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Scientific Basis for Olive Oil, Monounsaturated Fatty Acids, Anti-oxidants, and LDL Oxidation
Author : Eurosciences Communication in cooperation with the Institute for Arteriosclerosis Research, University of Münster, Germany
Low-density lipoprotein (LDL) is the major cholesterol-carrying particle in blood plasma. There is wide agreement that increased levels of LDL are causally related to atherosclerosis and the development of coronary heart disease (CHD). There is increasing evidence that LDL in its ‘native' state is not harmful; however, when it is altered by oxidation, it becomes a real threat within the arterial wall. The susceptibility of LDL to oxidation is determined by both internal (endogenous) and external (exogenous) factors. Among the latter, nutritional factors are extremely important, particularly the types of fatty acids and anti-oxidant vitamins in the diet. This Fact Sheet reviews the mechanisms of LDL oxidation and the role of nutritional factors in its prevention.
LDL oxidation (in atherogenesis)
Half of the cholesterol in the blood is carried in LDL, which is a spherical fat-protein particle consisting of an outer monolayer containing the protein apolipoprotein B (apo B), which surrounds a core containing triglycerides and/or cholesterol esters (non-polar fats). One LDL particle contains about 3600 fatty acids, half of which are polyunsaturated fatty acids (PUFAs). LDL also contains anti-oxidants, the most important being (alpha) a-tocopherol (vitamin E).
LDL oxidation (peroxidation) is a chain reaction initiated by free radicals, a mainly reactive oxygen species. PUFAs are very susceptible to lipid peroxidation and breakdown to a variety of by-products which bond to LDL apo B. LDL can be oxidised in vitro by exposing them to smooth muscle and endothelial cells, macrophages (derived from large cells called monocytes), or metal ions (Copper or Iron). LDL oxidation in vivo is poorly understood, and it may be reduced by the presence of anti-oxidants, e.g., ascorbic acid (vitamin C) in plasma. It is therefore likely that LDL oxidation occurs in the artery wall rather than in the blood stream. Vitamin E-enriched LDL is significantly more difficult to oxidise. LDL oxidation is likely to occur when the anti-oxidant ‘defences' are down, especially when a-tocopherol is depleted.
LDL oxidation and atherosclerosis
The essential step in the development of atherosclerosis begins as LDLs filter into the arterial wall and become entrapped in the intima, where they may undergo oxidative modification. Macrophages (cells formed when monocytes permeate the artery wall from the bloodstream) avidly take up this modified LDL, which contributes to their transformation to foam cells. The accumulation of foam cells in the intima results in the formation of fatty streaks. These do not produce significant obstruction of the artery, but they are gradually converted into fibrous plaques by a mechanism similar to scar formation. These, in turn, are gradually transformed into atherosclerotic lesions which underlie most clinical events.
Olive oil and LDL oxidation
There are several potential ways by which dietary fatty acids may influence the oxidation of LDL. The amount and composition of dietary fats affect the amount of LDL in the artery wall. Replacement of dietary saturated fats with monounsaturated fats (MUFAs) or PUFAs lowers LDL levels, thereby decreasing the amount of LDL entering the artery wall and so reducing the amount (and composition) available for oxidation. Because of its high MUFA content, olive oil appears to offer some protection against LDL oxidation (see Section entitled "Effects of dietary fatty acids on LDL oxidation"). Olive oil may afford additional protection by supplying LDL with potent anti-oxidants, such as vitamin E and phenolic compounds, which will be described later.
Effects of dietary fatty acids on LDL oxidation.
Various studies have investigated the role of MUFA and PUFA in reducing susceptibility to LDL oxidation. Studies in the rabbit model show that oleate-rich (oleic acid is the predominant fatty acid of olive oil) LDL is remarkably resistant to oxidation. Dietary studies in humans support this finding and show that the linoleic acid (the major dietary PUFA which is predominant in vegetable oils) content of LDL is strongly related to the rate and extent of oxidation, with LDL oxidation rate being increased during the studies involving the PUFA diet, compared to the MUFA diet. Further studies have tried to address whether such effects are due to PUFA-induced enhancement or a MUFA-induced inhibition of LDL oxidation. Dietary supplementation of olive oil suggests that the linoleic acid content of LDL is reduced and that there is less cellular uptake by macrophages and reduced susceptibility of LDL to oxidation.
Pro-oxidant activities of dietary fatty acids
Certain dietary fatty acids can change the monocyte membrane composition, thereby enhancing free radical production, and producing pro-oxidant effects. A study compared the effects of dietary supplementation with MUFA and n-3 (found in fish oils) or n-6 (linoleic acid) PUFA on superoxide anion (a free radical) generation in monocytes and macrophages. Only n-3 fatty acids reduced free radical production, while the monocytes from the MUFA or n-6 PUFA showed no change or increased levels. The mechanisms for this are unknown, and these results have not been reproduced. More studies on the role of different fatty acids on cellular pro-oxidant activity are needed; however, MUFA-enriched cells are less susceptible to oxidative damage (in direct comparison to n-6 PUFA), probably as a result of cell membrane fatty acid composition.
Antioxidant constituents of olive oil
Oxidative stress may play an important role in the development of several chronic diseases such as CHD and cancer. The possibility that dietary anti-oxidants, such as those found in olive oil, may protect against LDL oxidation has led to epidemiological and intervention studies.
Vitamin E (a-tocopherol)
Epidemiological studies have shown that high doses of vitamin E over at least two years, can significantly reduce CHD risk (31-65%). Short-term studies using lower doses have not shown this, however. This is also the finding from the majority of randomised intervention trials with vitamin E; however, these trials were not designed to assess cardiovascular end-points, their treatment duration was too short, and they employed sub-optimal doses of the vitamin. Several ongoing large-scale trials may help to resolve this issue. To date, only the Cambridge Heart Antioxidant Study (CHAOS) has been completed. This double-blind, placebo-controlled study of 2000 patients with established CHD, reported that high-dose vitamin E supplementation significantly reduced the incidence of non-fatal heart attacks but had no impact on cardiovascular or all-cause mortality.
Intervention trials have been criticised on the grounds that a few years of treatment may be inadequate to demonstrate benefit of anti-oxidants, and that anti-oxidant supplementation may be needed over 20 or more years, before any clinical benefit ensues.
Several studies have demonstrated that vitamin E supplementation results in increased levels of a-tocopherol both in plasma and in LDL particles. Furthermore, LDL showed a higher resistance against in vitro oxidation compared to the pre-study baseline. The degree of resistance was closely related to the vitamin dose received. Oxidative resistance is also higher in non-supplementing individuals who have higher plasma levels of a-tocopherol, than those with naturally occurring lower levels.
In addition to vitamin E, olive oil contains a variety of constituents which are responsible for its unique taste. Among these (comprising 2-3% of unrefined oil) are phenolic compounds, which are also found in vegetable foods and are biologically extremely important. These include simple phenols and phenolic acids e.g. flavonoids. These play a vital role to scavenge and detoxify free radicals, and can provide increased resistance to LDL oxidation and inhibit lipid peroxidation. Phenolic compounds have additional anti-inflammatory and anti-haemorrhagic effects.
Health benefits derived from potent phenolic flavonoids, also present in fruits and beverages such as tea and wine, have been observed in the Seven Countries and the Zutphen Elderly studies, where the average intake of flavonoids was inversely and independently correlated with CHD mortality. However, more studies are needed to confirm the cardioprotective properties of flavonoids.
Summary and conclusions
There is extensive evidence that oxidative modifications of LDL play a crucial role in atherogenesis. Oxidation of LDL begins with peroxidation of PUFA in the LDL particle. Thus the LDL fatty acid composition undoubtedly contributes to LDL oxidation. The fatty acid composition (and therefore, susceptibility to oxidation) of LDL is influenced by dietary fatty acids. Diets rich in MUFAs render LDL more resistant to LDL oxidative modification compared with diets rich in PUFAs, e.g., linoleic acid. In addition, the fatty acid composition of cell membranes is diet-dependent, and MUFA-rich diets also lead to a higher MUFA content of cell membranes and therefore higher cellular resistance to oxidative damage.
Dietary anti-oxidants such as vitamins E and C, flavonoids, etc., provide additional protection against oxidative stress. Recent studies indicate that not only a-tocopherol, but also phenolic compounds in olive oil may inhibit LDL oxidation and reduce the risk of atherosclerosis. Further research is needed to fully elucidate the mechanisms of action of phenolic compounds in vivo.
Much of the focus of attention on the Mediterranean diet has been on the cardiovascular benefits associated with a reduced saturated fat intake, and its high MUFA levels, as well as complex carbohydrate and fibre. Current evidence suggests that additional components, in abundance in the Mediterranean diet, namely anti-oxidants derived from fruit and vegetables, but additionally, from olive oil, may contribute to protection from CHD, cancer and other chronic disorders.
High intakes of MUFAs from olive oil consumption in the Mediterranean diet, may combine the advantages of lowering cholesterol and decreasing LDL and cell susceptibility to oxidation.
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