Lipids- Cholesterol

Now I get back on to talking about cholesterol! It's a molecule that I've mentioned a few times before due to its importance, so let's get down to studying it in more detail!

Structure of Cholesterol

I've already described most of the structure of cholesterol in my first post about lipids, and I can't be bothered going over the entire thing again here. I'll just note that it's only very weakly amphiphilic, as its only polar group is its -OH group on carbon 3. Oh, and the -OH group is equatorial in the chair conformation, w00t w00t. (Now you can go out and become the king or queen of trivia parties.)

Functions of Cholesterol

Cholesterol is important because of its many different functions. As alluded to in my second post about membranes, cholesterol is an important component of membranes as it "slots in" between phospholipids, making them longer, straighter and more closely packed together. This, in turn, increases membrane thickness and decreases membrane permeability. Cholesterol is also required for the synthesis of bile salts (which are required for fat digestion) as well as steroid hormones, which are important for various other functions.

Another interesting point of note is that the last precursor in the synthesis of cholesterol, 7-dehydrocholesterol, can also be used to synthesise vitamin D.

Bile Salts

Back when I spoke about lipid metabolism, I mentioned that bile salts help to emulsify fats and that I would go into more detail later. Well, "later" has become "now."

Bile salts are made in the liver from cholesterol. They have two parts: a cholate part (that's the bit that's directly synthesised from cholesterol) and a head group, such as taurine (in the case of taurocholic acid) or glycine (in the case of glycocholic acid). As these head groups are negatively charged at biological pH, bile salts are amphiphilic and can form micelles in solution. As well as helping to emulsify fats, bile salts can also aid in the excretion of poorly soluble compounds from the body, including cholesterol.

Cholesterol Synthesis

Joy... another chemical pathway to learn. At least we don't have to learn every single step in first year.

The first few steps of cholesterol synthesis involve the production of 3-hydroxy-3-methylglutaryl CoA, otherwise known as HMG CoA. HMG CoA can then be reduced via HMG CoA reductase to form 6-carbon mevalonate. This is the slowest step in the entire process, and thus it is the step most highly targeted by statin drugs that are prescribed to reduce blood cholesterol levels.

Mevalonate can then have two phosphate groups added to form mevalonate pyrophosphate. It can then be converted to form 5-carbon isopentenyl pyrophosphate. Isopentenyl pyrophosphate molecules can continuously add together to form 10-carbon geranyl pyrophosphate, then 15-carbon farnesyl pyrophosphate, and then finally 30-carbon squalene. Squalene is eventually converted to 27-carbon cholesterol.

Cholesterol Delivery to Cells

As mentioned in my post about triglyceride and fatty acid metabolism, lipids are often carried to cells in lipoproteins. Low-density lipoproteins (LDL) carry cholesterol to the cells, while high-density lipoproteins (HDL) bring cholesterol from the cells to the liver. Cholesterol is often carried in its cholesteryl ester form.

Uptake into the cells is driven by receptor-mediated endocytosis: that is, there are LDL-receptors on the outside of cells, and endocytosis is induced when LDL binds to them.

If there is more LDL than cells that need cholesterol, LDL can accumulate in the monocytes of the arteries. These monocytes will eventually die, leaving behind deposits of cholesteryl ester. These deposits are also known as atherosclerotic plaques, which can eventually lead to arterial narrowing and heart disease. This is why managing blood cholesterol is so important. Blood cholesterol can be managed through diet or through the use of certain drugs that either inhibit the action of HMG CoA reductase or prevent the reabsorption of bile salts (thereby increasing the amount of cholesterol that has to be consumed to restore the amount of bile salts). If you're worried about your cholesterol, though, talk to your doctor, not me.

Steroid Hormones

Cholesterol can be converted to pregnenolone via the action of an enzyme called Cytochrome P450. Pregnenolone can then be converted to other steroid hormones, such as cortisol, progesterone, testosterone and oestradiol, but details of these processes aren't in this first-year course so I'm not going to go into them (besides I don't know them anyway).

Synthesis of Vitamin D

As I mentioned earlier on in this post, 7-dehydrocholesterol, the final precursor of cholesterol, is used in the synthesis of vitamin D. When exposed to UV light, 7-dehydrocholesterol's structure can change to that of vitamin D3. To become activated, it has to be hydroxylated at C1 and C25 to form 1,25-dihydroxyvitamin D3, which is the active form of vitamin D. Vitamin D has several functions, including the regulation of Ca2+ uptake by the gut and inhibiting the proliferation of cells.