Manohar L. Garg

Dietary fat: exogenous determination of membrane structure and cell function.

Evidence indicates that principal features of the membrane involve structural organization of lipids in the form of a bilayer with functional proteins either bound to the bilayer surface or inserted into the bilayer and interacting within specific domains in the lipid milieux. In homeotherms, intrinsic and extrinsic factors apparently form the basis for determination of membrane lipid composition and thus membrane physicochemical properties. Moreover, many intrinsic metabolic controls, such as fatty acid desaturation and phospholipid biosynthesis, may be attenuated by change in the nature of the extrinsic or dietary influence. This review will focus on the role of dietary fat as a determinant of subcellular structural constituents to illustrate that feeding nutritionally adequate diets differing in fatty acid composition can induce physiological transitions in membrane function involving the activity of enzymes responsible for synthesis of membrane constituents, hormone‐activated functions and expression of activity in the cell nucleus.—Clandinin, M. T.; Cheema, S.; Field, C. J., Garg, M. L., Venkatraman, J., Clandinin, T. R. Dietary fat: exogenous determination of membrane structure and cell function. FASEB J. 5: 2761‐2769; 1991.

Biomarkers of lipid peroxidation, airway inflammation and asthma

Oxidative stress, specifically lipid peroxidation, is believed to contribute to the pathophysiology of asthma. This review highlights the pathways through which reactive oxygen species (ROS) may lead to lipid peroxidation. The potential of both the innate and acquired immune systems to activate inflammatory cells and release ROS that may overwhelm the host antioxidant defences and cause lipid peroxidation, accompanied by detrimental pathophysiological effects, are discussed. Despite the evidence demonstrating the importance of lipid peroxidation, systematic characterisation of oxidative stress and antioxidant defences has not been undertaken, largely due to the lack of appropriate biomarkers. This review discusses the emergence of isoprostanes (specifically 8‐isoprostaglandin F2α) as reliable, in vivo markers of lipid peroxidation, which provides an appropriate tool for studying oxidative stress. Furthermore, the development of techniques to study induced sputum and breath condensate, derived directly from the airway surface, enables the site of oxidative damage to be closely assessed. Evidence suggests that dietary changes that have occurred over recent years have increased susceptibility to lipid peroxidation, due to reduced antioxidant defences. To date, the limited number of longterm (>1 week) supplementation trials have been promising. However, the development of techniques to study isoprostanes in airwaylining fluid pave the way for further studies investigating the potential for antioxidant supplements to be used as routine therapy in asthma.

Docosapentaenoic acid (22:5n-3): A review of its biological effects

This article summarizes the current knowledge available on metabolism and the biological effects of n-3 docosapentaenoic acid (DPA). n-3 DPA has not been extensively studied because of the limited availability of the pure compound. n-3 DPA is an elongated metabolite of EPA and is an intermediary product between EPA and DHA. The literature on n-3 DPA is limited, however the available data suggests it has beneficial health effects. In vitro n-3 DPA is retro-converted back to EPA, however it does not appear to be readily metabolised to DHA. In vivo studies have shown limited conversion of n-3 DPA to DHA, mainly in liver, but in addition retro-conversion to EPA is evident in a number of tissues. n-3 DPA can be metabolised by lipoxygenase, in platelets, to form ll-hydroxy-7,9,13,16,19- and 14-hydroxy-7,10,12,16,19-DPA. It has also been reported that n-3 DPA is effective (more so than EPA and DHA) in inhibition of aggregation in platelets obtained from rabbit blood. In addition, there is evidence that n-3 DPA possesses 10-fold greater endothelial cell migration ability than EPA, which is important in wound-healing processes. An in vivo study has reported that n-3 DPA reduces the fatty acid synthase and malic enzyme activity levels in n-3 DPA-supplemented mice and these effects were stronger than the EPA-supplemented mice. Another recent in vivo study has reported that n-3 DPA may have a role in attenuating age-related decrease in spatial learning and long-term potentiation. However, more research remains to be done to further investigate the biological effects of this n-3 VLCPUFA.

Lipid peroxidation as determined by plasma isoprostanes is related to disease severity in mild asthma.

Oxidative stress is believed to play an important role in the pathophysiology of asthma. Recently discovered F2-isoprostanes, of which 8-iso-PGF2α is the most well-known isomer, have emerged as the most reliable marker of in vivo oxidative stress. The aim of this study was to examine 8-iso-PGF2α as a biomarker of oxidative stress in mild asthma in relation to endogenous and dietary antioxidant protection. Total (free and esterified) plasma 8-iso-PGF2α, plasma dietary antioxidants (vitamins E and C,β-carotene, Zn, and Se), and erythrocyte antioxidant enzyme activities (glutathione peroxidase and superoxide dismutase) were measured in 15 mild asthmatics and 15 age-and sex-matched controls. Total plasma 8-iso-PGF2α levels [median (quartile 1-quartile 3)] were significantly increased in the sthmatics [213 pg/mL (122–455) vs. 139 pg/mL (109–174), P=0.042]. The 8-iso-PGF2α levels were found to be associated with clinical asthma severity (P=0.044) and inhaled corticosteroid use (P=0.027) in asthmatics. No differences were observed in the plasma dietary antioxidant vitamins. The asthmatics had significantly lower plasma levels of Zn (P=0.027) and Se (P=0.006). Plasma Se correlated negatively with 8-iso-PGF2α (r=−0.725, P=0.002). No differences between the groups were observed for glutathione peroxidase or superoxide dismutase, however, superoxide dismutase activity was negatively associated with asthma severity (P=0.042). In conclusion, oxidative stress is increased in mild asthmatics, as reflected by increased plasma levels of 8-iso-PGF2α and a deficiency in plasma Zn and Se. The isoprostane 8-iso-PGF2α may provide a useful tool in intervention studies aimed at improving clinical status in asthma.

Airway inflammation is augmented by obesity and fatty acids in asthma.

Obesity and asthma are associated, but the mechanism(s) of the association have yet to be elucidated. The aim of this study was to assess airway inflammation in relation to obesity and plasma fatty acids in males and females with and without asthma. Obese (n=68) and nonobese (n=47) adults with asthma, and obese (n=16) and nonobese (n=63) healthy controls had induced sputum and venous blood samples analysed for inflammatory markers. There was a positive interaction between obesity and asthma on sputum neutrophil percentage (p=0.012) and C-reactive protein level (p=0.003). Although sputum eosinophil percentage was elevated in asthma (p=0.001), there was no effect of obesity (p=0.16). Sputum neutrophil percentage was positively associated with body mass index in females with asthma (&bgr;=1.015, 95% CI 0.258–1.772; p=0.009) and neutrophilic asthma was present in a greater proportion of obese compared with non-obese females (42.9% versus 16.2%; p=0.017). In males with asthma, sputum neutrophil percentage was positively associated with total plasma saturated fatty acids (&bgr;=0.108, 95% CI 0.036–0.180; p=0.004) and negatively with monounsaturated fatty acids (&bgr;= -0.068, 95% CI -0.131– -0.005; p=0.035). This was the first study to demonstrate an increase in neutrophilic airway inflammation in obese asthma. This relationship was significant only in females with asthma. In males, saturated and monounsaturated fatty acids were important predictors of neutrophilic airway inflammation in asthma.

Oat bran concentrate bread products improve long-term control of diabetes : A pilot study

OBJECTIVE To evaluate the long-term effects oat bran concentrate bread products in the diet of free-living subjects with non-insulin-dependent diabetes (NIDDM) via dietary, clinical, and biochemical methods. DESIGN A 24-week crossover study consisting of two 12-week periods. SUBJECTS/SETTING Eight men with NIDDM (mean age = 45 years) who lived in the community. Glucose and insulin profiles were conducted in a clinical investigation unit. INTERVENTION Palatable, high-fiber, oat bran concentrate (soluble fiber [beta-glucan] content = 22.8%) bread products were developed. Four randomly chosen subjects ate oat bran concentrate breads first; the other subjects ate control white bread first. MAIN OUTCOME MEASURES Dietary intake (four 48-hour dietary recalls per period) was assessed. Blood glucose and insulin (8-hour profiles) and lipid parameters after fasting were measured (at 0, 12, and 24 weeks). STATISTICAL ANALYSES PERFORMED Analysis of variance and repeated-measures analysis of variance. RESULTS Total energy and macronutrient intakes were similar in both periods. Mean total dietary fiber intake was 19 g/day in the white bread period and 34 g/day (9 g soluble fiber per day from oat bran concentrate) in the oat bran concentrate period. Body weight remained stable. Mean glycemic and insulin response areas (area under the curve) were lower (P < or = .05 and not significant, respectively) for the oat bran concentrate period than the white bread period. After breakfast, area under the curve for the oat bran concentrate period was lower for glucose (P < or = .01) and insulin (P < or = .05); insulin peak was reached earlier (P < or = .05) than in the white bread period. Dietary fiber intake was correlated negatively with insulin area under the curve (P < or = .05). Mean total plasma cholesterol and low-density lipoprotein cholesterol levels were lower (P < or = .01) in the oat bran concentrate period than in the white bread period. In the oat bran concentrate period, the mean ratio of low-density lipoprotein cholesterol to high-density lipoprotein cholesterol was reduced by 24% (P < or = .05). CONCLUSIONS The well-accepted oat bran concentrate bread products improved glycemic, insulinemic, and lipidemic responses.

Plasma n -3 polyunsaturated fatty acids are negatively associated with obesity

The objective of the present study was to investigate the relationship between plasma n-3 PUFA composition and weight status. A total of 124 adults, stratified by weight status: healthy weight (n 21), overweight (n 40) and obese (n 63) were recruited. Fasting blood samples, anthropometric measures and body composition were collected. Plasma fatty acid composition was determined by GC. BMI, waist circumference and hip circumference were inversely correlated with n-3 PUFA, EPA and DHA (P < 0.05 for all) in the obese group. Obese individuals had significantly lower plasma concentrations of total n-3 PUFA, compared with healthy-weight individuals (4.53 (SD 1.11) v. 5.25 (SD 1.43) %). When subjects were pooled and stratified into quartiles of total n-3 PUFA, a significant inverse trend was found for BMI (P = 0.002), waist circumference and hip circumference (P = 0.01 and P < 0.001 respectively). Higher plasma levels of total n-3 PUFA are associated with a healthier BMI, waist circumference and hip circumference. Our findings suggest that n-3 PUFA may play an important role in weight status and abdominal adiposity.

Anti-inflammatory and cardioprotective effects of n-3 polyunsaturated fatty acids and plant sterols in hyperlipidemic individuals.

BACKGROUND Risk factors of cardiovascular disease such as lipid aberrations, hypertension, abdominal adiposity and elevations in systemic inflammation, are prominent aetiologies in hyperlipidemia. Supplementation with n-3 PUFA is associated with a reduction in cardiovascular events through its hypotriglyceridemic, anti-aggregatory and anti-inflammatory properties. Plant sterols have potent hypocholesterolemic properties, although their effect on the inflammatory cascade is uncertain. This study investigated the effect of combined supplementation with n-3 PUFA and plant sterols on cardiovascular risk factors, blood pressure, body composition, markers of systemic inflammation and overall risk, in hyperlipidemic individuals. METHODS The study was a 3-week randomised, double-blind, placebo-controlled, 2 x 2 factorial design, in four parallel groups. Sixty hyperlipidemic participants were randomised to receive either sunola oil or 1.4 g/d n-3 PUFA capsules with or without 2g plant sterols per day. RESULTS The combination of n-3 PUFA and plant sterols reduced several inflammatory markers. High sensitivity C-reactive protein (hs-CRP) was reduced by 39% (P=0.009), tumor necrosis factor-alpha (TNF-alpha) by 10% (P=0.02), interleukin-6 (IL-6) by 10.7% (P=0.009), leukotriene B(4) (LTB(4)) by 29.5% (P=0.01) and adiponectin was increased by 29.5% (P=0.05). Overall cardiovascular risk was reduced by 22.6% (P=0.006) in the combination group. CONCLUSION We have demonstrated, for the first time that dietary intervention with n-3 PUFA and plant sterols reduces systemic inflammation in hyperlipidemic individuals. Furthermore, our results suggest that reducing inflammation provides a potential mechanism by which the combination of n-3 PUFA and plant sterols are cardioprotective.

Stimulation of mitochondrial reactive oxygen species production by unesterified, unsaturated fatty acids in defective human spermatozoa

Male infertility is a relatively common condition affecting 1 in 20 men of reproductive age. The etiology of this condition is thought to involve the excessive generation of reactive oxygen species by human spermatozoa; however, the cause of this aberrant activity is unknown. In this study we demonstrate that defective human sperm populations are characterized by high cellular contents of both esterified and unesterified fatty acids and a decrease in the proportion of the total fatty acid pool made up by docosahexaenoic acid. The free unsaturated fatty acid content of these cells was positively correlated with the induction of mitochondrial superoxide generation (P<0.001). This relationship was causal and mediated by the range of unesterified, unsaturated fatty acids that are present in human spermatozoa. Thus direct exposure of these cells to free unsaturated fatty acids stimulated mitochondrial superoxide generation and precipitated a loss of motility and an increase in oxidative DNA damage, two key attributes of male infertility. We conclude that defective human spermatozoa are characterized by an abnormally high content of fatty acids that, in their unesterified, unsaturated form, promote ROS generation by sperm mitochondria, creating a state of oxidative stress and a concomitant loss of functional competence.

Dietary restriction and exercise improve airway inflammation and clinical outcomes in overweight and obese asthma: a randomized trial

Obesity and asthma are associated conditions; however, the mechanisms linking the two remain unclear. Few studies have examined the effects of weight loss on inflammation and clinical outcomes in obese–asthma.