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.

Image Source: Wikipedia.

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

Table of Contents

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 takes place via the following step:

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

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

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.
Insulin hormone
Thyroid hormone
High fat, high carbohydrate diet

For example, statins decrease their synthesis.

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2% – https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/hmg-coa
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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
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