Cholesterol

 

Bile, membranes, hormones, vitamins and untimely death (and more)

Molecule of the Month - March 2014

 

 

Ben Benjamin – Torbay Hospital, Devon, UK

 

What is cholesterol?

 

Cholesterol is a large and complicated molecule. It is vital – animal life cannot exist without it. It can be made by all cells in our body – built up from simple small molecules. But it also has a dark side – our bodies don’t seem to be able to get rid of cholesterol and it can build up in arteries to cause blockage – and death from heart attacks and strokes.

 

Why is it called cholesterol?

 

Cholesterol was first identified in bile. That is why it is called cholesterol – chole- means ‘of bile’ – sterol refers to the four-membered ring which is very common in nature – see http://www.cyberlipid.org/sterols/ster0003.htm

 

How is it made?

 

The starting point for cholesterol synthesis is acetic acid, or vinegar. This is 2-carbon molecule which can be made from fat, sugars such as glucose and from proteins. Further bits are added on in a stepwise fashion until it is 30 carbon atoms – squalene.

Squalene is a useful substance – it is used to make earwax.

 

 

 

Text Box: With a bit of nifty bending squalene starts to look like cholesterol

 

It takes over 30 biochemical steps to make cholesterol from acetic acid. HMG Co-A reductase is the rate-limiting enzymatic step for cholesterol synthesis and is the target of statin drugs such as simvastatin. These drugs are very widely used to reduce cholesterol synthesis. Atorvastatin, invented by chemists at Parke-Davis has achieved sales of over $100 billion dollars since it was introduced in 1996.

 

What about cholesterol in our diet?

 

Most cholesterol in our diet comes from animal products. Egg yolks have a lot, so does some seafood, such as shrimps. Milk has quite a lot, because milk contains fat globules which are surrounded by a phospholipid bilayer (see below). The evidence suggests that cholesterol in our diet is not as important as the cholesterol we make ourselves in causing problems. It used to be thought that plants do not contain cholesterol, but that is not entirely true – see: http://bip.cnrs-mrs.fr/bip10/choles.htm

 

Why go to all that bother?

 

The main use for cholesterol, and other sterols, is to make better cell membranes. Cell membranes are principally comprised of phospholipids. These are long molecules with a hydrophilic phosphate group attached to long hydrophobic hydrocarbon chains. Phospholipids naturally form themselves into hollow balls – known as micelles – see:
http://hyperphysics.phy-astr.gsu.edu/hbase/organic/phoslip.html.

 

All the cells in our body have a membrane around them made of a double layer of phospholipids. The trouble with phospholipid membranes is that they are too leaky. It is important to keep small molecules such as water and ions (like sodium and potassium) on one side or the other. Cholesterol is incorporated into the membrane to make it stiffer, less floppy and less leaky. This is particularly important in nerve cells which need to keep ions in the right place. As a result, brains contain a lot of cholesterol.

 

Cholesterol, bile and gallstones

 

Cholesterol is the starting point for the manufacture of bile acids and bile salts. These compounds are excreted in the bile as detergents, along with cholesterol and phospholipids. The function is to emulsify fats we eat, and make it easier to digest them. Bile is a complicated mix of cholesterol, bile acids and phospholipids, which sometimes goes wrong and cholesterol (which is quite insoluble in water) precipitates out of solution and makes stones.

 

Text Box: Bile acid/bile salt – cholesterol with two OH groups and a COOH group to make it more effective as a detergent

Text Box: In the small intestine the bile salts help emulsify fats and work with the enzyme lipase to break it down

 

Hormones

 

Cholesterol is the starting point for a number of really important hormones. The most important is cortisol, made by the adrenal glands (small glands which live on top of each kidney). It is called cortisol because it is made by the adrenal cortex (the outside bit) and regulates a whole range of metabolic processes. We cannot survive without cortisol.

 

cortisol

 

Sex hormones made from cholesterol include testosterone (which increases muscle strength and makes men look like men) oestrogen and progestogens which are female hormones necessary for normal menstrual cycles and pregnancy.

 

testosterone

 

Vitamin D

 

This vitamin is made from cholesterol in the skin, using the energy of sunlight to convert 7-dehydrocholesterol to cholecalciferol. Vitamin D is vital for healthy bones and a good functioning immune system. The disease rickets is caused by a lack of vitamin D in the diet together with not enough sunshine

 

Why is cholesterol bad?

 

If we eat too much saturated fat, this gets incorporated into our cell membranes. Saturated fat has straight, rather than bent lipid chains. This means that the membranes need less cholesterol to keep them stiff and prevent leakage. But our liver still makes lots of cholesterol in the form of LDL (low density lipoprotein). Our cells are not interested in taking it up and it becomes oxidised and taken up into the lining of blood vessels. This cholesterol forms a lump inside the artery known as an atheromatous plaque. After many years this plaque can rupture and cause a blood clot to form in the artery. If it is a coronary artery this will result in a heart attack. If it is a brain artery the clot will cause a stroke.

Text Box: Blood vessel containing atheromatous plaque

 

Further reading:

 

There’s lots more about cholesterol on my blog: wardroundstuff.com

 

 

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