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Updated 31 July 2014

Cholesterol and lipids

Cholesterol is one of a large and important class of biological molecules called lipids, scientific jargon for fats.

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Summary

  • Cholesterol is one of a large and important class of biological molecules called lipids, which is scientific jargon for fats.
  • Apart from cholesterol, there are several other biologically important lipids in the body: fatty acids and their derivatives, triglycerides and phospholipids.
  • Cholesterol and triglycerides are transported in the bloodstream as lipoproteins. LDL and HDL are varieties of lipoproteins.
  • Triglycerides are stored as fatty acids in adipose tissue (the layer of visible fat under the skin and around organs).
  • Recent evidence suggests that raised triglycerides pose a risk for coronary artery disease. This is particularly true when raised triglycerides are part of the so-called metabolic syndrome, which is characterised by abdominal obesity, high blood pressure, reduced HDL cholesterol and diabetes or prediabetes.
  • There are two main sources of cholesterol and triglycerides: external (the diet) and internal (manufactured/recycled by the body).

What is cholesterol?

This fatty substance is present in the bloodstream and in all your tissues and cells. It’s necessary for human life and is made by the liver, although virtually all cells are capable of making it. We also get cholesterol from the foods we eat.

People often think that cholesterol is the root cause of all cardiovascular disease. This is partly true, but such a view is overly simplistic, because cholesterol also has a beneficial role to play in our body. Furthermore, fatty acids – another class of lipids – also influence health and disease, whether they occur in the walls of cells or in particles with cholesterol.

Cholesterol is one of a large and important class of biological molecules, called lipids, scientific jargon for fats.

Importantly, lipids help make up cell walls and compartments within each cell, much as we have walls in our houses. In this way the body can set up special entry and exit ports (doors) to control the movement of substances into and within cells.

Cholesterol also plays an essential role in other bodily functions such as digestion, manufacturing of hormones and protection of nerve endings.

Other lipids

Apart from cholesterol, there are several other biologically important lipids (fats) in the body:

  • Fatty acid derivatives. These can be used as an energy source and are transported in the blood bound to a protein called albumin.
  • Triglycerides consist of three fatty acids linked to a chemical substance called glycerol. Similarly to cholesterol, they are carried in the blood as complexes called lipoproteins.
  • Phospholipids. These are complex molecules of which the phosphate-containing end is water-soluble and the lipid end is not. Phospholipids form part of the cell walls.

Phospholipids and triglycerides are transported in the blood in the form of lipoprotein complexes. These complexes are graded according to size and lipid content, and there are six of them that are clinically important:

Lipoprotein

Size (nanometres)

% protein

% cholesterol

%

triglyceride

Chylomicrons

75-1 000

2

3

85-90

Chylomicron remnants

30-80

Increased over above

Increased over above

Decreased from above

Very-low density lipoproteins (VLDL)

30-80

8

16

55-65

Intermediate- density lipoproteins (IDL)

25-40

10

25

15-30

Low-density lipoproteins (LDL)

20

20

46

8-12

High-density lipoproteins (HDL)

7.5-10

50

16

3-10

These lipoprotein "shuttles" have specific functions. Of relevance are:

  • Chylomicrons. These are large particles that carry dietary fats from the intestine through the blood circulatory system. In muscle and adipose tissue there is an enzyme that will enable the removal of a large portion of the triglycerides in chylomicrons.
  • LDL. This delivers cholesterol to tissues, where it is used by growing cells that need cholesterol or may be deposited when in excess. This has earned it the name of "bad cholesterol".
  • HDL. This is known as "good cholesterol", because its main function is to remove cholesterol from cells and tissues and carry it back to the liver for excretion.

How lipids move around

Body components, including lipids, are continually being formed, used, degraded and replaced. The process entails transport of biological compounds between tissues, using the blood plasma as the main highway.

For lipids, this poses a problem since they’re generally not water-soluble.

The transport problem has been solved by incorporating cholesterol and triglycerides into the lipoproteins. (See "Other lipids - phospholipids".) These lipoproteins are classified according to their density or protein content.

  • LDL and HDL are the two varieties of lipoproteins that are most strongly associated with vascular disease.

HDL (“good” cholesterol)

An increased level of HDL cholesterol is associated with a lower risk of coronary heart disease (CHD). Conversely, low levels of HDL cholesterol are associated with an increased risk. This is why HDL is thought of as the "good" type of cholesterol.

However, it seems that it is not actually the cholesterol itself that is “good”, but the lipoprotein which carries it – in other words, high-density lipoprotein (HDL).

It appears that the HDL molecule itself can clean out excess cholesterol – including that which came from the “bad” LDL cholesterol which has accumulated in the walls of arteries – and take it back to the liver for reprocessing. It also performs antioxidant activities, which help protect arteries against atherosclerosis, the cause of CHD.

LDL (“bad” cholesterol)

Low-density lipoprotein (LDL) is very rich in cholesterol and, in excess, is the main cause of coronary and other artery disease.

Most of the cholesterol in the blood is carried in LDL, so your total cholesterol level is a reflection of the amount of LDL cholesterol in your blood.

While other lipoproteins are removed within hours or minutes, LDL remains in the bloodstream for nearly three days. But eventually it’s cleared, mostly by the liver.

The basic principle is simple: LDL is linked to another protein, called apoB. This recognises a specific receptor (LDL-R) on liver cell walls to which it docks before being taken into the liver cells.

The mechanism is important since it can be genetically faulty (a common occurrence among South Africans), leading to the heavy accumulation of LDL in the bloodstream and giving rise to the inherited disorder of familial hypercholesterolaemia.

When levels of LDL are high, the lipoprotein penetrates the lining of the blood vessels, leading to the development of atherosclerosis.

This build-up of atherosclerotic plaque causes narrowing of the arteries, a situation that can lead to a heart attack and stroke, among other complications.

Raised total cholesterol – reflected by raised LDL levels – is a major risk factor for heart disease and stroke.

What are triglycerides?

A triglyceride is a molecule formed by three fatty acid chains linked to a molecule of glycerol.

Triglycerides are carried in the blood as lipoprotein complexes (see article on "Other lipids" for more detail). Once they reach their target organ, triglycerides are split by enzymes to release the three fatty acids inside the tissues, where they are used as a source of energy or stored again as triglycerides. The visible evidence of this is the fat under the skin, but some fat can also be stored in the abdomen and organs. All tissues are able to use fats for energy, heart muscle in particular.

The amount of stored fat varies widely: in non-obese men it can make up 15% of body weight and in non-obese women, 21%. Deposition of the fat on the hips, buttocks and thighs (peripheral obesity) is believed to be less unhealthy compared with fat deposited in the abdomen (central obesity). The latter forms could be a manifestation of the metabolic syndrome with attendant increases of triglycerides, resistance to insulin, elevation of blood pressure and decrease in HDL.

There is another type of body fat known as “brown fat”, which is present more in infancy than in adulthood. This is found on the back, at the nape of the neck and around the major blood vessels. The function of brown fat is thought to be mainly concerned with insulation, heat production and for adapting to cold climates.

Triglycerides and heart disease

Triglycerides are usually measured as part of a standard blood lipid profile. But what do the results mean?

So far, all we know is that triglycerides have been associated with coronary artery disease (CAD). But there is no definite proof that they alone are actually a specific risk factor.

However, most people with raised triglycerides have other major risk factors for CAD such as obesity, diabetes and high blood pressure. This has made it difficult to sort out whether triglycerides are an independent risk factor.

The relationship between triglycerides and high-density lipoprotein (HDL) cholesterol is complex. Whenever triglycerides are increased, HDL decreases. So it may be that part of the problem with raised levels of triglycerides is that they come with lower levels of HDL.

However, there is recent evidence to suggest that raised triglycerides alone pose a risk for CAD. This is particularly true when raised triglycerides are part of the so-called metabolic syndrome, which is characterised by abdominal obesity, high blood pressure, reduced HDL cholesterol, and diabetes or prediabetes.

Where do cholesterol and triglycerides come from?

There are two main sources of cholesterol and triglycerides:

  • External sources: the diet
  • Internal sources: manufactured/recycled by the body, especially the liver

Fats from our diet
In terms of diet, cholesterol and triglycerides come mainly from eating animal products, fish, dairy products and various oils, which are then absorbed through the gut.

Eggs and shrimp have very high cholesterol content. For practical purposes, plants have no cholesterol. Plant products have cholesterol-like substances called phytosterols, which may compete with cholesterol for absorption. When consumed in very large amounts, they can lower cholesterol absorption and consequently lower blood cholesterol by about 5-10%.

In the intestine, the ingested cholesterol and triglycerides are assembled into special spherical packages called chylomicrons, which travel through the bloodstream to the liver. Most of the cholesterol in the diet stays in the chylomicrons and is taken up by the liver where it mixes with newly made cholesterol, made by the liver itself. Chylomicrons only remain in the blood stream for a short while. The liver is where fats are broken down and made from metabolic products of sugars and proteins. Not only does the liver make cholesterol, it also makes fatty acids, triglycerides and phospholipids for export to the rest of the body. The fats made in the liver are assembled with protein compounds called apolipoproteins to make a new, fat-rich lipoprotein called VLDL – very-low-density lipoproteins.

Again, the VLDLs lose most of their triglycerides as fatty acids to muscle and adipose tissue where they are either used or stored. Some of these are taken up by the muscles as fuel while the rest is laid down as fatty (adipose) tissue in the body. The fats in adipose tissue act as energy reserves – all too often never utilised!

But instead of excess being taken up by the liver, they are converted in the plasma (the liquid, non-cellular part of the blood) into a new form of lipoprotein called LDL or low-density lipoprotein. LDL is very rich in cholesterol and is known as the “bad” form of cholesterol. It is these particles which, in excess, can lead to atherosclerosis and coronary artery disease.

LDL remains in the blood stream for around three days before it is removed by the liver.

The mechanism whereby LDL is removed by the liver is important. LDL is linked to a protein called apoB. This recognises a specific receptor on the liver cell – the apoB-receptor also known as the LDL receptor. This allows LDL to “dock” at the receptor and so be taken up by the liver.

This is important because if the receptor is faulty, as happens in the case of familial hypercholesterolaemia, the LDL is not taken up. When this happens, an excess of LDL circulates in the blood stream, penetrating the vascular wall and leading to coronary artery disease.

There is another lipoprotein in this story – HDL or high-density lipoprotein. Of all the lipoproteins, only high-density lipoprotein (HDL) does not deposit cholesterol in tissues. Instead, it removes cholesterol, taking it back to the liver for excretion.

HDL has the ability to pick up excess free cholesterol from peripheral (non-liver) cells, including those accumulating in the arterial wall which predispose to coronary artery disease.

HDL returns the excess cholesterol directly to the liver. HDL also carries important protective antioxidant enzymes and other molecules which lessen the risk of coronary artery disease. It seems also to limit the adverse response of the arterial lining to lipoproteins, cells and clotting processes.

All these properties make HDL an effective anti-coronary disease agent. The cholesterol measured in HDL is therefore called "good" cholesterol.

This means that not only are your levels of cholesterol and triglycerides important, but also the levels of LDL and HDL.

High levels of LDL and low levels of HDL mean that you have a greater risk of coronary artery disease, and the opposite means that you’re better protected.

The amount of cholesterol and triglycerides made in the liver is influenced by the total energy (kilojoule) intake in the diet and the quantity and kind of fat consumed. That is one reason why diet is so important.

  • Eating saturated fats raises levels of LDL (“bad”) cholesterol; hence too much of these in the diet is harmful.
  • Mono- and polyunsaturated fats are much better for you than saturated fats. In fact eating certain unsaturated fats can actually decrease your total cholesterol levels.
  • When unsaturated vegetable fats are hydrogenated, the process produces yet another type of fatty acid as a side product, called a trans fatty acid. Not only do trans fatty acids raise LDL levels, and so the total levels of cholesterol, but they also lower the levels of HDL – known to protect against coronary artery disease.

Production in the body
Cholesterol is made mainly from acetyl-CoA, which is a breakdown by-product formed during fat digestion and also an intermediate in carbohydrate and amino acid metabolism. An important and rate-controlling enzyme called HMG-CoA reductase, is involved in this process.

The liver is an important hub of cholesterol metabolism in the body. The liver balances the daily requirements for cholesterol by sensing the amount it contains. It receives dietary and biliary cholesterol by taking in the remnants of chylomicrons and can also take in LDL cholesterol from the blood by expressing LDL receptors when necessary, and can draw on a stored form of cholesterol in its cells called cholesterol ester.

The liver exports cholesterol directly into bile, but also indirectly: it secretes bile acids made from cholesterol into the bile. The other form of export is as VLDL. When there is too little cholesterol in the liver, there is a programmed response to turn on HMGCoA reductase as well as LDL receptors to make good the deficit. When there is an excess of cholesterol in the liver, as in the case of a very cholesterol-rich diet, these two processes are switched off. The switching off of LDL receptors means less LDL is removed from the blood and the blood LDL cholesterol level rises by small amounts over a few weeks to reach a new level when the liver achieves a new, balanced state.

However, in some people cholesterol levels remain high, regardless of intake due to genetic abnormalities in the LDL receptor. For them, limiting fats in their diet may have very little influence on cholesterol levels.

Apart from making new cholesterol, the body recycles that used for bile production. Between 92% and 97% of the cholesterol in bile is reabsorbed from the gut and recycled back to the liver, where it can be reused.

Measuring lipoproteins

The lipoproteins (LPs) have historically been the focus of research into the causes of atherosclerosis and coronary artery disease.

They are still important to our understanding, though we now know that many other biological systems are also involved.

Because so many different factors – some still unknown – are involved in the development of atherosclerosis and CAD, it is difficult to accurately predict an individual’s risk for a heart attack. However, if someone suffers from extreme derangements or disorders, the risk is vastly increased and easier to predict.

The good news is that, for the majority of the population, preventative lifestyle interventions reduce the risk of future illness can to a great extent.

Measuring risk
Armed with information about lipoproteins, techniques were developed to measure HDL (“good”) and LDL (“bad”) cholesterol separately. Further research also began to illuminate the biological and other factors which determine the levels of these two plasma lipoproteins.

Levels of LDL cholesterol are directly linked to those of another protein – apoB – which is almost entirely carried by LDL. So, instead of measuring LDL cholesterol, scientists realised that measurement of apoB would give similar (but not identical) information.

It was also discovered that the LDL packages themselves became smaller and denser in certain disorders, including hypertriglyceridaemia (the medical term for raised triglyceride levels).

There is evidence that these forms of LDL are more likely to cause atherosclerosis than the normal version. They are called small-dense LDL or sd-LDL.

Read more about atherosclerosis here.

Reviewed by Prof David Marais, head of the Lipid Clinic at the University of Cape Town and Groote Schuur Hospital, September 2010.

 
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