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Cholesterol

Cholesterol, a steroid alcohol, performs a number of important functions in the body:

a structural component of the cell membrane
precursor of bile salts
steroid hormones, and vitamin D

As such, the cell needs a constant supply of cholesterol. Cholesterol biosynthesis and regulation is primarily mediated by the liver. 0.2-0.5 g of cholesterol is ingested daily, and 0.8-1.0 g/day is synthesized.

Cholesterol is transported to cells on LDL particles, which contain Apo B-100 that bind to LDL receptors. Cholesterol is then used, or esterified and stored by activity of the enzyme ACAT.

The transport of cholesterol according to need is not precise, and over time there is a gradual deposition of cholesterol in the tissues, particularly the endothelium. This can lead to atherosclerosis.

Serum Cholesterol Levels

The ideal mean of cholesterol levels is 4.1 mM for adults and 2.9 mM. However, currently the existing mean is 54. mM for adults and 4.1 mM for youth. Check this.

Effects of Diet on Cholesterol

Dietary cholesterol has minimal effect on plasma cholesterol levels. N-6 PUFAs can reduce LDL levels, as does the Mediterranean diet, rich in monounsaturated fat. N-3 PUFAs appear not to have an effect.

Maximally decreasing dietary cholesterol and saturated fats can reduce plasma levels by up to 20%.

Regulating Plasma Cholesterol

There are a number of ways to decrease plasma colesterol levels:

dietary intervention - decrease cholesterol and SFAs, increase PUFAs, and add fibre
statins - HMC CoA- reductase inhibitors
ezetimibe - inhibits cholesterol uptake in the gut, reducing serum cholesterol by up to 20%
vytorin - combination ezetimibe and simvastatin

Structure of Cholesterol

Cholesterol is very hydrophobic due to its four fused rings and its 8-carbon branched hydrocarbon chain. Steroids that have an 8-10 Carbon chain and a hydroxyl group are called sterols.

Most plasma cholesterol is esterified, with a FA attached to the C-3 hydroxyl group. Cholesterol esters are not normally found in membranes, and because of their hydrophobicity they must be transported either in lipoproteins or in bile salts.

Clinical Point: Plant sterols are poorly absorbed and are actively transported back to the interstine. They appear to bring with them cholesterol molecules, leading to the use of plant sterol esters (ie margarine) to reduce cholesterol levels.

Cholesterol Synthesis

Cholesterol is made in almost every tissue, though the liver, intestine, adrenal cortex and reproductive organs make the largest amounts. All the carbon atoms are provided by acetate, and NADPH is the reducing agent. It is driven by hydrolysis of the thioester bond of acetyl CoA and ATP, and occurs in the cytoplasm. Enzymes are both in the cytoplasm and on the ER membrane.

Three acetyl CoA molecules combine to form HMG CoA, with 6 carbons. Next, HMG-Coa is reduced to mevalonic acid by HMG CoA reductase, the rate-limiting step of cholesterol synthesis. This reaction releases CoA, making the reaction irreversible. From there many steps occur to lead to cholesterol synthesis.

Regulation

HMG CoA Reductase is regulated at the transcriptional level, by phosphorylation (inactivates), or by degradation.

Cholesterol levels affect HMG CoA reductase mRNA and protein stability
transcription of its gene is increased by Sterol Regulatory Element-Binding Protein (SREBP is usually associated with the ER membrane.
Insulin upregulates HMG CoA reductase transcription, while glucagon has the opposite effect.
Statins are structural analogues of HMG CoA, and are reversible competitive inhibitors of HPG CoA Reductase.

Cholesterol Degradation

As the ring structure of cholesterol cannot be broken down, it is converted into bile acids and salts, or excreted in the bile. Some of the cholesterol is modified by fecal bacteria to form coprostanol and cholestanol.