Omega-3 : Omega-6 balance

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Omega-3 and omega-6 are two types of polyunsaturated fatty acids. They are both required
for the body to function but have opposite effects when it comes to the inflammatory
response and cardiovascular health. Too much omega-6 and too little omega-3 are among
the causes for many diseases in modern society.

Fat is perhaps the most diverse class of dietary macronutrients in regards to nutritional
value and physiological effects. Currently, most people understand the differences between
the good (unsaturated fat), bad (saturated fat) and ugly (trans-fat) fats described in Fat
Metabolism 101. We know that oils derived from animal fat are not good for our health due
to their high levels of saturated fat and cholesterol, and that oils derived from plants are
generally good for our health due to their unsaturated fat content. However, not all
unsaturated fats are healthy. Many plant seed oils such as sunflower, peanut and corn oil
are rich in inflammatory polyunsaturated fatty acids (PUFAs) and devoid of anti-
inflammatory PUFAs. On the other hand, some plant seed oils such as canola and olive oil
have balanced PUFAs and are considered healthier. Therefore, it is important to distinguish
between the types of PUFAs in dietary oils for optimal health.

PUFAs are fatty acids that have two or more double bonds in each molecule. There are two
types of PUFAs in dietary oil: omega-3 and omega-6, also known as ω-3 and ω-6. They are
distinguished by the position of the first double bond. Omega-3 fatty acids have their first
double bond at the third carbon atom from the methyl end of the carbon chain while omega-
6 fatty acids have their first double bond at the sixth carbon atom from the methyl end
(Fig.1).

Figure 1. Structural representation of ALA (ω-3) and LA (ω-6), two essential fatty acids and
the most common PUFAs found in dietary oil. The red numbers represents the carbon
atoms counting from the methyl end of the chain. The blue counts from the carboxyl end.

The most common omega-3 fatty acids in the human diet are ALA, EPA, and DHA while
the most common omega-6 fatty acids are LA and AA (Table 1). The omega-3 fatty acid
ALA and the omega-6 fatty acid LA are referred to as essential fatty acids because the
body cannot synthesize them. Essential fatty acid deficiency can lead to dermatitis, stunted

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growth in infants and children, increased susceptibility to infection, and poor wound healing.
In human cells all long-chain omega-3 fatty acids are synthesized from ALA and all long-
chain omega-6 fatty acids are synthesized from LA.

Table 1.The most common omega-3 and omega-6 fatty acids and their dietary
sources

Types Abbreviation Common Name Structure Dietary Sources

Omega-3 ALA α-Linolenic acid C18 : 3 Oils: flaxseed, olive, canola

EPA Eicosapentaenoic acid C20 : 5 Fish oil, marine algae

DHA Docosahexaenoic acid C22 : 6 Fish oil, marine algae

Omega-6 LA Linoleic acid C18 : 2 Oils: corn, soybean,

sunflower, peanut

AA Arachidonic acid C20 : 4 Small amount in meat,

dairy products and eggs

Long-chain omega-3 fatty acids (EPA and DHA) provide many health benefits with regard
to their cardiovascular disease prevention properties and anti-inflammatory effects. DHA is
also directly involved in visual and neuronal cell development. Adequate amounts of
omega-6 fatty acids are also beneficial to human health since many bioactive signaling
molecules, especially ones involved in immune response and cardiomyocyte (muscle cells)
contraction, are derived from them. However, omega-6 fatty acids tend to be over-supplied
while omega-3 fatty acids are under-supplied in modern Western diets due to industrialized
food oil production. This overwhelming intake of omega-6 leads to hyperimmune responses
and interferes with the proper function of omega-3 fatty acids, causing detrimental effects
associated with chronic cardiovascular diseases and inflammatory responses (Table 2).

Table 2. The effects of Omega-3 and Omega-6 fatty acids on chronic diseases.

Chronic
Diseases Risk Factors Comments Omega-3 Omega-6

Cardiovascular Arrhythmias (irregular Causes sudden cardiac death Lowers Increases

Diseases heart beat)

Thrombosis (clot) Leads to myocardial infarction Lowers Increases

or stroke

Atherosclerotic plaque Leads to atherosclerosis Lowers Increases

HDL Good cholesterol Increases Lowers

LDL Bad cholesterol Lowers Increases

Triglycerides Cardiovascular risk factor Lowers Increases

Inflammatory IL-1 (Interleukin 1) Inflammation response Lowers Increases

Responses
IL-6 (Interleukin 6) Inflammation response Lowers Increases

CRP (C-reactive protein) Inflammation response Lowers Increases

Due to the opposing effects of omega-3 and omega-6 fatty acids, a healthy diet should
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contain a balanced omega-6:omega-3 ratio. Human beings evolved eating a diet with a
omega-6:omega-3 ratio of about 1:1. Modern Western diets exhibit omega-6:omega-3
ratios ranging between 15:1 to 17:1. Epidemiology and dietary intervention studies have
concluded that while an exceptionally high omega-6:omega-3 ratio promotes the
development of many chronic diseases, a reduced omega-6:omega-3 ratio can prevent or
reverse these diseases. For example, a ratio of 4:1 was associated with a 70% reduction in
mortality in secondary coronary heart disease prevention and a ratio of 2.5:1 reduced rectal
cell proliferation in patients with colorectal cancer. A lower omega-6:omega-3 ratio in
women was associated with decreased risk for breast cancer. 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 omega-6:omega-3 ratio is especially detrimental to carriers of certain

genetic variations. For example, minor allele carriers of the APOA5 gene have elevated
triglycerides levels and minor allele carriers of 5-lipoxygenase polymorphism in the gene
promoter region exhibit increased risk for atherosclerosis. Other gene polymorphisms that
are affected by this ratio include CD36 (a cell surface scavenger receptor) and TCF7L2 (a
transcription factor). Lowering the omega-6:omega-3 ratio is particularly important for these
variant carriers to prevent chronic diseases.

Fig.2 shows the fatty acid composition as well as the omega-6:omega-3 ratio in common
food sources. It is clear that many plant seed oils contain no omega-3. Long-term ingestion
of these oils without supplementing omega-3 from other sources will gradually incur
hyperimmune responses and associated chronic diseases. It is also clear that most animal-
based fats are actually well-balanced with regard to the omega-6:omega-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 has the most
balanced fatty acid composition, not only due to a good omega-6:omega-3 ratio, but also
because it contains a high percentage of monounsaturated fat which is beneficial to human
health. Olive oil, although moderately high in the omega-6:omega-3 ratio, also contains a
high percentage of monounsaturated fat. Most importantly, olive oil also contains a high
amount of antioxidants and the substance squalene that has been shown to have 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 omega-3. Flaxseeds oil is also a rich
source of omega-3. It is a good option to use for a omega-3 supplement.

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Figure 2. The fatty acid composition and ω-6:ω-3 ratio in most common dietary fat.

The opposing effects of omega-3 and omega-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 omega-3 derived
signaling molecules are anti-inflammatory, omega-6 derived are pro-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 impacting
the function of the membrane.

PUFAs metabolism
Once consumed from the diet and inside human cells, PUFAs are stored in the
phospholipids of the cell and organelle membranes or 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 chains and more double bonds by the same set of enzymes (enlogases and
desaturases). However, omega-3 and omega-6 fatty acids are not inter-convertible in
human and animals. All the longer chain products derived from omega-3 fatty acids remain
omega-3, and omega-6 derivatives remain omega-6 (Fig.3). For example, AA (omega-6)
can be synthesized from LA (omega-6), but not from ALA (omega-3) in the human body.

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Similarly, DHA (omega-3) and EPA (omega-3) can be synthesized from ALA (omega-3), but
not from LA (omega-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 the human body. Dietary essential PUFAs, LA (ω-6) and
ALA (ω-3), are further processed to become longer carbon chains with more double bonds
by a series of reactions catalyzed by the same set of enzymes desaturase and elongase in
the 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 omega-6 are pro-arrhythmic (irregular heart beat
or muscle contraction) and pro-inflammatory while the signal molecules derived from
omega-3 are anti-arrhythmic and anti-inflammatory (Table 3).

Table 3. Opposite effects of omega−3 and omega−6 derived signaling

molecules.

AA (ω-6) derived EPA & DHA (ω-3) derived

Molecules Function Molecules Function

Types
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 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 atom
(‘eicosa’ means 20 in Greek) signal molecules shown in Table 3, except for 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 the cell surface or through nuclear hormone receptor
transcription factors directly. Some of the signaling molecules are generated in most of the
cells while others are cell type specific. The same signaling molecules can bind to different
GPCRs to activate totally opposite pathways. For example, prostaglandin PGE2 causes
bronchoconstriction (the constriction of airways in the lungs) when it binds to the receptor
EP1 whereas the same molecule causes bronchodilation (the relaxation of the airways in
the lungs) when it binds 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
dictate the exact physiological effect.

Prostaglandins are a group of fatty acid derivatives that have 20 carbon atoms and
include a 5-carbon ring structure. Historically it was believed these molecules were
secreted by the 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 omega-6 fatty acid AA derived PGI2 (also known as prostacyclin) and
PGE2 have pro-arrhythmic effects, whereas the omega-3 fatty acid EPA-derived
prostaglandins PGI3 and PGE3 are anti-arrhythmic (Lin et al, 1997).

Thromboxanes are a group of fatty acid derivatives that have 20 carbon atoms and
include 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

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platelet aggregation. Whereas the omega-3 fatty acid EPA derived TXA3 and TXB3 has
opposite effect. The TXB2-mediated platelet aggregation and vasodilation is also inhibited
by EPA-derived prostaglandins.

Leukotrienes are a group of fatty acid derivatives that have 20 carbon atoms and include
three conjugated double bonds in their structure. The omega-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 omega-3 fatty acid derived LTB5 blocks biosynthesis
of the LTB4 thereby exhibiting anti-inflammatory effects.

Lipoxins (LX) are derived from the omega-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 molecules. The anti-inflammatory
effect of LXA4 is unusual in the sense that most of the omega-6 fatty acid derived
eicosanoids are pro-inflammatory.

Resolvins are omega-3 fatty acid 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 for asthma. It is evident that such compounds and
their metabolism have considerable protective effects in acute inflammation and/or chronic
inflammatory disease.

Usually an acute inflammation in response to infection or tissue damage appears as heat,

redness, swelling and pain. At the 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 omega-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 inflammation through removal of
leukocytes together with cellular debris.
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Cox and Lox: key enzymes for the synthesis of signaling
molecules from PUFAs
The key enzymes that are responsible for the production of signaling molecules from
PUFAs are Cox (cyclo-oxygenases) and Lox (lipoxygenases).

There are two Cox isozymes in the 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 omega-6 fatty acid AA to the
prostaglandin-2 series and thromboxane-2 series molecules and the omega-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 the omega-6 fatty acid AA to leukotriene-4-series
and lipoxins. These same enzymes also convert the omega-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 and montelukast, and the anti-parasite drug, diethylcarbamazine, are
lipoxygenases inhibitors.

A unique feature about resolvin synthesis is that both Cox and Lox enzymes are involved.
In the presence of aspirin, the enzyme Cox-2 is acetylated. The acetylated Cox-2, which
can no longer convert omega-6 fatty acid AA, converts the omega-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 the Cox activity devoted to
omega-6 fatty acid AA metabolism results in limited resolvin synthesis. Therefore, it is
reasonable to believe that dietary supplementation of omega-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 omega-3 and omega-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 modulate
target gene expression involved in lipid metabolism pathways. Some also directly interact
with the master transcription factor NF-κB to influence immune response.

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PPARs are master regulators of lipid and energy metabolism. The functions of the three
types of PPAR (PPARα, PPARγ and PPARδ) and their interactions with fatty acids are
discussed in more details here. 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 acid
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 effects via several distinct
mechanisms (Fig. 3). For example, ligand-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 omega-3 and omega-6 fatty acids and their
metabolites are natural ligands for all types of PPARs with differential potency (Krey et al,
1997). The omega-3 fatty acids EPA and DHA are more potent as in vivo activators of
PPARα than omega-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 ligands 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 IκB, 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 a ligand for RXRa. The conjugated LA isomer trans-9, trans-11-CLA activates
SREBP-1c. Over-expression of PPARα and PPARγ inhibit 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).
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PUFAs and membrane function
PUFAs contribute to increased cell membrane fluidity. The numbers of hormone receptors
on the 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 via increased PUFA intake was attributed to an increased 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 the 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 the 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 result in a more flexible carbon chain conformational change. Since
omega-3 fatty acids in general have more double bonds than omega-6 fatty acids, they
provide more membrane fluidity than omega-6 fatty acids. The omega-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 omega-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 omega-6:omega-3 ratio theory

As described above, omega-3 and omega-6 fatty acids compete for the same enzymes to
produce eicosanoids and DHA-derived signaling molecules with opposing physiological
functions. While omega-6 derived signaling molecules are pro-inflammatory, omega-3
derived are anti-inflammatory. These two types of PUFAs and their metabolites also
interact with transcription factors to modulate the target gene regulation. Moreover, omega-
3 and omega-6 fatty acids also compete to incorporate into cell membranes, directly
impacting the function of the membrane. The opposing effects of omega-3 and omega-6
fatty acids lead to the omega-6:omega-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 omega-6:omega-3 ratio theory proposes that the
genetic makeup of human beings is adapted to a diet in which the ratio of omega-6:omega-
3 was about 1. In today’s Western diets the ratio is 15:1 to 17:1. Many of the chronic
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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 omega-6:omega-3 in dietary fat that is incompatible
to our genetic makeup. Therefore, reducing your omega-6:omega-3 ratio to roughly 1:1 by
including healthy oils or an omega-3 dietary supplement in your diet can help promote
optimal health.

The omega-3 side effects

No side effect has been associated with omega-3 rich food. However, high intake of
omega-3 supplements, such as more than 3 grams of fish oil daily, may increase the risk of
bleeding. Higher doses of omega-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 and mineral oil may 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.

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PMID:10934192
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