Biosynthesis of cholesterol and its regulation

Last Updated on May 13, 2020 by Sagar Aryal

• Cholesterol levels in the body originate from its biosynthesis and diet.
• Most of the cholesterol used by active adults is produced in the liver, which produces ~70% of daily cholesterol demand (~1 gram).
• The other 30% originates from dietary absorption.
• Biosynthesis of cholesterol commonly happens in the endoplasmic reticulum of hepatic cells.
• It starts with acetyl-CoA, which is basically taken from an oxidation response in the mitochondria.
• In spite of that, acetyl-CoA can be taken from the cytoplasmic oxidation of ethanol by acetyl-CoA synthetase.
• Acetyl-CoA and acetoacetyl-CoA are transformed into 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) by HMG-CoA synthase.

Image Source: Wikipedia.

The following products should be synthesized first before leading to the biosynthesis of cholesterol:

The Biosynthesis of HMG-CoA

The synthesis of HMG-CoA takes place in the following steps:

• 2 acetyl CoA molecules combine to form acetoacetyl- CoA, in the presence of enzyme thiolase.
• The 3rd molecule of acetyl CoA is added to form 3-Hydroxy-3-Methylglutaryl CoA (HMG-CoA). This takes place in the presence of enzyme HMG-CoA synthase. It is a cytosolic enzyme.

Mevalonate Synthesis

Mevalonate synthesis takes place via the following step:

• HMG-CoA is reduced to mevalonate using the HMG-CoA Reductase enzyme.
• This is the regulatory step in cholesterol synthesis.

The synthesis of cholesterol

Finally, the biosynthesis of cholesterol is here with the simplest discussion ever:

• 5-pyrophosphomevalonate is formed from Mevalonate. This occurs in the presence of a kinase.
• 5-pyrophosphomevalonate is decarboxylated to isopentyl pyrophosphate (IPP). This occurs in the presence of decarboxylase and ATP.
• IPP is converted to 3-3-dimethylallyl pyrophosphate (DPP). This takes place in the presence of isomerase.
• IPP and DPP condense to form geranyl pyrophosphate (GPP).
• The second molecule of IPP combines with GPP forming Farnesyl pyrophosphate (FPP).
• Two molecules of FPP combine to form 6 isoprenoid unit squalene. This reaction occurs in the presence of squalene synthase.
• Squalene is converted to lanosterol, catalyzed by squalene monooxygenase. This enzyme uses molecular oxygen and NADPH. The hydroxylation of squalene triggers the cyclization of cholesterol.
• In a multistep process, lanosterol is converted to cholesterol and as a result, the following things occur:
  • shortening of carbon chains from 30 to 27 carbons
  • removal of two methyl groups at carbon number 4
  • migration of double bonds from C-8 to C-5
  • reduction of a double bond between C-24 and C-25

Upregulation and downregulation of cholesterol

Above all, the most important part in the biosynthesis of cholesterol is its up-regulation as well as downregulation which are focused as follows:

Upregulation by stimulating the synthesis of HMG-CoA Reductase

1. Sterol regulatory element-binding protein (SREBP) is cleaved by low cholesterol levels from SREBP-cleaving activating protein (SCAP) complex, hence the target genes for HMG-CoA Reductase are activated.
2. Insulin hormone
3. Thyroid hormone
4. High fat, high carbohydrate diet

Downregulation by inhibiting HMG-CoA Reductase:

1. High cholesterol level, SREBP-SCAP complex formed, HMG-CoA is not synthesized.
2. Glucagon
3. Glucocorticoids
4. Drugs that inhibit HMG-CoA Reductase

For example, statins decrease their synthesis.

References and Sources

• 4% – https://www.sigmaaldrich.com/content/dam/sigma-aldrich/docs/Sigma/General_Information/2/biofiles_issue12.pdf
• 2% – https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/hmg-coa
• 2% – https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4519939/
• 2% – https://quizlet.com/124658623/chapter-16-flash-cards/
• 2% – https://en.wikipedia.org/wiki/Hydroxymethylglutaryl-CoA_synthase
• 2% – http://site.iugaza.edu.ps/mzaharna/files/2015/02/Ch18.1-Cholesterol-and-Steroid-Metabolism-.pptx
• 1% – https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/cholesterol-synthesis
• 1% – https://wikimili.com/en/Cholesterol
• 1% – https://quizlet.com/104053806/cholesterol-flash-cards/
• 1% – http://watcut.uwaterloo.ca/webnotes/Metabolism/Cholesterol.html