Latest Findings of Omega-3 Long Chain-Polyunsaturated Fatty Acids: From Molecular Mechanisms to New Applications in Health and Diseases

Essential fatty acids—linoleic and linolenic—are metabolized to long-chain polyunsaturated fatty acids (LC-PUFAs) such as arachidonic acid (AA) and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), respectively, throughout a series of desaturation and elongation steps. LC-PUFAs are essential for a variety of physiological functions including brain development, cardiac function, inflammatory response, and homeostasis. These roles at the cellular level include modulation of signal transduction via effect of bioactive cell membranes and by regulating the expression of a wide array of genes through different transcription factors such as peroxisome proliferator-activated receptors (PPARs), sterol regulatory-element binding protein (SREBP), carbohydrate response-element binding protein (ChREBP) and nuclear factor κB (NFκB) mainly to control the transcription of target genes including those encoding proteins involved with lipid and carbohydrate metabolism, thermogenesis, and cell differentiation. However, more work is required to delineate these actions and to have a better understanding of the beneficial role of LC-PUFAs in order to comprehend the action of these fatty acids in the pathogenesis of various diseases. Integrative analysis including nutritional, biochemical, genetic and immunological studies may provide information about the identification of specific molecular mechanisms involved in the beneficial effects of n3 LC-PUFAs such as DHA and EPA intake and their metabolic derivates on health promotion or disease burden.

The purpose of this review is to provide an overview regarding the role of ω-3 and ω-6 long-chain polyunsaturated fatty acids (LC-PUFAs), arachidonic acid (AA) and docosahexaenoic acid (DHA) on normal growth and maturation of the central nervous system and retina of the fetus, newborn and infant. Numerous studies have shown that DHA is associated with higher scores on tests of visual and neural development in infants and children. We also present progress concerning the molecular mechanism triggered during pregnancy and lactation to support LC-PUFAs requirements. During pregnancy, the fetus demands LC-PUFAs, which are provided through placental transfer. Placental transfer of fatty acids involves a multi-step process of uptake and translocation facilitated by specific proteins that favor DHA and AA over other fatty acids. After birth, the newborn acquires the LC-PUFAs from milk or formula. LC-PUFAs from cord blood and breast milk are acquired from the maternal diet, mobilized from reserves, or synthesized de novo in the maternal organism from the precursors linoleic acid (LA) and linolenic acid (LNA). The mother adapts her metabolism to support this draining of LC-PUFAs through mammary tissue, using a high rate of dietary uptake and allowing the expression of enzymes responsible for LC-PUFAs synthesis. We have demonstrated that mammary tissue, together with the liver, plays an important role in the synthesis of ω-3 and ω-6 LC-PUFAs to supply to the product in pregnancy and lactation.

Recently, there has been an increase in research into the relationship between long-chain n-3 polyunsaturated fatty acids (n-3 PUFAs) and cognitive function although the topic remains controversial. In epidemiological studies, fatty fish or n-3 PUFAs consumption has been found to be associated with a reduced risk of cognitive decline or dementia. In addition, higher proportion of total n-3 PUFAs or higher ratio of n-3 to n-6 PUFAs on erythrocyte membranes have been found to be associated with a lower risk of cognitive decline. Furthermore, in some animal models, docosahexaenoic acid (DHA, C22:6n-3) or eicosapentaenoic acid (EPA, C22:5n-3) administration have been found to improve learning ability and reduce Aβ amyloid deposition. However, findings from clinical trials of n-3 PUFAs supplementation to improve cognition in older people have been inconsistent. Some sub-group analyses have suggested that people with mild dementia or mild cognitive impairment may benefit most. Contradictory results may be clarified by better controlling possible confounders, more consistency in interventions and outcome measurements, and longer follow-up. Larger but possibly more focused trials should be considered along with efforts to develop better biomarkers for intervention response.

n-3 Long-chain polyunsaturated fatty acids (n-3 LC-PUFAs) reduce inflammation through several mechanisms; therefore, components of the metabolic syndrome (MetS) may be treated with n-3 LC-PUFAs not only because of their anti-inflammatory effect but also through other mechanisms that reduce vascular reactivity, oxidative stress, and insulin resistance. In this chapter, the positive effects of n-3 LC-PUFAs on each component of the MetS are analyzed. Although information regarding the effect of n-3 LC-PUFAs on obesity is discordant, it seems to either inhibit weight gain or decrease inflammatory status; thus, a positive effect is expected. Regarding the effect on hypertension, evidence shows that treatment with n-3 LC-PUFAs reduces blood pressure by modulating vascular reactivity and reducing arterial thickness. In the case of dyslipidemia, the triacylglycerollowering properties of n-3 LC-PUFAs are among the best established in vivo actions. These fatty acids also decrease the assembly and secretion of very-low-density lipoproteins (VLDL), increase the conversion of VLDL to LDL particles, and increase β-oxidation of other fatty acids in mitochondria. Finally, insulin sensitivity is improved by treatment with n-3 LC-PUFAs due to actions on lipid dysregulation, adiponectin production and by their role as ligands to peroxisome proliferator-activated receptors. In conclusion, evidence mainly from randomized trials supports the positive effect of n-3 LC-PUFAs in all four components of the MetS. Such beneficial roles act at the cellular and the molecular levels and have been demonstrated in animal and human experimental studies and at the community level. Therefore, use of n-3 LC-PUFAs may be widely recommended to decrease the MetS and subsequently decrease the risk for type 2 diabetes and cardiovascular disease.

Studies in humans and animal models have demonstrated that fish oil, a natural source of n-3 long chain polyunsaturated fatty acids (LC-PUFA), has clinical significance in the prevention and reversal of insulin resistance. Many studies support that higher proportion of serum and cell-membrane n-3 PUFA can improve insulin sensitivity and prevent type 2 diabetes (T2D). However, epidemiological and dietary intervention studies in healthy, obese and diabetic individuals have produced conflicting results on the metabolic effects of dietary n-3 PUFA. The present chapter discusses updated evidence on this matter, analyzes the possible reasons for these inconsistencies, and the possible mechanisms by which n-3 LC-PUFA may prevent or revert insulin resistance. The use of these fatty acids should be part of integral strategies, considering age, gender, metabolic or health status and other variables. This strategy should include changes in lifestyle, adhering to a healthy diet and regular physical activity. Although this is encouraging in the perspective of insulin resistance prevention, further clinical and basic studies must be designed to confirm and complete our knowledge in this field.

Depression and cardiovascular diseases (CVDs) are highly comorbid diseases, implying common mechanisms interplay between these two. According to recent clinical and basic studies, omega-3 polyunsaturated fatty acids (n-3 PUFAs) seem to be a possible interface. N-3 PUFAs deficiency is associated with dysfunctions of neuronal membrane stability and transmission of neurotransmitters, which might connect to the etiology of mood and cognitive dysfunction of depression. N-3 PUFAs is essential in balancing the immune function by reducing membrane arachidonic acid and prostaglandin E2 synthesis, which have been linked to the somatic manifestations of CVDs and depression. The role of n-3 PUFAs in immunity and neural function further supports the hypothesis of psychoneuroimmunology of depression and CVDs and provides an excellent interface between ‘mind’ and ‘body.’ This review is to provide an overview across evidences of the role of n-3 PUFAs in depression and CVD, and to propose possible mechanisms by which they may act at molecular and cellular levels.

The prevalence of allergic diseases has importantly increased in the last years in some parts of the world. The related causes are poorly known. However, it is thought to be associated to a complex interaction of genetic and environmental factors. There’s some epidemiological evidence that the reduction in omega-3 long chain polyunsaturated fatty acids (ω-3 LC-PUFAS) intakes with the increased allergy prevalence. At this time, there’s not enough evidence to recommend ω-3 LC-PUFAS supplementation, neither in the pregnant mother, nor in the breastfeeding mother, in order to prevent allergic disease development in high risk population (primary prevention). However, current studies are too heterogeneous and consider only ω-3 LC-PUFAS intake at lower doses. We need to develop more studies with high dose of ω-3 LC-PUFAS to elucidate that issue. Similarly, there are no conclusive data about the prevention of allergy development in high risk infants feeding with ω-3 LCPUFAS supplementation. ω-3 LC-PUFAS consumption may reduce the use of anti-inflammatory drugs in the treatment of asthma, probably because both of them exert their effects, almost in part, through the same molecular actions. There may be a role of lipid mediators derived from ω-3 LC-PUFAS metabolism (lipoxins and resolvins) in the resolution of allergic asthma inflammation. Hence, synergy between ω-3 LC-PUFAS and drugs may take place and represent an adjunctive therapy in asthma (secondary prevention). Placebo-controlled studies with highquality methodology design are required so as to draw better conclusions, especially with the employment of ω-3 LC-PUFAS at high doses (2-4 grams per day).

The n-3 long-chain polyunsaturated fatty acids (LC-PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have demonstrated a beneficial effect on reducing morbidity and mortality of some highly prevalent chronic diseases. Therefore, there is considerable interest in establishing recommendations for EPA and DHA. The Institute of Medicine of The National Academies in 2002 established that 10% (~100 mg/day) of the acceptable macronutrient distribution range from α-linolenic acid (ALA) can be provided from EPA and DHA in order to avoid deficiencies and to support adequate neurodevelopment and growth. However, most of these data were obtained from epidemiological investigations rather than from clinical research. Additionally, this amount represents the average intake of these n-3 fatty acids in a healthy population but is not a dietary reference intake (DRI); hence, this amount has been qualified as low according to the scientific community. Considering the enormous health benefits based on several specific effects of n-3 LC-PUFAs, DRIs should be re-evaluated in light of the new evidence and the recommendations of numerous international federal agencies. At the present time, there is evidence of beneficial for prevention of coronary heart disease (CHD) and cardiac death at intakes of 250 to 500 mg/day of EPA + DHA as well for pregnant, lactating and childbearing woman whose daily consumption should be at least 200 mg of DHA. Meanwhile, evidence is inconclusive for preterm infants and other pathological entities such as cognitive decline and affective disorders.