Dyslipidemia Part 2 - Cholesterol and cholesterol biosynthesis
The general recommendation regarding cholesterol levels is: The lower, the better.
A permanent increase in cholesterol levels is one of the most important risk factors
for atherosclerosis and, therefore, cardiovascular diseases.
Where does the cholesterol in the body come from and how can levels be decreased?
A healthy diet plays an important role, but it won’t often be enough to lower cholesterol
levels on its own.
So, why is this the case?
Well, around one-third of cholesterol comes from food, particularly animal products, such
as meat, butter, and egg yolk.
The remaining two-thirds are produced by the body that is controlled by a complex regulatory
mechanism.
Before we take a detailed look at the development of atherosclerosis, let’s delve into the
physiological functions and biosynthesis of cholesterol in this Chalk Talk episode.
Let’s begin with the structure of the cholesterol molecule.
Cholesterol is a lipid that belongs to the steroid family due to its characteristic ring
system.
This ring system, also known as the sterane skeleton, is composed of three C6 rings and
one C5 ring.
Most of the cholesterol molecule is made up of carbon and hydrogen atoms and is, therefore,
nonpolar, that is, hydrophobic.
Only its single hydroxyl group is polar.
This makes the molecule an alcohol, which is correspondingly termed cholesterol.
According to the chemical nomenclature, the suffix -ol is used for alcohols.
The alcohol group is of biochemical importance, as due to its polarity and, therefore, hydrophilicity,
cholesterol is an amphiphilic molecule.
Also, under the cleavage of water, fatty acids can bind to the OH group, and form completely
nonpolar and hydrophobic cholesterol esters.
However, the amphiphilic nature of the non-esterified cholesterol molecule is crucial for its primary
function in the body: It’s an elementary component of almost all biological membranes.
Here, the polar hydroxyl group is positioned outward, while the nonpolar sterol skeleton
extends into the lipid bilayer.
The incorporation of cholesterol makes the membranes more stable and fluid: At high temperatures,
its rigid structure restricts lipid mobility; at low temperatures, it prevents the lipids
from packing closely together, thereby increasing membrane rigidity.
Moreover, cholesterol is the starting substance for bile acid synthesis, as you may have guessed
from its name: It originates from the Greek words chole meaning bile and stear meaning
fat.
So, bile acids are, therefore, also steroids.
In addition, cholesterol serves as the precursor for the synthesis of steroid hormones, such
as glucocorticoids and several sex hormones.
For this, it’s converted initially into pregnenolone in the adrenal gland.
All other corticosteroids are then formed from pregnenolone.
You can find an overview of these hormones and their functions in the corresponding AMBOSS
article.
Also, the synthesis of vitamin D produced in the body occurs through cholesterol.
So, it isn’t surprising that an important substance like cholesterol can be produced
by the body when required.
Principally, cholesterol can be produced in all tissues.
Though, the most important sites of synthesis are the liver and intestines, as well as the
brain, as cholesterol can’t pass through the blood-brain barrier.
The first steps in cholesterol synthesis occur in the cytosol, whereas the final steps take
place in the smooth endoplasmic reticulum.
The different reactions can be divided into the mevalonate pathway, also termed the HMG-CoA
reductase pathway and further cholesterol synthesis.
Acetyl-CoA is used as a starting material and converted first to acetoacetyl-CoA, then
to HMG-CoA.
By the way, these first two reaction steps are part of ketogenesis.
In the third step, HMG-CoA is then reduced to mevalonate by the enzyme HMG-CoA reductase.
This enzyme is the most important of all those involved: It catalyzes the rate-limiting step
and is, therefore, the key enzyme in cholesterol biosynthesis.
This reaction requires two reducing equivalents of NADPH and H+.
For the further conversion of mevalonate, the molecule needs to be activated.
Like in many other biochemical processes, this occurs through ATP-mediated phosphorylation.
Altogether, three ATP molecules transfer one phosphate group each to mevalonate.
The first two phosphate groups are bound to the oxygen on the C5 atom.
Mevalonate-5-phosphate is initially formed, and then mevalonate-5-pyrophosphate.
The third phosphate group reacts with the OH group on the C3 atom, producing an unstable
intermediate, 3-Phospho-5-pyrophosphomevalonate.
From this intermediate, the enzyme mevalonate pyrophosphate decarboxylase cleaves a carboxyl
group as CO2, and the final incorporated phosphate group as a phosphate ion.
As a result, isopentenyl pyrophosphate, in short IPP, is formed.
In addition to the activating pyrophosphate group, IPP possesses a double bond.
By rearranging this double bond, an isomer is formed, dimethylallyl pyrophosphate, in
short, DMAPP.
Both molecules can be reversibly interconverted into one another via isopentenyl pyrophosphate
isomerase.
So, the mevalonate pathway comprises the reactions starting from acetyl-CoA to IPP and DMAPP.
This mixture can form isoprene, which has two double bonds, can polymerize easily and
forms a multitude of important natural substances, known as terpenes.
The most well-known terpenes are found in essential oils in plants.
One of these is geraniol, which, for example, gives geraniums their fragrance.
During cholesterol synthesis, geraniol is produced in its pyrophosphate form, geranyl
pyrophosphate, in short GPP.
It’s formed by combining one unit each of IPP and DMAPP, cleaving off one of the pyrophosphate
groups.
The catalyzing enzyme is GPP synthase.
In the next reaction step, another IPP unit binds to the molecule, producing farnesyl
pyrophosphate, in short, FPP.
The enzyme responsible is FPP synthase.
Farnesol is also an essential oil that is mainly found in roses.
For the next reaction steps, farnesyl pyrophosphate is transported into the smooth ER.
Here, two farnesyl residues are coupled by squalene synthase, resulting in the formation
of squalene.
Squalene synthase requires one NADPH and H+ to cleave both pyrophosphate groups during
the reaction.
So, squalene is nonpolar, consisting entirely of carbon and hydrogen atoms.
It’s composed of six isoprene units and, thereby, 30 carbon atoms.
Squalene is too large and nonpolar to have a fragrance.
To possess a smell, a substance needs to be small enough to disperse in air and have a
polar functional group.
Squalene can then be easily oxidized by oxygen at its double bonds.
Through squalene monooxygenase, squalene epoxide forms.
Now, we’d like to show this molecule because it’ll provide you with a first glimpse of
the sterane skeleton that’s about to be formed.
An epoxide is a three atom ring, which forms when an oxygen atom incorporates into a double
bond.
The epoxy group here is activated by protonation, initiating a cascade reaction.
In this reaction, the double bonds in the molecule fold over, consequently leading to
the formation of a sterane skeleton.
The resulting product is lanosterol, with the reaction catalyzed by lanosterol synthase.
Afterward, a further eight reactions follow in which only the functional groups on sterane
are converted to form cholesterol.
Now, if you consider the total synthesis of cholesterol, you’ll notice that a considerable
amount of energy-rich compounds are required: Altogether, there are 18 acetyl-CoA, 18 ATP,
and 14 NADPH and H+ per molecule of cholesterol.
Such an energy-consuming metabolic process needs to be precisely regulated by the body.
This physiological regulation is controlled by transcription factors as well as by allosteric
inhibition of the key enzyme.
The activity of HMG-CoA reductase is inhibited by the product of metabolism, cholesterol,
and by AMP, which is present in increased quantities when the cell lacks energy.
HMG-CoA reductase is also an important target for cholesterol-lowering medicinal drugs,
which we’ll look at in part 4 in our episode on lipid-lowering agents.
But before we do, we’ll delve into the development of atherosclerosis in the next episode.
If you’d like, try testing your knowledge on cholesterol synthesis with a quiz on the
next slide.