Lipid Oxidation
By Chris D. Meletis, ND
In 1956, a now famous article appeared titled, Aging: a theory based on free radical and radiation chemistry in the Journal of Gerontology written by Denham Harman. In his theory of aging he mentioned that the oxidation of LDL cholesterol was the earliest molecular event that triggers the process of atherosclerosis, or hardening of the arteries.1
At that time, the notion that LDL oxidation was the earliest molecular event leading to atherosclerosis was really just a “medical hypothesis” that needed many years (actually decades) of corroborating scientific data before it was indeed accepted as fact. It is now accepted as fact, although the exact implications of LDL cholesterol oxidation are still being explored in human studies and animal experiments.
Decades of experimentation with atherosclerosis using in vitro models and animal models eventually produced a skeleton outline of how hardening of the arteries begins at the molecular level and finally progresses to bulges in the artery wall, which cause partial or complete blockage of arteries in various critical areas. Eventually, eruptions or bursting of these atherosclerotic pockets can occur and this extremely serious phenomenon is referred medically as “erupting atherotomas” or “unstable erupting atherotomas.”
The subject of vascular disease covers an enormous area of scientific research that will not be reviewed here. In this article, I will present a basic outline of LDL oxidation leading to atherosclerosis in a more narrow sense and explain why antioxidants are a critical component of any regimen designed to support healthy cholesterol levels.
Cholesterol—Not the Bad Guy It’s Made Out to Be?
| The Ability of Select Antioxidants to Protect Lipids from Oxidation and Improve Heart Health | |
|---|---|
| N-acetyl cysteine | Increases levels of glutathione, which minimizes the lipid peroxidation of cellular membranes. |
| Bilberry | Protects against DNA damage and LDL oxidation. |
| Turmeric | Main component curcumin is a potent inhibitor of LDL oxidation. |
| Green Tea | Inhibits low-density lipoprotein-induced proliferation of rat vascular smooth muscle cells. |
| Grape Seed Extract | Protects LDL against oxidation generated by various compounds. |
| Lutein | Reduces atherosclerosis lesion size in rodent models of heart disease and thought to protect against the development of atherosclerosis based on epidemiological studies. |
| Rosemary | Protects against a lipid-damaging substance known as peroxynitrite; Often used to stop the oxidation of fats in beef and cooked oils. |
Cholesterol is an absolutely essential compound in the animal kingdom. Just as plants use cellulose as the building blocks of the structural components of their trunks, stems, leaves and roots, animals use cholesterol as their building blocks for cell membranes and other structural components. Cholesterol is the basic structural building block for hormones and various other molecules essential to animal and human life.
The notion that the cholesterol molecule itself is “bad” is an inaccurate notion. Furthermore, the popular notion that there is “good” cholesterol and “bad” cholesterol also is an oversimplified view of cholesterol transport. This notion of “good” versus “bad” cholesterol originated as a misunderstanding of the fact (the earliest example a 1980 article) that there is a forward and reverse cholesterol transport system from the liver, which produces most of the cholesterol in the body.5 LDL cholesterol particles (often referred to as “bad cholesterol”) carry cholesterol from the liver to the “loading docks,” or receptor sites on the endothelial cells and peripheral cells, where the cholesterol is then transported for cellular construction and repair purposes.
HDL cholesterol particles are the main reverse cholesterol transport system which carry excess cholesterol away from the peripheral and artery cells back to the liver. This is why HDL has been termed “good cholesterol.” The liver then takes in the excess returned cholesterol where it is excreted it into the bile as free cholesterol destined for the colon, or converted by the liver into cholesterol bile acids.6
There are three pathways that deliver cholesterol to arterial vessels and other peripheral cells—the lipid absorption pathway, the exogenous pathway (from the food intake of cholesterol) and the endogenous pathway where cholesterol is produced directly by the liver. All three pathways can result in an over accumulation of cholesterol in the peripheral cells and especially an over accumulation in the artery cells which leads to atherosclerosis.7
The Real Culprit—LDL Oxidation
LDL cholesterol delivery from the liver thorough the bloodstream is the weakest link in the delivery system. Free radicals in the bloodstream attack and oxidize the LDL cholesterol, and chemically modify it enough so that the receptor sites or the “loading docks” on the artery cell walls (the endothelial cells) no longer recognize it and reject it. However, the immune system scavenger cells, the macrophages, do have receptor sites that immediately recognize the oxidized LDL cholesterol at the endothelial artery lining. The source of these free radicals in the blood are mostly copper and iron, which act as catalysts taking ordinary hydrogen peroxide and converting it into the more powerful hydroxyl radical.8-10
This is the beginning of chaos at the molecular and cellular level. Macrophages “read” the oxidized cholesterol molecule (OXY-LDL) as a foreign invader, just like bacteria or other non-self proteins, because their receptor sites recognize it as a foreign protein. Through a process called phagocytosis, the macrophages engulf the oxidized cholesterol particle at the endothelial “loading dock” and eventually transport it back deeper into the arterial wall to the intimal cells or simply stay at the surface where the fusion product appears as fatty streaks on the artery wall. Eventually other immune responses take place and the whole particle becomes a foam cell.11-12
Small amounts of oxidized LDL that are engulfed by macrophages can be absorbed, broken down, and disposed of in the artery. But what if there is so much oxidized LDL/macrophage product that the disposal mechanism in the artery is saturated or oversaturated? This leads to foam cell buildup in the artery wall resulting in calcification and cellular debris accumulation where a bulge occurs in the artery wall. Sufficiently large artery bulges can block off or slow blood circulation in critical arteries such as coronary arteries, and carotid or vertebral arteries leading to the brain. Artery plaque formation and its clearance by resorption are a dynamic balance between plaque formation and plaque removal.12-13
A 2008 human trial measuring oxidized LDL (OXY-LDL, or Ox-LDL-C) as a key factor in initiating and accelerating atherosclerosis was conducted in patients with a diagnosis of coronary artery disease. The researchers used the ratio of OXY-LDL to albumin in patient blood as one of their primary measures. The diseased groups included patients with acute myocardial infarction, unstable angina pectoris, stable angina pectoris, and dyslpidemia (high cholesterol and high blood lipids). In all diseased groups, OXY-LDL was higher than levels seen in normal control patients. In groups complicated with hypertension or diabetes, the oxidized LDL ratio was seven times higher than the normal control group.14
The researchers concluded that with a 95.7 to 97.5 percent prediction rate, the blood level of OXY-LDL was a better biomarker than total cholesterol (TC), triglycerides (TG), HDL-C (HDL cholesterol) or LDL-C (low density lipoprotein cholesterol) in diagnosing people with coronary artery disease.14
Earlier research had shown in patient studies that oxidized LDL cholesterol can be formed in two ways, membrane damage (lipid peroxidation) of LDL fatty acids by metal ions, mainly iron in the blood, or by enzymatic damage independent of metal ions. The difference is academic, however, because the end result is the same—the release of aldehydes, which in both cases causes the LDL particle damage. The researchers concluded that there are two forms of oxidized LDL cholesterol. The one form of OXY-LDL is a marker for coronary atherosclerosis in general whereas the other form, MDA-modified LDL, is a good marker of artery plaque instability.15-16
A 1996 study revealed that patients at high risk for atherosclerosis, including those patients with renal failure, diabetes, hypercholesteremia and hypertension, had LDL with an increased susceptibility to oxidation in comparison to LDL from healthy patients. The authors mentioned that supplementation with nutritional antioxidants to humans, gene susceptible mice, or hypercholesteremic patients, have been shown in various studies to reduce the susceptibility of LDL to oxidation. “This effect could be associated with a reduction in the size of the atherosclerotic lesion and may thus contribute to attenuation of the atherosclerotic process,” the researchers stated.17
Antioxidants and Lipid Oxidation
The ultimate healthy goal of cholesterol transport through the blood is to make sure that the reducing antioxidant potency of the blood is sufficient to “quench” free radicals before they attack the fatty acid portions of the LDL particle. This means that the antioxidant levels in the blood are sufficiently high to avoid or minimize this problem. At the same time, the fat-soluble antioxidant content of the LDL particle should be sufficiently high to prevent the oxidation of the fatty acids, the phospholipids in the LDL particle. Therefore, fat-soluble and water-soluble antioxidants play key roles in preventing oxidized cholesterol in both the blood and in the LDL particles themselves.18-20
In studies, antioxidants have an excellent record of preventing atherosclerosis, especially in European and foreign human clinical trials of longer duration. However, in “intervention” studies where there is fully advanced atherosclerosis in patients and antioxidant therapy is used to intervene in a well established disease state, the results range from mixed to disappointing. Most of this data means that antioxidants prevent cholesterol oxidation and atherosclerosis in the first place, but do not reverse it once it is expressed as fully developed atherosclerosis.21-22
Vitamins A, C and E are some of the best-known antioxidants. These powerful antioxidants can work synergistically with other antioxidants to help reduce the extent of lipid oxidation occurring in the body. N-acetyl cysteine, bilberry, rosemary, turmeric, green tea, grape seed, and lutein are some of the most powerful and well-researched antioxidants. Consuming a formula that combines these synergistic antioxidants (such as Extension Antioxidant) is one of the most important steps to reduce the damaging effects of lipid oxidation.
N-acetyl cysteine helps increase levels of glutathione, the body’s “master antioxidant,” which minimizes the lipid peroxidation of cellular membranes known to occur with oxidative stress.23 Bilberry anthocyanosides are extremely powerful antioxidants that can protect against DNA damage and LDL oxidation.24 Research into another free-radical quencher—rosemary—has found it to be a potent antioxidant.25 Other botanicals used to fight free radicals include turmeric, which contains curcumin, a potent inhibitor of LDL oxidation.26 Green tea extract also has demonstrated antioxidant abilities both in vitro and in vivo.27 Grape seed and lutein are two other antioxidants that should be included in any regimen designed to quench free radicals and reduce lipid oxidation.28-29
Conclusion
The oxidation of LDL in the blood and on the artery wall plays a key role in the formation of atherosclerosis. LDL particles carry cholesterol from the liver to the peripheral cells, including the cells that line the arteries, and this is called the forward cholesterol transport system. Low antioxidant status of the blood and LDL particles, and other sources of oxidative stress, cause oxidative modifications to LDL by free radicals. Immune system cells, the macrophages, recognize the modified LDL cholesterol particles and engulf them. Eventually, further modifications convert this fused particle into a foam cell. Foam cell buildup in the arteries and the microcirculatory system cause bulges and streaks in the artery wall that we call atherosclerosis, or hardening of the arteries. Supplementation with a key group of antioxidants can help stop LDL oxidation from occurring and are therefore a critical component of any heart health regimen.
References
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