PolyunsaturatedFatty Acids and TheirTherapeutic Functions

Fatty acids with chain length of 10 carbon atoms or less are referred to as short-chain fatty acids, and they are all saturated. Fatty acids having up to 14 carbon atoms are medium-chain fatty acids and those with more than 14 carbon atoms are long-chain fatty acids, which may be saturated or unsaturated.

• ω-3 and ω-6 (also referred as n-3 and n-6 fatty acids) denote fatty acids, in which the first double bond starts at 3 and 6 carbons from the methyl end, respectively.

• The symbol, 18:4 ω-3 identifies a fatty acid, with 18 carbon atoms and four double bonds, the first double bond occurring after the third carbon atom.

• The human diet contains long-chain PUFA belonging to the n-6 and n-3 families.

• Major dietary n-6 PUFA include linoleic, C18:2w6 (18:2); γ-linolenic, C18:3w6 (18:3); and arachidonic, C20:4w6 (20:4) acids, whereas major dietary ω-3 PUFA include α-linolenic, C18:3w6 (18:3); eicosapentaenoic acid (EPA), C20:5w3 (20:5); docosahexaenoic acid (DHA), C22:6w3 (22:6); and to some extent, docosapentaenoic acid.

• Linoleic, α– linolenic acids (ALA), and γ-linolenic acids are present in large quantities in foods of plant origin, such as oils from corn, maize, sunflower seed, cottonseed, soybean, linseed, and canola.

• Arachidonic acid (AA) originates from muscle and organ meats, or alternatively may be synthesized within the body by successive desaturation and chain elongation of linoleic acid (LA).

• EPA and DHA are synthesized by desaturation and chain elongation of ALA within the human body. When present in equimolar concentration, LA and ALA compete for conversion to their respective longer chain products, AA and eicosapentaenoic acid.

• Marine oils are rich sources of long-chain PUFA of the ω-3 type. The ω-3 fatty acids, 20 carbon EPA and the 22 carbon DHA are have been studied most extensively. EPA contains five double bonds and DHA, six double bonds.

• From a structural point of view, these fatty acids in natural state are cis isomers, whereas processing may give rise to the formation of large quantities of trans isomers.

• They are, however, present in high quantities in vegetable oils (canola, soybean, and sunfl ower) and nuts such as peanuts and almonds.

• The fatty acids, which have attracted particular attention from therapeutic point of view, are EPA and DHA.

• The biogenesis of these fatty acids in fish has been studied. Long-chain PUFAs containing 20 or more carbon atoms such as AA and EPA, and 22 carbon atoms DHA are formed from the 18-carbon LA and ALA by the process of chain elongation and desaturation.

• Fish have the ability to synthesize the saturated and monounsaturated fatty acids de novo, and also to selectively absorb and metabolize dietary fatty acids including long-chain PUFA.

• Mammals and fish are generally incapable of de novo synthesis of C18:2 (n-6), C18:3 (ω-3), C20:4 (n-6), C20:5 (ω-3), and C22:6 (ω-3), and dietary sources of these fatty acids are likely to be essential for them.

• This is because marine fish lack or have a very low activity of desaturase enzyme for the synthesis of the fatty acid. Thus, marine finfish accumulate large amounts of DHA and EPA, which are synthesized by phytoplankton of the marine food chain.

NUTRITIONAL VALUE OF LIPIDS

• The total amounts of EPA and DHA are about 20% of total fatty acids in various commercial fish oils.

• Essential fatty acids (EFAs) are shown to improve glucose tolerance, which is associated with type 2 diabetes and also reduces development of adipose fat. Linoleic and linolenic acids also provide increased benefits to the cardiovascular system. Two recent studies showed benefits of ALA in cardiovascular disease.

• Experiments using breast cancer cell lines showed that the fatty acid dramatically cut the levels of an oncogene, called Her-2/neu, which occurs in high levels in more than a fifth of breast cancer patients and associated with highly aggressive tumors.

Conjugated linoleic acid (CLA)

• Conjugated linoleic acid (CLA) derived from ruminant animal sources (e.g., beef, lamb, and dairy) and also plant (e.g., safflower) sources, have been reported to contain antioxidant and anticancer properties. CLA is found in seafood, but to a lesser extent.

• A majority of research to date has been focused to study the biological effects of the cis-9, trans-11 and trans-10, cis-12 CLA isomers. Dairy derived CLA, for example, has been shown to inhibit carcinogenesis in experimental animals and also help control obesity.

HEALTH BENEFITS OF OMEGA-3 FATTY ACIDS

• The beneficial effects of ω-3 fatty acids can be classified into two main areas.

• First, these fatty acids sustain normal healthy life through the reduction of blood pressure and plasma triglycerides and cholesterol, together with increased blood coagulation time.

• EPA and DHA are important for maintenance of normal blood flow as they lower fibrinogen levels

and prevent platelets from sticking to each other.

• Fish oil supplementation has been beneficial to control high blood pressure.

• The impact of ω-3 PUFA on blood pressure, which reported an intake of nearly 3 g EPA and DHA per day (which is equivalent to 6–10 capsules of commercial fish oil supplements or two servings of 100 g portion of fish rich in ω-3 PUFA has shown that certain foods which are high in ω-3 fatty acids—such as salmon oil and also ground flaxseed and walnuts—may help to lower blood pressure.

Cardiovascular Disease

• The longevity of Eskimos was later attributed to the high contents of fish-derived EPA and DHA in their diets.

• Studies conclusively showed that diets rich in fish and fish oils are associated with a reduced risk of coronary heart disease.

• Further, epidemiological studies suggested that individuals at risk of CHD benefited from the consumption of plant and marine derived ω-3 fatty acids. More evidences have shown that fish consumption favorably affected CHD mortality, especially nonsudden death from myocardial infarction.

• Recent studies have further established an inverse relationship between fish intake and CHD death. In addition, fish intake was associated with a reduced progression of coronary artery atherosclerosis in postmenopausal women with CHD.

• DHA was recently shown to reduce cholesterol particle size in children. The study suggested that taking DHA supplements could reduce the risk of children with high cholesterol from developing heart disease in later life.

• Women who reported consuming diets rich in oils containing ALA seemed to have a lower risk of heart disease and sudden cardiac death than women whose diets were low in the plant derived fatty acid.

Cancer• An inverse relationship has been noted between

blood levels of EPA and DHA and the risk of prostate cancer and adenocarcinoma (böbrekte görülen kanser).

• In addition, EPA and DHA have also been reported to

act positively against cancer effects such as cachexia (abnormal weight loss) or survival rate in end-stage cancer.

• The consumption of the fish oil capsule rich in ω-3 fatty acids restored cell production to normal levels in bowel cancer patients. It has been found that consumption of fish with high content of ω-3 fatty acids reduced the risk of renal cell carcinoma (RCC), a common form of kidney cancer.

Pregnancy and Infancy

• DHA is an important structural component of the membranes of the brain, nervous tissue, and eye.

• In mammals, DHA is present at very high levels in the phospholipids of the brain and neurological tissues and is, therefore, important in normal development of the central nervous system of the infant.

• The content of DHA in human brain increases almost four times during the first 3 months of pregnancy as well as postnatal life.

• A normal adult human brain contains more than 20 g DHA, which contributes to improved memory functions.

• DHA is also high in retina, and testes and sperm.

Distribution, therefore, suggests that DHA is important for vision and nervous functioning in humans.

• Deficiency in DHA has been associated with visual impairment and delayed cognitive development.

• Recent research has shown that DHA display a variety of beneficial effects in fetal development.

• During pregnancy, EFAs, especially, AA and DHA, play an important role in maternal health and neonatal development.

• An adequate intake of DHA and EPA is particularly important during pregnancy and lactation. During pregnancy, and 2 years of postnatal life, the infant gets DHA and also EPA through mother, since the infant is unable to synthesize these EFAs.

• Both LA and ALA can serve as precursors for DHA, their ratio should be around 7:1, as generally found in human milk. Studies on human volunteers have shown that conversion of ALA to EPA can occur, whereas conversion of ALA to DHA is restricted, indicating a need for supplementation of DHA in the diet.

• Several studies have clearly indicated significantly higher levels of intellectual capabilities (in terms of IQ) in children who have received DHA during their initial years.

• Children deficient in DHA may exhibit behavioral problems. It was found that consuming DHA and whole fish were independently related to lower hostility rates and attention-deficit hyperactivity disorder compared to those who had not consumed DHA or fish.

• While fish has a DHA:EPA ratio of 3.0:4.1, the contents of DHA is lower in fish oil, with a DHA:EPA ratio of 1:2. Supplementation of diet of these children with fish oil can result in improvement in their behavior.

• Increased incorporation of DHA into margarines and baby foods has been promoted to enhance brain memory development.

• Fish oil supplementation reduces overweight, and in patients with inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disorders, supplementation result in significant relief, due to improved joint tenderness and grip strength.

• Improvement in the flavor of fish oils (e.g., development of various deodorized fish oils), development of various innovative delivery systems for fish oils in foods (e.g., emulsions, sirups, and gels) and government level support of health claims for ω-3 fatty acids and fish oils in Europe and the United States, have also been pointed out.

• Factors underlying the popularity of ω-3 oils, particularly fish oils, their recommended daily indices, clinical trials showing their benefits on cardiovascular health, and prevention of arthritis, inflammation, and allergy, child development, mental alertness, cognitive function and mood have been pointed out in these campaigns.

Nutraceutical Potentials of ω-3 Fatty Acids

• Prevention from atherosclerosis• Protection against arrhythmias• Reduce blood pressure• Beneficial for diabetic patients• Fight against manic-depressive illness• Reduce symptoms in asthma patients• Protection against chronic obstructive

pulmonary diseases• Prevent various cancers• Provide bone health• Improve brain functions in children

MODE OF ACTION

• The beneficial effects could be due to favorable changes in vascular inflammation and endothelial dysfunction.

• The mode of action of EPA and DHA in health is considered to function through their ability to give rise to a class of pharmacologically important groups of compounds such as prostaglandins, prostacyclins, thromboxanes, and leukotrienes (collectively called as eicosanoids).

• Linoleic acid (w-6) is converted to arachidonic acid (AA) and Alpha-linolenic acid is converted to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).

• Eicosanoids include the prostaglandins (PG), thromboxane (TXA) and leukotrienes (LT).

• Prostaglandins and thromboxanes are generated via cyclooxygenase (COX) enzymes, whereas leukotrienes is produced from PUFA by lipoxygenase metabolism.

• AA is easily oxidized to linear or cyclic peroxides by the enzymes—lipoxygenase and cyclooxygenase, respectively—which participate in the form of hydroxy fatty acids to form leukotrienes.

• PUFAs of the ω-6 family produce eicosanoids (PGE2, TXA2, and LTB4) which aggregate platelet potently. Strongly stimulates platelet aggregation, strongly narrows blood vessels.

• EPA and DHA cannot be oxidized by cycloxygenase and hence their presence reduces the synthesis of leukotrienes.

• In general, availability of sufficient quantities of EPA and DHA helps to alleviate the problems caused by AA-generated eicosanoids.

• Prostaglandins synthesized from ω-3 acids also have additional therapeutic uses including control of blood pressure and relieving bronchial asthma.

• Changes in the composition of fatty acids are known to influence insulin sensitivity, and the ratio of ω-3 to ω-6 PUFA is associated with increased incidence of coronary heart disease (CHD).

• Higher w-6/w-3 fatty acid ratio of the diet may be associated with hip fractures,and possibly osteoporosis.

RECOMMENDED CONSUMPTION LEVELS OF OMEGA-3 PUFA

• The World Health Organization recommends consumption of 1–2 servings of fi sh, containing 200–500 mg of EPA and DHA, per week.

• The American Heart Association recommends healthy individuals to consume 2–3 oz serving of fatty fi sh per week and that the persons diagnosed with cardio vascular diseases consume 1 g each of the fatty acid per day.

• An amount of 0.3–0.5 g per day of EPA and DHA and 0.8–1.1 g per day of LA has been recommended to control CHDs.