Current Pharmaceutical Design - Volume 15, Issue 36, 2009

Polyunsaturated fatty acids (PUFA) are a family of lipids with more than one double bond in their molecule, that are identified by the position of the last double bond in their structure. The main groups are ω-3 PUFA, including alpha linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), and ω-6 PUFA including linoleic acid (LA) and arachidonic acid (AA). Few other nutritional substances have attracted in recent years more attention than pufa. Starting from the pioneer studies performed in Eskimos on the influence of fish on cardiovascular disease risk more than 30 years ago [1], the interest for the health benefits of these compounds has rapidly increased, as shown by the presence of more than 3500 papers on this topics reported in the pubmed since the year 2000 [2]. In this issue of the Journal the evidence concerning the benefits of PUFA in several diseases and conditions is critically discussed. Cardiovascular disease is the first area in which ω-3 PUFA have been investigated and where their benefits have been more clearly demonstrated not only in epidemiological studies but also in randomized controlled trials. Supplementation with ω-3 PUFA is effective in the treatment of hypertriglyceridemia [3] and in the reduction of mortality after myocardial infarction as well as in heart failure patients [4]. Several biological mechanisms can explain these beneficial effects: ω-3 PUFA have anti-arrhythmic, anti-thrombotic, anti-atherosclerotic properties. Moreover, PUFA are also involved in different mitochondrial processes, including mitochondrial calcium homeostasis, gene expression, respiratory function, ROS production and mitochondrial apoptosis [5]. Experimental studies have shown a beneficial effect of PUFA, both ω-3 and ω-6, on body composition, with a reduction of fat mass [6]. Since obesity is becoming a world wide epidemics, this activity deserves further investigation in humans. According to several reports, a higher dietary intake of PUFA seems to reduce the risk of developing type 2 diabetes and it might also improve metabolic control in patients with type 2 diabetes [7]. The anti-inflammatory effects of PUFA [8] suggest that they might represent an important treatment for inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease, although current evidence cannot be considered conclusive [9]. Kidney diseases leading to chronic renal insufficiency are increasing in the population: recent data from animal as well as human studies raise the hope that a higher dietary intake of PUFA may be protective against the progression to chronic kidney disease [10]. Also osteoporosis is a common condition, particularly in older subjects, with a high impact on health care expenditure. Although PUFA have been proposed as possible agents to treat this condition, more evidence is needed before they can be recommended in clinical practice [11]. Depression will become the second more important cause of disability in the population and therefore the availability of new therapies to reduce its burden is a major aim in this area. Although epidemiological findings increasingly suggest an inverse association between ω-3 PUFA and depression, with supportive biological plausibility, current evidence is not conclusive, due to methodological limitations of intervention trials [12]. Last but not least PUFA might offer a promising intervention in the prevention of dementia, an hypothesis that is currently being tested in ongoing trials [13]. In conclusion, except in the area of cardiovascular disease, the available evidence is not sufficiently strong to recommend the use of PUFA for the prevention or treatment of several diseases. Given the large potential benefits of PUFA on human health, new properly designed randomized clinical trials are required to clarify the role of PUFA. Furthermore, it would be important to investigate whether in each specific condition a diet enriched in PUFA, e.g. by increasing the intake of fish and several oils, would provide an adequate amount of them or a supplementation should always be recommended [14].

Polyunsaturated fatty acids (PUFA) are a family of lipids including some subgroups identified by the position of the last double bond in their structure. PUFA n-3 include alpha linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), while PUFA n-6 include linoleic acid (LA) and arachidonic acid (AA). Since PUFA n-3 consumption has been shown to be inversely correlated with coronary heart diseases (CHD) incidence, clinical trials have been principally conducted by administering fish oil supplements or purified PUFA n-3. The relationship between dietary PUFA n-3 and CHD is believed to be only partially mediated by their effects on plasma lipoprotein profile. PUFA n-3 have shown to reduce only slightly total and LDL cholesterol, probably as they crowd saturated fatty acids out of diet. Data on HDL cholesterol suggest that PUFA n-3 produce only a small increase in this fraction. The effect of PUFA n-3 supplementation on plasma triglycerides (TG) is much more important, with a reduction of about 25% in normolipidemic subjects and about 50% in hypertriglyceridemic patients. This effect seems to be mediated by an inhibition of hormone-sensitive lipase, and VLDL secretion, and an increase in apo B liver degradation. They also increase lipoprotein lipase activity resulting in a reduction of post-prandial TG. PUFA n-3 might be used as second line therapy, additional or alternative to fibrates and nicotinic acid, in the treatment of severe hypertriglyceridemia. Furthermore, the addition of PUFA n-3 to statin therapy might contribute to normalize TG levels in patients with combined hyperlipidemia.

Full text available

Several observational and experimental studies show the beneficial effects of ω-3 poly-unsaturated fatty acids (PUFA) in cardiovascular disease. The results from such studies justify supplementation of ω-3 PUFA in primary and secondary prevention of several clinical conditions, including coronary heart disease, sudden cardiac death and heart failure. Supplementation of ω-3 PUFA is also indicated as monotherapy in the treatment of hypertriglyceridemia. Analysis of their biological actions suggests a variety of anti-arrhythmic, anti-thrombotic, anti-atherosclerotic and antiinflammatory mechanisms underlying their clinical benefits.

Type and quantity of ingested dietary fat contribute to the onset and progression of chronic diseases such as diabetes, obesity or arteriosclerosis. Attention is increasingly focussing on effective therapies for these diseases as well as functional foods that impede the development of insulin resistance and obesity. Studies provided evidence showing polyunsaturated fatty acids of the omega-3 and the omega-6 families play beneficial roles in prevention and treatment of diseases as diverse as Alzheimer's disease, cancer and cardiovascular diseases such as myocardial infarction, arrhythmia, atherosclerosis and hypertension. Strongest evidence is derived from in vitro experiments on cultured cells and animalbased studies, while the results from clinical studies are inconclusive. After ingestion, polyunsaturated fatty acids are distributed to cells and enriched in cellular membranes, where they influence cellular metabolism and survival. Polyunsaturated fatty acids are involved in various mitochondrial processes including mitochondrial calcium homeostasis, gene expression, respiratory function, ROS production and mitochondrial apoptosis. Therefore, mitochondria play a central role in the mechanisms underlying the protective effects of polyunsaturated fatty acids. The complex mechanisms involved in the effects of polyunsaturated fatty acid on mitochondrial actions depend on structural properties, cellular uptake, shuttling and metabolism, competition with intracellular stores as well as inherent properties of fatty acid metabolites. This review will summarize recent findings on the effects of various types of polyunsaturated fatty acids on mitochondria.

Obesity is becoming a major public health problem worldwide. Its prevalence is increasing as well as the burden of diet-related chronic diseases including hypertension, diabetes, cardiovascular disease, stroke, and certain cancers. The link between obesity and chronic diseases is well established. Obese individuals are two to three times more likely to die prematurely than their lean counterparts, primarily due to the association between obesity and type 2 diabetes and CHD. Over the past 20 years, there has been an increase in the scientific interest in the impact of omega-3 and omega- 6 fatty acids on human health. Several epidemiological and experimental studies have been published on the cardiovascular (CV) benefits of omega-3 fatty acids. Fish and fish oil are rich sources of omega- 3 fatty acids, specifically eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Alpha-linolenic acid (ALA) is an omega-3 fatty acid present in seeds and oils, green leafy vegetables, and nuts and beans. Linoleic acid (LA), an omega-6 fatty acid, is present in grains, meats, and the seeds of most plants. In addition, conjugated linoleic acid (CLA) , a group of positional and geometric isomers of linoleic acid characterized by the presence of conjugated dienes, seems to confer specific cardiovascular benefits. The potential for unsaturated fatty acids to counteract the negative effects of obesity is substantial and deserves further investigation.

The prevalence of type 2 diabetes is increasing continuously, especially in older people. Such a rapidly rising risk has been linked to physical inactivity and evolutionary changes in dietary patterns (mainly characterized by a greater intake in dietary fat). Increased physical activity in any age group is associated with a lower risk of developing type 2 diabetes. Epidemiological studies also reported a lower incidence of type 2 diabetes in individuals who consumed n-3 polyunsaturated fatty acids (PUFA), while intake of total, saturated and/or monounsaturated fat was associated with increased risk of type 2 diabetes in glucose-intolerant individuals. Furthermore, the beneficial effects of PUFA consumption on cardiovascular disease were mainly attributed to their effects on reducing triglyceride levels, increasing high density lipoprotein cholesterol, and improving endothelial function through anti-inflammatory mechanisms and reduced platelet aggregation. In addition to common diabetic complications such as dyslipidemia and cardiovascular disease, elderly people with type 2 diabetes are at greater risk of specific geriatric syndromes, such as cognitive decline and physical disability. The threats of physical disability, loss of independence and loss of cognitive performance which diminish quality of life may ultimately be the greatest concern for those with type 2 diabetes. In this review we will address: i) specific dietary fat intake patterns and the development of insulin resistance and type 2 diabetes, ii) the effects of PUFA supplementation on glucose metabolism, diabetic dyslipidemia and cardiovascular disease, iii) the potential advantages of PUFA supplementation on cognitive decline and physical disability in the elderly.

Inflammation is part of the normal host response to infection and injury. However, inappropriate inflammation contributes to several diseases, including inflammatory bowel disease (IBD) and rheumatoid arthritis (RA). Both conditions are characterized by the excessive production of inflammatory cytokines, arachidonic acid (AA)-derived eicosanoids, and other inflammatory agents (e.g., reactive oxygen species, adhesion molecules). By virtue of their antiinflammatory action, ω-3 polyunsaturated fatty acids (PUFA) may be beneficial in inflammatory diseases. A large body of evidence supports a protective effect of ω-3 PUFA in experimental animal and ex-vivo models of Crohn's disease (CD), Ulcerative colitis (UC) and RA. Although fish oil supplementation in patients with IBD results in ω-3 PUFA incorporation into gut mucosal tissue and modification of inflammatory mediator profiles, the evidence of clinical benefits of ω-3 PUFA is weak. On the other hand, more convincing data support the efficacy of ω-3 PUFA in reducing pain, number of tender joints, duration of morning stiffness, use of non-steroidal anti-inflammatory drugs and improving physical performance in RA patients. In both IBD and RA further clinical trials with large sample size are needed to clarify the efficacy of ω-3 PUFA as a treatment.

Chronic kidney disease (CKD) is a major public health problem and can result in end-stage renal disease with need for dialysis or transplantation. In Europe up to 12% of the adult population had some renal impairment, while in the United States the end stage of CKD has increased dramatically from 209.000 in 1991 to 472.000 in 2004. Diabetes and hypertension are major causes of kidney pathology. Infection, particularly ascending infection, is more common with increasing age, as both immune function declines and associated pathology predisposing to infection, such as obstructive uropathy, becomes more common. Most pathological changes in the kidney appear to be initiated by oxidative stress, followed by an inflammatory reaction. Oxidative stress results from an imbalance between free radicals and their detoxification by endogenous and exogenous scavengers, including polyunsatured fatty acids (PUFA). Recent studies showed that PUFA supplementation slowed the rate of loss of renal function in patients with IgA nephropathy. Then, studies of omega-3 supplementation in dialysis patients describe salutary effects on triglyceride levels and dialysis access patency. We examined the relationship between total plasma PUFA levels and change in creatinine clearance over a threeyear follow-up in the older persons enrolled in the InCHIANTI study, a population-based epidemiology study conducted in Tuscany, Italy. This study showed that older adults with low total plasma PUFA levels have a greater decline in creatinine clearance over three years of follow-up. These findings suggest that a higher dietary intake of PUFA may be protective against progression to chronic kidney disease.

The essential polyunsaturated fatty acids (PUFAs) comprise 2 main classes: n-6 and n-3 fatty acids. The most common source of n-6 fatty acids is linoleic acid (LA) which is found in high concentrations in various vegetable oils. Arachidonic acid (AA), the 20-carbon n-6 fatty acid, is obtained largely by synthesis from LA in the body. The n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic (DHA) are found in fish and fish oils. Long-Chain polyunsaturated fatty acids (LCPUFAs) and lipid mediators derived from LCPUFAs have critical roles in the regulation of a variety of biological processes including bone metabolism. There are different mechanisms by which dietary fatty acids affect bone: effect on calcium balance, effect on osteoblastogenesis and osteoblast activity, change of membrane function, decrease in inflammatory cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α), modulation of peroxisome proliferators-activated receptor γ (PPARγ). Animal studies have shown that a higher dietary omega-3/omega-6 fatty acids ratio is associated with beneficial effects on bone health. In spite of increasing evidence of the positive effects of dietary fats on bone metabolism from animal and in vitro studies, the few studies conducted in humans do not allow us to draw a definitive conclusion on their usefulness in clinical practice.

Brain lipids contain a high proportion of polyunsaturated fatty acids (PUFA), which are a main component of cell membranes. Omega -3 (ω-3) PUFA eicosapentaeoic acid (EPA) and docosahexaenoic acid (DHA) are the most common PUFA in the brain. The physiological roles of ω-3 PUFA in the brain include regulation of cell membrane fluidity, dopaminergic and serotoninergic transmission, membrane-bound enzymes and cellular signal transduction. They are also thought to play a role in brain glucose metabolism, eicosanoid synthesis, gene expression, cell growth and protection from apoptosis. Increasing evidence from animal and human research shows ω-3 PUFA depletion may play an etiological role in several inflammatory, autoimmune and neuropsychiatric disorders. In particular, an association between ω-3 PUFA and depression was repeatedly suggested in observational and experimental studies on populations affected by major depression, depressed mood or post-partum depression. Consistently, the potential therapeutic role of ω-3 PUFA dietary supplementation was tested in clinical trials on depression. The current review identifies and evaluates available epidemiological evidence of a negative relationship between ω-3 PUFA and depression and examines its biological plausibility. Although current evidence increasingly supports an inverse association between ω-3 PUFA and depression, the validity of findings from observational and experimental research is limited by several methodological issues. Further studies with larger sample sizes and more sophisticated design are required to provide convincing evidence of a causal relationship between ω-3 PUFA and depression.

Polyunsaturated fatty acids (PUFA) play a crucial role in cerebral structure and function. Omega-3 PUFA is an exciting area of research, with docosahexaenoic acid (DHA) emerging as a new potential agent for prevention of cognitive decline and treatment of Alzheimer's disease. Preclinical studies suggest that DHA maintains membrane fluidity, improves synaptic and neurotransmitter functioning, enhances learning and memory performances and displays neuroprotective properties. Several epidemiological studies supported the association between Omega-3 PUFA consumption and a lower prevalence of dementia. Although data are divergent, a growing body of evidence supports the view that regular consumption of dietary fish and seafood (which are rich in omega-3 PUFA) prevents cognitive decline. Finally, at present, few data are available from randomized clinical trials (RCTs). on the association between cognition and Omega-3. Ongoing RCTs that assess the effect of Omega-3 might provide new evidence on prevention and treatment of dementia. In this review, we summarize preclinical and clinical research suggesting that DHA exerts beneficial effects on cognitive function with ageing.

Large doses of omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are used to treat several diseases including hypertriglyceridemia in humans. Modest levels of EPA and DHA may be obtained from food, particularly from fatty fish. This review presents the literature examining the differences between omega-3 fatty acid dietary supplementation and prescribed omega-3-acid ethyl esters (P-OM3). Reports published between 1995 and 2007 containing sources, recommended intake, and differences in the various formulations of omega-3 fatty acids were sought in PubMed and the Food and Drug Administration (FDA) Websites. However, lack of head-to-head clinical trials using both P-OM3 and dietary-supplement omega-3 fatty acids is the greatest limitation of this review. Although many kinds of omega-3 fatty acid dietary supplements are available, the efficacy, quality, and safety of these products are questionable because they are beyond any pharmaceutical control. Thus, P-OM3 is the only FDA approved omega-3 fatty acid product which is available in the United States as an adjunct to diet to improve human health.