived from the omega 3 fatty acid, alpha-linolenic acid, and arachidonic acid (AA, all cis 5,8,11,14-20:4) and docosatetraenoic acid (all cis 7,10,13,16-22:4), both derived from the omega 6 fatty acid, linoleic acid. Experimental studies in animals have shown that diets lacking omega 3 PUFA lead to substantial disturbances in neural function, which in most circumstances can be restored by the inclusion of omega 3 PUFA in the diet. In the past 10 years there has been an emerging interest in treating neuropsychological  disorders (depression and schizophrenia) with omega 3 PUFA. This paper discusses the clinical studies conducted in the area of depression and omega 3 PUFA and the possible mechanisms of action of these PUFA. It is clear from the literature that DHA is involved in a variety of processes in neural cells and that its role is far more complex than simply influencing cell membrane properties.

Effects of dietary fat and conjugated linoleic acid on plasma metabolite concentrations and metabolic responses to homeostatic signals in pigs

Sixteen female cross-bred (Large White × Landrace) pigs (initial weight 65 kg) with venous catheters were randomly allocated to four treatment groups in a 2×2 factorial design. The respective factors were dietary fat (25 or 100 g/kg) and dietary conjugated linoleic acid (CLA; 0 or 10 g CLA-55/kg). Pigs were fed every 3 h (close to ad libitum digestible energy intake) for 8 d and were bled frequently. Plasma glucose and non-esterified fatty acid (NEFA) responses to insulin and adrenaline challenges were determined on day 8. Plasma concentrations of NEFA were significantly increased (10·5 and 5·4 % for low- and high-fat diets respectively, P=0·015) throughout the experiment, suggesting that there was a possible increase in fat mobilisation. The increase in lipolysis, an indicator of ß-adrenergic stimulated lipolysis, was also evident in the NEFA response to adrenaline. However, the increase in plasma triacylglycerol (11·0 and 7·1 % for low- and high-fat diets respectively, P=0·008) indicated that CLA could have reduced fat accretion via decreased adipose tissue triacylglycerol synthesis from preformed fatty acids, possibly through reduced lipoprotein lipase activity. Plasma glucose, the primary substrate for de novo lipid synthesis, and plasma insulin levels were unaffected by dietary CLA suggesting that de novo lipid synthesis was largely unaffected (P=0·24 and P=0·30 respectively). In addition, the dietary CLA had no effect upon the ability of insulin to stimulate glucose removal.

Dietary intakes and food sources of Omega-6 and Omega-3 polyunsaturated fatty acids.

Both n−6 and n−3 polyunsaturated fatty acids (PUFA) are recognized as essential nutrients in the human diet, yet reliable data on population intakes are limited. The aim of the present study was to ascertain the dietary intakes and food sources of individual n−6 and n−3 PUFA in the Australian population. An existing database with fatty acid composition data on 1690 foods was updated with newly validated data on 150 foods to estimate the fatty acid content of foods recorded as eaten by 10,851 adults in the 1995 Australian National Nutrition Survey. Average daily intakes of linoleic (LA), arachidonic (AA), α-linolenic (LNA), eicosapentaenoic (EPA), docosapentaenoic (DPA), and docosahexaenoic (DHA) acids were 10.8, 0.052, 1.17, 0.056, 0.026, and 0.106 g, respectively, with longchain (LC) n−3 PUFA (addition of FPA, DPA, and DHA) totaling 0.189 g; median intakes were considerably lower (9.0 g LA, 0.024 g AA, 0.95 g LNA, 0.008 g EPA, 0.006 g DPA, 0.015 g DHA, and 0.029 g LC n−3 PUFA). Fats and oils, meat and poultry, cereal-based products and cereals, vegetables, and nuts and seeds were important sources of n−6 PUFA, while cereal-based products, fats and oils, meat and poultry, cereals, milk products, and vegetable products were sources of LNA. As expected, seafood was the main source of LC n−3 PUFA, contributing 71%, while meat and eggs contributed 20 and 6%, respectively. The results indicate that the majority of Australians are failing to meet intake recommendations for LC n−3 PUFA (>0.2 g per day) and emphasize the need for strategies, to increase the availability and consumption of n−3-containing foods.

α-linolenic acid and the risk of prostate cancer. What is the evidence?

Purpose
Several studies have examined the association between polyunsaturated fatty acids and prostate cancer risk. We evaluated the evidence on the association between the essential polyunsaturated fatty acid, known as α-linolenic acid, and the risk of prostate cancer in humans.
Materials and Methods
We comprehensively reviewed published studies on the association between α-linolenic acid and the risk of prostate cancer using MEDLINE.
Results
A number of studies have shown a positive association between dietary, plasma or red blood cell levels of α-linolenic acid and prostate cancer. Other studies have demonstrated either no association or a negative association. The limitations of these studies include the assumption that dietary or plasma α-linolenic acid levels are positively associated with prostate tissue α-linolenic acid levels, and measurement errors of dietary, plasma and red blood cell α-linolenic acid levels.
Conclusions
More research is needed in this area before it can be concluded that there is an association between α-linolenic acid and prostate cancer.

The a-linolenic acid content of green vegetables commonly available in Australia

Green vegetable consumption has long been considered to have health benefits mainly due to the vitamins, minerals and phytonutrients (such as vitamin C, folate, antioxidants etc) contained in a vegetable-rich diet. Additionally, green vegetables are known to contain a relatively high proportion of omega-3 polyunsaturated fatty acids (PUFAs), primarily in the form of alpha-linolenic acid (18:3n-3). However, there are no data available on the fatty acid composition and concentration of green vegetables commonly consumed in Australia. The present study determined the fatty acid content of 11 green vegetables that are commonly available in Australia. The total fatty acid concentrations of the vegetables under study ranged from 44 mg/100 g wet weight in Chinese cabbage to 372 mg/100 g in watercress. There were three PUFAs in all vegetables analyzed; these were 16:3n-3, 18:2n-6, and 18:3n-3 fatty acids. Sample vegetables contained significant quantities of 16:3n-3 and 18:3n-3, ranging from 23 to 225 mg/100 g. Watercress and mint contained the highest amounts of 16:3n-3 and 18:3n-3, and parsley had the highest amount of 18:2n-6 in both percentage composition and concentration. Mint had the highest concentration of 18:3n-3 with a value of 195 mg/100 g, while watercress contained the highest concentration of 16:3n-3 at 45 mg/100 g. All 11 green vegetables contained a high proportion of PUFAs, ranging from 59 to 72% of total fatty acids. The omega-3 PUFA composition ranged from 40 to 62% of total fatty acids. Monounsaturated fatty acid composition was less than 6% of total fatty acids. The proportion of saturated fatty acids ranged from 21% in watercress and mint to 32% of total fatty acids in Brussels sprouts. No eicosapentaenoic and docosahexaenoic acids were detected in any of the samples. Consumption of green vegetables could contribute to 18:3n-3 PUFA intake, especially for vegetarian populations.

1-14C-Linoleic Acid distrubution in various tissue lipids of guinea pigs following an oral dose

A recent study on the metabolism of 1-¹⁴C-α-linolenic acid in the guinea pig revealed that the fur had the highest specific activity of all tissues examined, 48 h after dosing. The present study investigated the pattern of tissue lipid labeling following an oral dose of 1-¹⁴C-linoleic acid after the animals had been dosed for the same time as above. Guinea pigs were fed one of two diets with a constant linoleic acid content (18% total fatty acids) and a different content of α-linolenic acid (0.3 or 17.3%) from weaning for 3 wk and 1-¹⁴C-linoleic acid was given orally to each animal for 48 h prior to sacrifice. The most highly labeled tissues (dpm/mg of linoleic acid) were liver, followed by brain, lung and spleen, heart, kidney and adrenal and intestines, in both diet groups. The liver had almost a three-fold higher specific activity than skin and fur which was more extensively labeled than the adipose and carcass. Approximately two-thirds of the label in skin plus fur was found in the fur which, because of a low lipid mass, would indicate that the fur was highly labeled. All tissues derived from animals on the diet with the low α-linolenic acid level were significantly more labeled than the tissues from the animals on the high α-linolenic acid diet, by a factor of 1.5 to 3. The phospholipid fraction was the most highly labeled fraction in the liver, free fatty acids were the most labeled fraction in skin & fur, while triacyglycerols were the most labeled in the carcass and adipose tissue. In these tissues, more than 90% of the radioactivity was found in fatty acids with 2-double bonds in the tissue lipids. These data indicate that the majority of label found in guinea pig tissues 48 h after dosing was still associated with a fatty acid fraction with 2-double bonds, which suggests there was little metabolism of linoleic acid to more highly unsaturated fatty acids in this time frame. In this study, the labeling of guinea pig tissues with linoleic acid, 48 h after dosing, was quite different from the labeling with α-linolenic acid reported previously. The retention of the administered radioactivity from ¹⁴C-linoleic acid in the whole body lipids was 1.6 times higher in the group fed the low α-linolenic acid diet (diet contained a total of 1.8 g PUFA/100 g diet)compared with the group fed the high α-linolenic acid diet (diet contained 3.6 g PUFA/100 g diet). The lack of retention of ¹⁴C-labeled lipids in the whole body would be consistent with an increased rate of β-oxidation of the labeled fatty acid on the diet rich in PUFA, a result supported by other studies using direct measurement of labeled carbon dioxide.

Saturated, but not n-6 polyunsaturated, fatty acids induce insulin resistance: role of intramuscular accumulation of lipid metabolites

Consumption of a Western diet rich in saturated fats is associated with obesity and insulin resistance. In some insulin-resistant phenotypes this is associated with accumulation of skeletal muscle fatty acids. We examined the effects of diets high in saturated fatty acids (Sat) or n-6 polyunsaturated fatty acids (PUFA) on skeletal muscle fatty acid metabolite accumulation and whole-body insulin sensitivity. Male Sprague-Dawley rats were fed a chow diet (16% calories from fat, Con) or a diet high (53%) in Sat or PUFA for 8 wk. Insulin sensitivity was assessed by fasting plasma glucose and insulin and glucose tolerance via an oral glucose tolerance test. Muscle ceramide and diacylglycerol (DAG) levels and triacylglycerol (TAG) fatty acids were also measured. Both high-fat diets increased plasma free fatty acid levels by 30%. Compared with Con, Sat-fed rats were insulin resistant, whereas PUFA-treated rats showed improved insulin sensitivity. Sat caused a 125% increase in muscle DAG and a small increase in TAG. Although PUFA also resulted in a small increase in DAG, the excess fatty acids were primarily directed toward TAG storage (105% above Con). Ceramide content was unaffected by either high-fat diet. To examine the effects of fatty acids on cellular lipid storage and glucose uptake in vitro, rat L6 myotubes were incubated for 5 h with saturated and polyunsaturated fatty acids. After treatment of L6 myotubes with palmitate (C16:0), the ceramide and DAG content were increased by two- and fivefold, respectively, concomitant with reduced insulin-stimulated glucose uptake. In contrast, treatment of these cells with linoleate (C18:2) did not alter DAG, ceramide levels, and glucose uptake compared with controls (no added fatty acids). Both 16:0 and 18:2 treatments increased myotube TAG levels (C18:2 vs. C16:0, P < 0.05). These results indicate that increasing dietary Sat induces insulin resistance with concomitant increases in muscle DAG. Diets rich in n-6 PUFA appear to prevent insulin resistance by directing fat into TAG, rather than other lipid metabolites.

Effect of dietary fatty acids on the intestinal permeability of marker drug compounds in excised rat jejunum

The aim of this study was to explore the effects of diets containing saturated fatty acids (SFA), monounsaturated fatty acids (MUFA), and ω-3 and ω-6 polyunsaturated fatty acids (ω-3 and ω-6 PUFA, respectively) on the passive and active transport properties of rat jejunum using marker compounds. Rats were fed diets supplemented with 18.4% (w/w) lipid (4 groups) or standard rat chow (1 group) for a period of 30 days. At the end of the dietary period, mucosal scrapings were taken for the determination of membrane phospholipids, and the apparent jejunal permeability of radiolabelled marker compounds was determined using modified Ussing chambers. Changes in the phospholipid content of the brush border membrane reflected the different lipid content of the diets. The passive paracellular permeability of mannitol was not significantly affected by the fatty acid composition of the diet, although there was a trend toward decreased mannitol permeability in the rats fed both the ω-3 and ω-6 PUFA diets. In comparison, the transcellular diffusion of diazepam was reduced by 20% (P < 0.05) in rats fed diets supplemented with ω-3 and ω-6 PUFA. In the lipid-fed rats, the serosal to mucosal flux of digoxin, an intestinal P-glycoprotein substrate, was reduced by 20% (P < 0.05) relative to the chow-fed group, however there were no significant differences between the different lipid groups. The active absorption of D-glucose via the Na+-dependent transport pathway was highest in the SFA, MUFA and PUFA ω-3 dietary groups, intermediate in the low-fat chow group and lowest in the PUFA ω-6 group, and was positively correlated with short-circuit current. These studies indicate that dietary fatty acid changes can result in moderate changes to the active and passive transport properties of excised rat jejunum.

The role of omega-3 fatty acids in mood disorders

Research has established that docosahexaenoic acid (DHA), a long-chain omega-3 polyunsaturated fatty acid (PUFA), plays a fundamental role in brain structure and function. Epidemiological and cross-sectional studies have also identified a role for long-chain omega-3 PUFA, which includes DHA, eicosapentaenoic acid, and docosapentaenoic acid, in the etiology of depression. In the past ten years, there have been 12 intervention studies conducted using various preparations of longchain omega-3 PUFA in unipolar and bipolar depression. The majority of these studies administered long-chain omega-3 PUFA as an adjunct therapy. The studies have been conducted over 4 to 16 weeks of intervention and have often included small cohorts. In four out of the seven studies conducted in depressed individuals and in two out of the five studies in bipolar patients, individuals have reported a positive outcome following supplementation with ethyl-eicosapentaenoic acid or fish oil containing long-chain omega-3 PUFA. In the three trials that researched the influence of DHA-rich preparations, no significant effects were reported. The mechanisms that have been invoked to account for the benefits of long-chain omega-3 PUFA in depression include reductions in prostaglandins derived from arachidonic acid, which lead to decreased brain-derived neurotrophic factor levels and/or alterations in blood flow to the brain.

The role of fatty acids in satiation and satiety

Background – Satiation and satiety describe the events which lead to meal termination and the maintenance of hunger induced by physical and metabolic events following food ingestion. Fatty acids, components of dietary fat (triglyceride) may be important, if not essential components of satiation and satiety. Emerging evidence suggests fatty acid now constitutes a sixth taste modality and orally sensed fatty acids mediate unique cephalic and hormonal responses priming the body for fat digestion, and may contribute to sensory specific satiety. Once ingested, fatty acids are sensed in the gastrointestinal tract (GIT) where they cause the release of hormones, stimulate the vagus and enter the blood stream where they act a number of organs (brain, liver) to influence satiety.
Objective – To review the role of fatty acids in sensory and metabolic satiation and satiety.
Design – Literature search and review of papers from the past decade on satiety, satiation, fat taste and fatty acids.
Outcomes – The physiological significance of gustatory fat detection is still unclear, but it may signal the nutritious content of fat similar to the tastes of sweet or umami which signal the presence of carbohydrate or proteins. Like other tastants, fatty acid taste sensitivity is thought to vary in the population and differences in sensitivity may influence dietary choice and fat intake. Fatty acid taste may contribute to sensory specific satiety as foods are eaten. Animal models have observed an inverse relationship between oral fatty acid sensitivity and fat consumption, which leads to obesity. Observations that the obese have heightened preferences for, and consume more fat than lean individuals questions whether such a relationship may also be apparent in humans. At the GIT, fatty acids are sensed by enterocytes and bind to receptors, transporters or ion channels where they initiate gut-brain communication over nutrient status through the vagus and cause the release of satiety hormones which lead to meal termination. Inefficient fatty acid sensing at either or both locations is thought to accompany the aetiology of obesity.
Conclusion – Variations in sensitivity to fatty acids may alter preferences and consumption of fats or hormonal responses to fat ingestion which influence sensory-specific, metabolic and subjective satiety.