Fat is perhaps the most diverse class of dietary macronutrients (the other three classes are carbohydrates, proteins and fibers) concerning the nutrition value and physiological effects on human health. Currently, most people understand the good (unsaturated fat), the bad (saturated fat) and the ugly (trans fat) that have been described in “Fat Metabolism 101”. We know that animal fat derived oils are not good to human health due to their high content of saturated fatty acids and cholesterol, and that plant seeds derived oils are good due to the high content of unsaturated fat and zero cholesterol. Few people, however, realize that not all unsaturated fats are good to human health. Many plant seeds oils such as sunflower oil, peanut oil and corn coil are rich in polyunsaturated fatty acids (PUFAs) that are pro-inflammatory and devoid of the PUFAs that are anti-inflammatory. On the other hands, some plant seeds oils such as rapeseed oil (Canola) and olive oil has balanced PUFAs that are overall good for human health. Therefore, it is important to distinguish the type of PUFAs in dietary oils.
PUFAs are fatty acids that have two or more double bonds in each molecule. There are two types of PUFAs in dietary oil: ω-3 and ω-6. They are distinguished by the position of the first double bond counting from the methyl end of the carbon chain. The ω-3 fatty acids are PUFAs with the first double bond occurs at the third carbon atom from the methyl end of the carbon chain. The ω-6 fatty acids are PUFAs with the first double bond occurs at the sixth carbon atom from the methyl end of the carbon chain (Fig.1).
The most common ω−3 fatty acids in human diet include ALA, EPA, and DHA. The most common ω−6 fatty acids are LA and AA (Table 1). The ω−3 fatty acid ALA and the ω−6 fatty acid LA are also essential fatty acids since they are indispensible for normal physiology yet human body cannot synthesize them, thus has to obtain them from diet. Essential fatty acid deficiency leads to dermatitis, decreased growth in infants and children, increased susceptibility to infection, and poor wound healing. In human cells, besides dietary intake, all the long-chain ω−3 fatty acids are synthesized from ALA and all the long-chain ω−6 fatty acids are synthesized from LA.
Overall, ω−3 fatty acids are anti-cardiovascular diseases and anti-inflammation while ω−6 fatty acids are pro-cardiovascular diseases and pro-inflammation. Long-chain ω−3 fatty acids (EPA and DHA) provide many health benefits with regard to its cardiovascular diseases prevention and anti-inflammation effects. DHA, a long-chain ω−3 fatty acid, is also directly involved in visual and neuronal cells development. Adequate amount of ω−6 fatty acids are also beneficial to human health since many bioactive signaling molecules, especially the ones that are involved in immune response and cardiomyocytes contraction, are derived from them. However, in modern Western diet, ω−6 fatty acids tend to be over supplied while ω−3 fatty acids under supplied due to industrialized food oil production from sources that were otherwise unavailable. The overwhelmingly over-intake of ω−6 leads to hyper immune responses and interferes with the proper function of ω−3 fatty acids, causing detrimental effects that are blamed for chronic cardiovascular diseases and inflammatory responses (Table 2).
Due to the opposing effects of ω−3 and ω−6 fatty acids, it is advocated that a healthy dietary regime should contain a balanced ω−6:ω−3 ratio. Human beings evolved on a diet with a ratio of ω−6:ω−3 about 1:1 and our genetic makeup is well adapted to this ratio. Modern Western diets are deficient in ω-3 while are excessive in ω-6 fatty acids, exhibiting a ω−6:ω−3 ratio from 15:1 to 17:1. Epidemiology and dietary intervention studies have concluded that while the exceptionally high ω−6:ω−3 ratio promotes the development of many chronic diseases, reduced ω−6:ω−3 ratio prevents or reverses these diseases. For example, a ω−6:ω−3 ratio of 4:1 was associated with a 70% reduction of mortality in secondary prevention of coronary heart disease. A ratio of 2.5:1 reduced rectal cell proliferation in patients with colorectal cancer. The lower ω−6:ω−3 ratio in women with breast cancer was associated with decreased risk. A ratio of 2:1–3:1 suppressed inflammation in patients with rheumatoid arthritis, and a ratio of 5:1 had a beneficial effect on patients with asthma, whereas a ratio of 10:1 had adverse consequences.
Furthermore, a high ω−6:ω−3 ratio is especially detrimental to populations with certain genetic variations. For example, the minor allele carriers of the APOA5 -1131T>C polymorphism have elevated triglycerides levels and the minor allele carriers of 5-lipoxygenase polymorphism in the gene promoter region exhibit increased risk for atherosclerosis. Other gene polymorphisms that interacts with the ω−6:ω−3 ratio include CD36 (a cell surface scavenger receptor) and TCF7L2 (a transcription factor) genotypes. Therefore, keep a low dietary ω−6:ω−3 ratio is important to prevent chronic diseases.
Fig.2 provides the fatty acids composition as well as ω−6:ω−3 ratio in common food sources. It is noticeable that many plant seeds oils contain no ω−3. Long term usage of these oils without supplement from other ω−3 rich sources will gradually and accumulatively inflict hyper immune response and associated chronic diseases. It is also noticeable that most animal based fat are actually well balanced with regard to the ω−6:ω−3 ratio (chicken fat is an exception). But due to the high percentage of saturated fat, consumption of animal fat still needs to be restricted in an appropriate amount. Overall, Canola oil represents the most balanced fatty acids composition, not only a good ω−6:ω−3 ratio, but also a high percentage of monounsaturated fat that is beneficial to human health. Olive oil, although moderately high in the ω−6:ω−3 ratio, also contains high percentage of monounsaturated fat. Most importantly, olive oil also contain high amount of antioxidant and the substance squalene that has been shown anti-cancer effects. Therefore, olive oil is another good choice of healthy food oil. Deep sea fish oils such as salmon fat are excellent sources of ω−3. Flaxseeds oil is rich in ω−3. It is a good source of ω−3 supplement.
The opposing effects of ω−3 and ω−6 fatty acids on human health are due to three molecular mechanisms: 1) they compete for the same set of enzymes to produce signaling molecules that have opposing physiological functions. While ω−3 derived signaling molecules are pro-inflammatory, ω−6 derived are anti-inflammatory; 2) they compete for direct transcription factors binding to modulate the expression of different sets of target genes; and 3) they compete to incorporate into cell membranes, directly impact the function of membrane.
PUFAs metabolism
Once consumed from diet and enters human cells, PUFAs are either stored in phospholipids of cell and organelle membranes and in glycerides and phospholipids of lipid bodies in human cells. When needed, these fatty acids are released from phospholipids by PLA2 (phospholipase A2) and are further converted to signaling molecules. Shorter chain PUFAs LA and ALA can be further processed to produce longer carbon chain and more double bonds by the same set of enzymes (enlogases and desaturases). However, ω−3 and ω−6 fatty acids are not inter-convertible in human and animals. All the longer chain products derived from ω−3 fatty acid will remain ω−3, and ω−6 derivatives remain ω−6 (Fig.3). For example, AA (ω−6) can be synthesized from LA (ω−6), but not from ALA (ω−3) in human body. Similarly, DHA (ω−3) and EPA (ω−3) can be synthesized from ALA (ω−3), but not from LA (ω−6). In addition, both types are also precursors of, and share the enzymes to produce, signaling molecules that work through cell surface receptors like the GPCRs (G protein coupled receptors) as well as through nuclear hormone receptor transcription factors directly to regulate processes related to cardiovascular function and inflammation response.
Figure 3. Metabolism of PUFAs in human body. Dietary essential PUFAs LA (ω-6) and ALA (ω-3) are further processed to become longer carbon chain and more double bonds PUFAs by a series of reactions catalyzed by the same set of enzymes desaturase and elongase in endoplasmic reticulum. The final β-oxidation step occurs in peroxisomes.
The long-chain PUFAs AA (ω-6), EPA (ω-3) and DHA (ω-3) are substrates for the production of signal molecules (colored coded purple to indicate pro-inflammation and blue for anti-inflammation) catalyzed by the enzymes Cox (cyclooxygenase) and Lox (lipoxygenase).
PUFA derived signaling molecules
Overall, the signal molecules derived from ω−6 are pro-arrhythmic (irregular heart beat or muscle contraction) and pro-inflammatory while the signal molecules derived from ω−3 are anti-arrhythmic and anti-inflammatory (Table 3).
Table 3. Opposite effects of ω−3 and ω−6 derived signaling molecules.
| Types |
AA (ω-6) derived |
EPA & DHA (ω-3) derived |
| Molecules |
Function |
Molecules |
Function |
| Prostaglandins |
PGE2 |
Pro-arrhythmic |
PGE3 |
Anti-arrhythmic |
| PGI2 |
Pro-arrhythmic |
PGI3 |
Anti-arrhythmic |
| Thromboxanes |
TXA2 |
Platelet activator |
TXA3 |
Platelet inhibitor |
| TXB2 |
Vasoconstriction |
TXB3 |
Vasodilatation |
| Leukotrienes |
LTB4 |
Pro-inflammatory |
LTB5 |
Anti-inflammatory |
| LTC4 |
Pro-inflammatory |
|
| LTE4 |
Pro-inflammatory |
| Lipoxin |
LXA4 |
Anti-inflammatory |
| Resolvins |
|
RVE1 |
Anti-inflammatory |
| RVD |
Anti-inflammatory |
| NPD1 |
Anti-inflammatory |
Most of the signal molecules derived from PUFAs are eicosanoids, the 20-carbon atoms (eicosa- means 20 in Greek) signal molecules shown in Table 3, except RVD and NPD1, which are DHA derived 22-carbon atoms signaling molecules. All of these signaling molecules are autocrines or paracrines that act locally, on the cells or in the vicinity of the cells where they are manufactured. They activate different pathways either through GPCRs (G protein coupled receptors) on cell surface or through nuclear hormone receptor transcription factors directly. Some of the signaling molecules are generated in most of the cells. Others are cell type specific. The same signaling molecules can bind to different GPCRs to activate totally opposite pathways. For example, the prostaglandin PGE2 causes bronchoconstriction (the constriction of the airways in the lungs) when bind to the receptor EP1 whereas the same molecule causes bronchodilatation (the relaxation of the airways in the lungs) when bind to the receptor EP2. Therefore, the effect of one signaling molecule on a whole body depends on its interaction with many other factors. A combination of different signaling molecules, different cell types and different GPCRs dictates the exact physiological effect. Overall, ω−6 derivatives are pro-arrhythmic and pro-inflammation and ω−3 derivatives are anti-arrhythmic and anti-inflammation (Schmitz & Ecker, 2008).
Prostaglandins are a group of fatty acids derivatives that have 20 carbon atoms that including a 5-carbon ring structure. Historically it was believed these molecules were secreted by prostate gland, hence named prostaglandins. It is now known that many other tissues secrete prostaglandins for various functions. In relevance to the topic discussed here, the ω−6 fatty acid AA derived PGI2 (also known as prostacyclin) and PGE2 have pro-arrhythmic effects, whereas the ω−3 fatty acid EPA-derived prostaglandins PGI3 and PGE3 are anti-arrhythmic (Lin et al, 1997).
Thromboxanes are a group of fatty acids derivatives that have 20 carbon atoms that including a 6-carbon ether-containing ring structure. Named for their roles in thrombosis, the formation of blood clot, thromboxanes are a vasoconstrictor and facilitate platelet aggregation. Thromboxane-2 series TXA2 and TXB2, produced by activated platelets, have prothrombotic properties, stimulating activation of new platelets as well as increasing platelet aggregation. Whereas the ω−3 fatty acid EPA derived TXA3 and TXB3 has opposite effect. The TXB2-mediated platelet aggregation and promote vasodilatation is also inhibited by EPA-derived prostaglandins.
Leukotrienes are a group of fatty acids derivatives that have 20 carbon atoms that including three conjugated double bonds in their structure. The ω−6 fatty acid derived LTB4 is a potent chemotactic agent for leukocytes. It increases vascular permeability, induces release of lysosomal enzymes and accelerates reactive oxygen species production. It also leads to the production of inflammatory cytokines like TNFa, IL-1 and IL-6. The leukotrienes LTC4, LTD4 and LTE4 increase vascular permeability and promote hypersensitivity. These 4-series leukotrienes are believed to be responsible for hypersensitivity reactions that are involved in asthma, psoriasis, allergic rhinitis, gout, rheumatoid arthritis, adult respiratory distress syndrome, neonatal pulmonary hypertension, and inflammatory bowel disease. The ω−3 fatty acid derived LTB5 blocks biosynthesis of the LTB4 therefore exhibits the anti-inflammatory effect.
Lipoxins (LX) are derived from the ω−6 fatty acid AA and manufactured in leukocytes. There are two types of lipoxins, LXA4 and LXB4. Both types inhibit chemotaxis of polymorphonuclear leukocytes, and may have roles in inflammation and wound healing. LXA4 appears to oppose some leukocyte responses to leukotrienes. For example, the binding of LXA4 to polymorphonuclear leukocytes inhibits chemotactic responses and degranulation induced by LTB4. By competing for receptor sites, LXA4 inhibits vasoconstriction induced by LTD4. By inhibiting neutrophil and eosinophil migration and adhesion, lipoxins act as anti-inflammatory signaling molecule. The anti-inflammatory effect of LXA4 is unusual in the sense that most of the ω−6 fatty acid derived eicosanoids are pro-inflammatory.
Resolvins are ω−3 fatty acids derived compounds, so named because they were first encountered in resolving inflammatory exudates. Neuroprotectins are resolvins first discovered in brain tissue. The resolvins have strong anti-inflammatory effects in addition to some immunoregulatory activities at picomolar to nanomolar concentrations. They are part of the molecular mechanisms that contribute to removal of inflammatory cells and restoration of tissue integrity once the need for the inflammatory response is over. The neuroprotectins appear to operate in the same way as the resolvins in brain tissue. The anti-inflammatory effects of NPD1 protect retinal epithelial cells from apoptosis induced by oxidative stress. In addition, it has protective effects in animal models of stroke and of Alzheimer's disease. Amongst its activities in non-neuronal tissues, it promotes apoptosis of T cells and it has beneficial effects towards asthma. It is evident that such compounds and their metabolism have considerable protective effect in acute inflammation or chronic inflammatory disease.
Usually, an acute inflammation in response to infection or tissue damage appears as heat, redness, swelling and pain. At cellular level, it is characterized by edema, accumulation of leukocytes, and then by accumulation of monocytes and macrophages. Leukotrienes (especially LTB4) and prostaglandins (PGE2 and PGD2) derived from ω−6 fatty acid AA are actively involved in the early stages of the inflammatory process. As tissues return to health, resolvins and lipoxins promote resolution of the inflammation through removal of the leukocytes together with cellular debris. The balance of dietary ω−3 and ω−6 fatty acids affects the production of these signaling molecules, thereby determines the duration and extent of each stage of inflammation.
Cox and Lox: key enzymes for signaling molecules synthesis from PUFAs
The key enzymes that are responsible for the production of signal molecules from PUFAs are Cox (cyclo-oxygenases) and Lox (lipoxygenases). Most signal molecules are either the product of Cox or that of Lox.
There are two Cox isozymes in human body: COX-1 and COX-2. COX-1 is considered a constitutive enzyme, being found in most mammalian cells. COX-2 is an inducible enzyme, becoming abundant in activated macrophages and other cells at sites of inflammation. Both Cox-1 and Cox-2 convert the ω−6 fatty acid AA to the prostaglandin-2 series and thromboxane-2 series molecules, and the ω−3 fatty acids EPA and DHA to the prostaglandin-3 and thromboxane-3 series, and resolvins (Fig. 3). Both Cox-1 and Cox-2 are the targets of nonsteroidal anti-inflammatory drugs (NSAIDs). The anti-inflammation medicine aspirin, which irreversibly inhibits Cox-1 more than Cox-2, causes the reduction of inflammation, analgesia (relief of pain), the prevention of clotting, and the reduction of fever through the decreased production of prostaglandins and thromboxanes.
Lox is a family of enzymes that convert ω−6 fatty acid AA to leukotriene-4-series and lipoxins. These same enzymes also convert ω−3 fatty acids EPA to leukotriene-5-series and DHA to resolvins (Fig. 3). The two major isozymes of Lox are 5-lipoxygenase and 15-lipoxygenase. The former is responsible for the synthesis of leukotrienes in myeloid cells and the later lipoxins in leukocytes. The asthma treatment drugs zileuton, montelukast and anti-parasite drug diethylcarbamazine are lipoxygenases inhibitors.
A unique feature about resolvin synthesis is that they are the action of both Cox and Lox enzymes. In the presence of aspirin, the enzyme Cox-2 is acetylated. The acetylated Cox-2, which can no longer convert ω−6 fatty acid AA, converts the ω−3 fatty acid EPA or DHA into the substrates for 15-Lox, which further converts the substrates into resolvins. In the absence of aspirin, 15-Lox can still convert EPA and DHA to resolvins through similar pathways for lipoxin biosynthesis. Without aspirin, most of Cox activity devoted to ω−6 fatty acid AA metabolism, resolvin synthesis is much limited. Therefore, it is reasonable to believe that dietary supplements of the precursor ω-3 fatty acids, taken together with aspirin, may ameliorate the clinical symptoms of many inflammatory disorders by regulating the time course of resolution via the production of resolvins.
PUFAs on gene expression: Fatty acids as direct ligands for transcription factors
Many ω-3 and ω-6 fatty acids directly bind to nuclear hormone receptor transcription factors like peroxisome proliferator receptors (PPARs), retinoid X receptors (RXRs), liver X receptors (LXRs) and a basic helix–loop–helix leucine zipper (bHLH-LZ) transcription factor sterol regulatory element-binding protein 1c (SREBP-1c) to modulates target gene expression involved in lipid metabolism pathways. Some also directly interact with the master transcription factor NF-kB to influence immune response.
PPARs are master regulators of lipid and energy metabolism. The functions of the three types PPAR in human (PPARα, PPARγ and PPARδ) and their interactions with fatty acids have been described in the “PPARs and energy metabolism” review. In brief, PPARα regulates the expression of target genes involved in liver fatty acid oxidation (fat burning to produce energy) during fasting; PPARγ, regulates the expression of target genes involved in lipid synthesis in adipocytes (energy storage); and PPARδ regulates the expression of target genes involved in fatty acids synthesis in liver and the genes involved in fat burning in muscle. In addition to energy metabolism, all three types of PPARs exhibit anti-inflammation effect via several distinct mechanisms (Fig. 3). For example, ligands activated PPARα and PPARγ down regulate the expression of immune responsive genes by binding directly to transcription factors NF-κB, STAT1 and AP-1, preventing them from activating immune responsive genes such as cytokines (IL-1, IL-2, IL-6, IL-12,TNF-α), chemokines (e.g., IL-8, MIP-1α, MCP1), adhesion molecules (e.g., ICAM, VCAM and E-selectin), and inducible effector enzymes (iNOS and COX-2) (Delerive et al 1999; Ricote et al, 1999; Chung et al, 2000). Alternatively, the fatty acid metabolites of PPARs can act as agonists or antagonists of other transcription factors including NF-κB, STAT1 and AP-1. Various ω-3 and ω-6 fatty acids and the metabolites are natural ligands for all types of PPARs with differential potency (Krey et al, 1997). The ω-3 fatty acids EPA and DHA are more potent as in vivo activators of PPARα than ω-6 fatty acids although EPA binds all PPARs with a Kd ranging between 1 and 4 µM. Even stronger activators are the eicosanoids derived from EPA, DHA and AA. Leukotriene B4 and 8-HEPE (hydroxyeicosapentaenoic) are potent and specific ligand for PPARα. Others such as 9-HODE (9-hydroxyoctadenoic acid) and 13-HODE are specific for PPARγ whereas PGJ2 can activate all three types of PPARs (Desvergne & Wahli, 1999).
PUFAs also inhibit NF-κB activity directly. EPA and DHA blocks NF-κB through decreased degradation of the inhibitory subunit of NF-κB (IκB) in cultured pancreatic cells, THP-1 macrophages and human monocytes. AA-derived EETs inhibit NF-κB translocation and activation by blocking the IκB-kinase complex (IKK). Inactive IKK is associated with the active inhibitor IkB, which functionally retains NF-κB in the cytoplasm and renders it inactive (Schmitz & Ecker, 2008).
PPARs function by forming heterodimers with RXRs, which also form homodimers or heterodimers with retinoic acid receptors (RARs), and LXRs to regulate target genes involved in multiple cellular processes such as the retinoid signaling pathway and lipid anabolism and catabolism. LXRs activate the expression of SREBP-1c, a dominant lipogenic gene regulator and cholesterol metabolism controller. PUFAs modulate the heterodimer formation between different nuclear receptors through directly binding to individual factors or by ligand competition. It has been shown that DHA is a RXR ligand while AA is ligand for RXRa. The conjugated LA isomer trans-9, trans-11-CLA activates SREBP-1c. Over-expression of PPARα and PPARγ inhibited LXR induced SREBP-1c promoter activity through a reduction of LXR/RXR complex formation. Additionally, AA, LA and DHA are ligands for farnesoid X receptor (FXR), the nuclear receptor for bile acids metabolism. Stimulation of FXR enhances the expression of a short heterodimer protein, which has a negative feedback effect on LXR activity. A very recent study describes a novel mechanism for fatty acid regulation of hepatocyte nSREBP-1. DHA suppresses hepatocyte nSREBP-1 through 26S-proteasome and ERK-dependent pathways (Schmitz & Ecker, 2008; Russo, 2009).
PUFAs and membrane function
PUFAs contribute to increased cell membrane fluidity. The numbers of hormone receptors on cell membrane is determined by cell fluidity. A rigid membrane limits while a fluid membrane increases the number of receptors. For example, enhanced cell membrane fluidity by increasing PUFA intake was attributed to an increases number of insulin receptors, an increased affinity of insulin to its receptors and a reduced insulin resistance. Cell membrane fluidity by PUFAs also interferes with T-cell receptor (TCR). TCR stimulation activates Lck and Fyn, two members of the Src family, leading to the activation of ERK cascade of signal transduction. Treatment of Jurkat T cells with EPA and AA results in marked incorporation of PUFAs into phosphatidylethanolamine. This event leads to displacement of palmitate-labeled Lck and Fyn from the lipid rafts, a membrane microdomain that organizes receptor trafficking, and down-regulation of ERK signaling. Replacement of palmitoyl group by AA or EPA results in Fyn loss of function since the kinase reduces its interaction with the lipid rafts (Russo, 2009).
Cell membrane fluidity is significantly impacted by the number of double bonds in PUFAs. More double bonds lead to more flexible carbon chain conformational change. Since ω−3 fatty acids in general have more double bonds than ω−6 fatty acids, they provide more membrane fluidity than ω−6 fatty acids. The ω−3 fatty acid DHA, for example, is required in the nervous system for optimal neuronal and retinal function and influences signaling events that are vital for neuronal survival and differentiation. DHA is incorporated into phosphatidylserine (PS) in neurons. Clustering of PS at the cytosolic side of membrane lipid rafts facilitates translocation and activation of Akt, a serine–threonine protein kinase. This leads to a suppression of caspase-3 activation and cell death. In the case of ω−3 deficiency, DHA is replaced by DPA (docosapentaenoic acid, 22:5, ω−6) in neuronal cells, resulting in less PS clustering and Akt translocation, thus less cell survival (Simons & Vaz, 2004) and consequent memory loss, learning disabilities, and impaired visual acuity.
The ω -6 : ω-3 ratio theory
As described above, ω−3 and ω−6 fatty acids compete for the same enzymes to produce eicosanoids and DHA derived signaling molecules with opposing physiological functions. While ω−3 derived signaling molecules are pro-inflammatory, ω−6 derived are anti-inflammatory. These two types of PUFAs and their metabolites also interact with transcription factors directly to modulate the target gene regulation. Moreover, ω−3 and ω−6 fatty acids also compete to incorporate into cell membranes, directly impact the function of membrane. The opposing effects of ω−3 and ω−6 fatty acids lead to the ω−6:ω−3 ratio theory, advocated actively by Artemis Simopoulos through many reviews and dietary books (Simopoulos & Robinson, 1999; Simopoulos, 2006; 2008).
Based on evidence from studies on the evolutionary aspects of diet, modern day hunter-gatherers, and traditional diets, the ω−6:ω−3 ratio theory proposes that the genetic makeup of human beings is adapted to a diet in which the ratio of ω−6:ω−3 was about 1. In today’s Western diets the ratio is 15/1 to 16.7/1. Many of the chronic conditions—cardiovascular disease, diabetes, cancer, obesity, autoimmune diseases, rheumatoid arthritis, asthma and depression—are associated with increased production of thromboxane A2 (TXA2), leukotriene B4 (LTB4), IL-1β, IL-6, TNF and CRP. The increase of these factors is due to the high ratio of ω−6:ω−3 in dietary fat that is incompatible to our genetic makeup. Therefore, decrease the ω−6:ω−3 ratio to roughly 1:1, either through smart choice of dietary oil or through food supplement, is the key to stay health.
The ω -3 side effects
No side effect has been associated with ω-3 rich food. However, taking too much dietary supplements, such as more than 3 grams of fish oil daily, may increase the risk of bleeding. Higher doses of ω-3 dietary supplements may also compromise your immune function. Most of the side effects and precautions for fish oil also pertain to cod liver oil with a few exceptions. Cod liver oil contains both vitamin A and D. Consuming excessive amounts of these two vitamins can cause toxicity and dangerous side effects. Moreover, certain medications, as well as mineral oil may also interfere with the absorption of vitamin A. In addition, using vitamin A at higher dosages in conjunction with synthetic vitamin A derivatives can result in an increased risk of toxicity.
References
Chung S.W. Kang B.Y. Kim S.H. Pak Y.K. Cho D. Trinchieri G. Kim T.S (2000). Oxidized low density lipoprotein inhibits interleukin-12 production in lipopolysaccharide-activated mouse macrophages via direct interactions between peroxisome proliferator-activated receptor-gamma and nuclear factor-kappa B. J. Biol. Chem. 275:32681–32687. PubMed:10934192
Delerive P. De Bosscher K. Besnard S. Vanden Berghe W. Peters J.M. Gonzalez F.J. Fruchart J.C. Tedgui A. Haegeman G. Staels B (1999). Peroxisome proliferator-activated receptor alpha negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-kappaB and AP-1. J. Biol. Chem. 274:32048–32054. PubMed:10542237.
Desvergne B, Wahli W (1999). Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr Rev 20:649–688.
Krey G, Braissant O, L'Horset F, Kalkhoven E, Perroud M, Parker MG, Wahli W (1997). Fatty acids, eicosanoids, and hypolipidemic agents identified as ligands of peroxisome proliferator-activated receptors by coactivator-dependent receptor ligand assay. Mol Endocrinol. 11(6):779-91. PMID:9171241
Li Y, Kang JX, Leaf A (1997). Differential effects of various eicosanoids on the production or prevention of arrhythmias in cultured neonatal rat cardiac myocytes. Prostaglandins. 54(2):511-30. PMID:9380795
Ricote M, Huang JT, Welch JS, Glass CK (1999). The peroxisome proliferator-activated receptor(PPARgamma) as a regulator of monocyte/macrophage function. J Leukoc Biol. 66(5):733–9.
Russo GL (2009). Dietary n-6 and n-3 polyunsaturated fatty acids: from biochemistry to clinical implications in cardiovascular prevention. Biochem Pharmacol. Mar 15;77(6):937-46. PMID:19022225
Schmitz G, Ecker J (2008). The opposing effects of n-3 and n-6 fatty acids. Prog Lipid Res. Mar;47(2):147-55. PMID:18198131
Simons K, Vaz WL (2004). Model systems, lipid rafts, and cell membranes. Annu Rev Biophys Biomol Struct;33:269–95. PMID:15139814
Simopoulos AP (2006). Evolutionary aspects of diet, the omega-6/omega-3 ratio and genetic variation: nutritional implications for chronic diseases. Biomedicine & Pharmacotherapy 60:502–507. PMID:17045449
Simopoulos AP (2008). The importance of the omega-6/omega-3 fatty acid ratio in cardiovascular disease and other chronic diseases. Exp Biol Med (Maywood). 233(6):674-88. PMID:18408140.
Simopoulos AP and Robinson J (1999). The Omega Diet: The Lifesaving Nutritional Program Based on the Diet of the Island of Crete. HarperCollins. New York.
