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Cholesterol and Statins


Cholesterol is an important lipid present as a structural component of all cell membranes and is also a precursor of steroid hormones and bile acids. In excess, it accumulates in deposits of atherosclerotic plaque on the walls of blood vessels, leading to restrictions and interruptions of the circulation that can result in angina, heart attacks, stroke, claudication, other vascular complications, and some of these are fatal. Populations with low cholesterol levels have less coronary heart disease (CHD) than those with higher cholesterol levels, but individuals moving from populations with a low average cholesterol to one with a high average cholesterol show increases in their cholesterol levels and risk of CHD.

Cholesterol is transported in the blood in particles made up of protein and lipid, called lipoproteins, of which there are four main classes:

Low density lipoproteins (LDL)

LDL-cholesterol accounts for 60-70% of total serum cholesterol. It is the most atherogenic lipoprotein, and is the major target of cholesterol lowering treatments. It is sometimes referred to as "bad" cholesterol.

High density lipoproteins (HDL)

HDL-cholesterol accounts for 20-30% of total serum cholesterol. Levels are inversely correlated with CHD risk, which may be due to a protective effect, or to the fact that low HDL-cholesterol levels are associated with other atherogenic factors. It is sometimes referred to as "good" cholesterol.

Very low density lipoproteins (VLDL)

These are rich in triglycerides, but account for 10-15% of total serum cholesterol. Partially degraded VLDL (VLDL remnant) is enriched with cholesterol, and seem to be atherogenic.


These are rich in triglycerides, and partially degraded chylomicron remnants are probably atherogenic

Total cholesterol is usually subdivided into either HDL-cholesterol and LDL-cholesterol, or HDL-cholesterol and non-HDL-cholesterol.

Atherosclerotic plaques

At low cholesterol levels lipoproteins travel throughout the circulatory system without problem, but at higher levels, LDL particles begin to stick to the vessel wall, creating a lesion. The particles become susceptible to oxidation or other modifications, and the permeability of the endothelium increases, allowing further accumulation of LDL. Macrophages then adhere to the lesion and accumulate cholesterol, forming a fatty streak. A plaque is formed when the fatty streak is overlaid with a layer of scar tissue.

HDL particles may intervene directly in this process by removing cholesterol from the engorged macrophages (reverse cholesterol transport), and possibly through antioxidant and anti-inflammatory effects, limiting the damage.

Vessels have some capacity to "remodel", maintaining the size of the lumen, but large plaques can limit flow at times of increased demand. For instance, plaque occluded blood vessels in the heart restrict flow of blood on exercise, leading to the cardiac pain we call exercise-induced angina. Plaques become unstable and rupture, particularly in the presence of high levels of LDL, and it is this that causes most acute coronary events.

Lesions, fatty streaks and plaques form throughout the vasculature. The process may take many years, and the individual will be asymptomatic. Lowering LDL in early life (lifestyle changes may be sufficient) aims to prevent or slow down plaque formation. Once symptoms (eg angina) are experienced, the disease is already established. Treatment needs to be more aggressive (lifestyle changes and pharmacotherapy), aiming to stabilise plaques and prevent acute coronary events.

How do statins work?

The body can synthesise up to 1 gram of cholesterol per day, while only 20-40 mg per day is absorbed from food. Serum cholesterol levels correlate with saturated fat intake much more closely than with dietary cholesterol intake. Most cholesterol is synthesised in the liver, and statins work primarily by inhibiting an enzyme involved in its synthesis.

3-hydroxy-3-methyglutaryl coenzme A (HGM CoA) is converted into mevalonate, a precursor of cholesterol, in the presence of the enzyme HGM CoA reductase. This rate-limiting step in cholesterol biosynthesis is blocked by statins (HGM CoA reductase inhibitors).

Reduced cholesterol synthesis results in lower levels of hepatic cholesterol, and up-regulation of LDL receptor activity in the liver. There is greater uptake of serum LDL and other non-HDL particles by the LDL receptors, leading to lower levels of total and non-HDL cholesterol in the circulation.

Statins also raise HDL levels by about 5%, but the mechanism is unclear, and how much this contributes to the overall reduction in CHD risk is uncertain. Evidence is also accumulating for effects of statins that are independent of cholesterol lowering. In particular they restore and improve endothelial function.