Olive Oil_Fact Sheet 08C

Olive Oil and its role of LDL Oxidation in atherogenesis

The role of LDL oxidation in atherogenesis
According to the so-called oxidation hypothesis, one of the initial steps in
atherogenesis is the oxidative modification of LDL and the uptake of the modified
lipoprotein particles by macrophages, which in turn become lipid laden cholesterolrich cells, so-called foam cells1. An accumulation of foam cells in the arterial wall is
the first visible sign of atherosclerosis and is termed fatty streak 2. Although the
relevance of the oxidation hypothesis has not been fully established, much supportive
data has been generated in the last decade. LDL has been shown to be oxidised in
vivo3, autoantibodies to oxidised LDL have been found in humans 4, and LDL
extracted from human atherosclerotic lesions demonstrates many of the physical,
chemical and biological properties of in vitro oxidised LDL5. Furthermore, the
measurement of the susceptibility of LDL to oxidation has been shown to correlate
independently with the extent of atherosclerosis6.
It is well known that oxidation of LDL can be initiated in vitro by incubating isolated
LDL particles with cells (macrophages, lymphocytes, smooth muscle cells, or
endothelial cells), metal ions (copper or iron), enzymes, oxygen radicals, or UVlight7-9. However, less is known about the mechanisms by which LDL becomes
oxidised in vivo. There is evidence that LDL is protected against oxidation in plasma
by water-soluble antioxidative substances, such as ascorbic acid, ureic acid, or
bilirubin. Thus, it is likely that the majority of oxidative modification of LDL occurs
in the artery wall, where LDL is largely isolated from the plasmatic antioxidants.
Recent evidence suggests, that metal ions (copper or iron) and the enzymes
myeloperoxidase and lipoxygenase play major parts in the modification of LDL10.
If LDL is exposed to pro-oxidative conditions, it becomes depleted of its
antioxidants. The oxidation of the LDL polyunsaturated fatty acids (PUFA) to lipid
hydroperoxides starts when most of the antioxidant defence has been lost. The
decomposition of PUFA leads to a lot of further modifications in the LDL-particle,
e.g. oxidation of cholesterol or modifications of apo B 7; 11. These modifications have
two major effects. First, molecules with high biological potential are generated.
These include substances that are chemotactic for monocytes and lymphocytes,
cytotoxic or that directly alter gene expression of arterial wall cells (Table 1).
Second, the modifications of apo B lead to changes in the receptor specificity of the
LDL particle and increase its affinity to the so-called scavenger receptors. Native
LDL mainly binds to the LDL-receptor. Because the number of LDL-receptors on
cells is regulated by intracellular free cholesterol content, cells can only take up
limited amounts of LDL by means of these receptors. On the other hand, scavenger
receptors, a family of structurally heterogenous proteins located on the surface of
endothelial cells, monocytes and macrophages12, are not feedback-regulated by
1

intracellular cholesterol content. By means of scavenger receptors the cells can take
up modified LDL in an unregulated manner and accumulate huge amounts of
cholesterol and cholesterol esters. Because these features of modified LDL promote
atherosclerosis it should be a lingering concern to minimise the susceptibility of LDL
to oxidation.