90 6.35 Cholesterol Synthesis

Acetyl-CoA is also used to synthesize cholesterol. As shown below, there are a large number of reactions and enzymes involved in cholesterol synthesis.

Simplifying this, acetyl-CoA is converted to acetoacetyl-CoA (4 carbons) before forming 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). HMG-CoA is converted to mevalonate by the enzyme HMG-CoA reductase. This enzyme is important because it is the rate-limiting enzyme in cholesterol synthesis.

A rate-limiting enzyme is like a bottleneck in a highway, as shown below, that determines the flow of traffic past it.

Rate-limiting enzymes limit the rate at which a metabolic pathway proceeds. The pharmaceutical industry has taken advantage of this knowledge to lower people’s LDL levels with drugs known as statins. These drugs inhibit HMG-CoA reductase and thus decrease cholesterol synthesis. Less cholesterol leads to lower LDL levels, and hopefully a lower risk of cardiovascular disease.

The brand name of the statins approved for use in the US are⁴:

• Lipitor
• Lescol
• Mevacor
• Pravachol
• Crestor
• Zocor
• Livalo

The first link below talks about the new cholesterol guidelines, in which statins are prescribed at set therapeutic doses based on assessed cardiovascular risk rather than treating LDL and HDL to target levels. The second link is to the online calculator that can be used to estimate individual’s risk based on results from the Framingham Heart Study. The third link talks about a drug that was effective at lowering LDL, increasing HDL, but did not improve cardiovascular disease outcomes. This finding is consistent with the new cholesterol guidelines deemphasizing HDL and LDL target levels. The fourth link below describes some new cholesterol lowering drugs, which have shown some promising preliminary results.

The body synthesizes approximately 1 gram of cholesterol a day, whereas it is recommended that we consume less than 0.3 gram a day. A number of tissues synthesize cholesterol, with the liver accounting for ~20% of synthesis. The intestine is believed to be the most active among the other tissues that are responsible for the other 80% of cholesterol synthesis⁵.

References & Links

1. https://en.wikipedia.org/wiki/Statin#/media/File:HMG-CoA_reductase_pathway.png

2. http://en.wikipedia.org/wiki/File:Squalene.svg

3. http://en.wikipedia.org/wiki/File:Bottleneck.svg

4. http://www.medicinenet.com/statins/page3.htm

5. Gropper SS, Smith JL, Groff JL. (2008) Advanced nutrition and human metabolism. Belmont, CA: Wadsworth Publishing.

Links

3 Things to Know About the New Cholesterol Guidelines – http://well.blogs.nytimes.com/2013/11/12/3-things-to-know-about-the-new-cholesterol-guidelines/