Content Reviewers:Rishi Desai, MD, MPH
As it turns out, we make most of our cholesterol ourselves, but some comes through the diet.
Cholesterol synthesis, also called the mevalonate pathway, happens in the smooth endoplasmic reticulum of a cell.
It begins with 2 acetyl-CoA molecules getting joined together by the enzyme acetyl-CoA acyl-transferase.
The result is a 4-carbon molecule called acetoacetyl-CoA and then a free CoA molecule.
Next, the enzyme HMG-CoA synthase combines acetoacetyl-CoA and acetyl-CoA to form a 6-carbon molecule called 3-hydroxy-3-methylglutaryl CoA, or HMG-CoA - so 3 acetyls and the an free CoA molecule.
Then, an enzyme called HMG-CoA reductase reduces HMG-CoA into mevalonate, by removing a CoA-SH and a water molecule.
This step with HMG-CoA reductase is the rate-limiting step of cholesterol synthesis.
In other words, the rate of this reaction determines the overall rate of cholesterol synthesis - it’s like the slowest step in the assembly line for a factory.
Now, cholesterol synthesis is regulated by a trio of proteins - sterol regulatory element binding protein - or SREBP and two others that just go by SCAP and INSIG-1.
Let’s say that cholesterol levels drop because there’s less cholesterol coming into the cell from the diet.
In that situation, INSIG-1 falls off of SREBP, like pulling a pin from a grenade, and the SREBP-SCAP complex then gets cleaved by cellular enzymes.
The cleaved SREBP floats into the nucleus, and binds to the sterol regulatory element on the DNA.
When it binds, it increases expression of the genes encoding HMG-CoA reductase.
That leads to more HMG-CoA reductase, which speeds up endogenous cholesterol synthesis.
Once HMG-CoA reductase has made the 6 carbon mevalonate, it then undergoes a number of additional enzyme-mediated transformations before it becomes cholesterol.
First, the enzyme mevalonate-5-kinase uses adenosine triphosphate, or ATP, to phosphorylate mevalonate, creating mevalonate-5-phosphate.
Then, phosphomevalonate kinase uses another ATP to phosphorylate mevalonate-5-phosphate, making mevalonate pyrophosphate.
Finally, mevalonate pyrophosphate decarboxylase removes a carboxyl group from it, forming a 5 carbon molecule called isopentenyl pyrophosphate.
Next, geranyl transferase condenses 3 of these isopentenyl pyrophosphate molecules to form a 15 carbon molecule called farnesyl pyrophosphate.
Then, the enzyme squalene synthase condenses two molecules of farnesyl pyrophosphate to form a 30 carbon molecule called squalene.
Squalene is pretty cool, it’s the last linear precursor to cholesterol and it’s also what helps sharks float. Yep - you heard that right.
Okay next, an enzyme called oxidosqualene cyclase converts linear squalene molecule into a structure with rings - a process called cyclization.
The result is our first sterol intermediate, called lanosterol.
From there, there are 19 steps of successive modifications, like molding a lump of clay into a beautiful bowl; that convert lanosterol first into 27 carbon 7-dehydrocholesterol, and then finally into 27 carbon cholesterol!