Biosynthesis of cholesterol and its regulation

  • 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.

The Biosynthesis of HMG-CoA

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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

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