Synthesis

Approximately half of our total cholesterol is provided through dietary intake and the other half is synthesised. Synthesis occurs in all cells but most occurs in the liver. The liver makes cholesterol via the following pathway:

1. In glycolysis, glucose is converted into pyruvate and subsequently acetyl CoA in the mitochondria.

2. Acetyl CoA molecules then combine to produce hydroxymethylglutaryl CoA (HMG-CoA).

3. An enzyme called HMG-CoA reductase then produces mevalonic acid and eventually, via the 'mevalonate pathway', this gets converted into cholesterol.

Transport

LDL cholesterol ('bad' cholesterol)

Cholesterol made in the liver gets packaged into low-density lipoproteins (LDLs). These transport cholesterol from the liver to peripheral tissues. LDLs increase the amount of cholesterol circulating in the blood.

HDL cholesterol ('good' cholesterol)

Excess cholesterol is removed from tissues by high-density lipoproteins (HDL) and transported back to the liver where it is eliminated, primarily in bile acid. HDLs therefore reduce the amount of cholesterol circulating in the blood.

Functions

Uses of cholesterol include:

• Bile salts - these are important in the emulsification and absorption of lipids in the small intestine.
• Precursor to steroid hormones including:
  • adrenocortical hormones (e.g. cortisol and aldosterone)
  • sex hormones (e.g. progesterone, oestrogens, testosterone)
• Precursor to cholecalciferol (vitamin D3).
• Cholesterol is abundant in nervous tissue and is essential for nerve transmission.

In arteries, damage to the tunica intima (a.k.a 'endothelial dysfunction') occurs with age and is exacerbated by risk factors such as hypertension, smoking etc.

This damage leads to the infiltration of monocytes from the blood into the tunica intima, where they become macrophages.

Low-density lipoproteins are produced in the liver and contain lots of cholesterol and triglycerides. Once released from the liver they circulate in the blood and deliver cholesterol to tissues.

The macrophages possess LDL 'scavenger' receptors to which LDLs circulating in the blood can bind.

These macrophages become saturated with cholesterol and triglycerides, and in this state they are known as foam cells.

Eventually these foam cells apoptose and the resulting collection of lipids forms the beginnings of an atheromatous plaque.

Proliferation of this plaque causes narrowing of the arterial lumen, which can compromise blood flow distally and cause ischaemia.

Narrowing of the lumen can become critical when complicated by the formation of a thrombus at the site of the narrowing.

The turbulent blood flow at the site of the narrowing increases the risk of a thrombus forming.

A thrombus may completely occlude the lumen, leading to acute ischaemia and infarction of distal tissue.

Statins are inhibitors of the enzyme HMG-CoA reductase which is the enzyme essential in hepatic cholesterol synthesis.

Statins inhibit a portion of the binding site of HMG-CoA reductase thus inhibiting the binding of HMG-CoA so its conversion into cholesterol is diminished.

In response to reduced cholesterol synthesis, the liver upregulates the expression of hepatic LDL receptors in order to scavenge cholesterol from lipoproteins that are circulating in the blood.

This reduces the level of LDL cholesterol in the blood and slows the process of atheromatous plaque formation.