Dyslipidemia – Part 1: Chylomicrons and Lipoproteins
Long-lasting excess cholesterol favors the development of atherosclerosis. With its high cholesterol content, LDL is also called the “bad cholesterol”. Another risk …
Dyslipidemia Part 1: Chylomicrons and lipoproteins
When is it important to take action against
high cholesterol levels?
What can and should be done?
These questions arise almost daily in family
Dyslipidemia, or disorders of lipid metabolism,
play a role in most cardiovascular diseases.
They’re the most important identified risk
factor for the development of atherosclerosis.
Notably, elevated cholesterol and triglyceride
levels can cause health problems.
Over the span of four Chalk Talk episodes,
we’ll be taking a closer look at the origin
of cholesterol in the body, how atherosclerosis
develops, how dyslipidemias are recognized
based on laboratory parameters, and how they’re
In this episode, we'll start with an overview
of fat metabolism, followed by looking at
the structure and physiological function of
From a chemical perspective, the lipids in
the body encompass different molecules, such
as free fatty acids, triglycerides, and cholesterol.
Though, they all have one thing in common:
They’re hydrophobic, that is, aren’t soluble
This is because their molecular structure
is largely nonpolar.
In contrast, water is polar, causing these
molecules to repel each other.
For this reason, lipid transport through the
aqueous environment of the body is a complex
In the blood, free fatty acids are mostly
bound to albumin, which accounts for the majority
of plasma proteins.
All other lipids are transported in lipoproteins.
These are transport complexes that comprise
apolipoproteins, among other components.
Because both terms sound quite similar, you’ll
need to pay attention here: Apolipoproteins
are actually proteins.
Lipoprotein is the umbrella term for the transport
complexes that comprise both lipids and proteins.
Before we delve into the lipoprotein structure,
let's take a look at how lipids act in water:
Due to the repulsion between the polar water
molecules and the nonpolar lipid molecules,
the contact area between both is at a minimum.
Accordingly, lipids form spherical structures
Lipids aren’t usually completely hydrophobic
but have a small polar portion, for example,
the head group of phospholipids.
Therefore, lipids arrange themselves in a
The polar heads form the hydrophilic outer
layer of the micelle and the nonpolar hydrocarbon
tails form the micelle core.
This is also what happens to hydrophobic food
Now, let’s delve into dietary fat absorption:
Fatty acid esters from food are enzymatically
cleaved in the stomach and duodenum by lipases
This process is called lipolysis.
Afterward, lipids form mixed micelles, together
with bile acids and fat-soluble vitamins.
In the small intestine, these micelles migrate
to the membrane of the epithelial cells, termed
enterocytes, where they disintegrate again.
The enterocyte membrane consists largely of
lipids, so most dietary fats can passively
diffuse through it.
Also, there are some carriers for free fatty
acids or cholesterol.
For example, the NPC1L1 transporter carries
cholesterol and other sterols from the intestinal
lumen into the enterocytes.
We’ll encounter this transporter again when
we look at lipid-lowering agents in part 4
of this Chalk Talk series.
In the cytosol of the enterocytes, lipid resynthesis
occurs, during which triglycerides and cholesterol
Together with phospholipids and apolipoproteins,
they form aggregates.
The polar components of phospholipids, cholesterol,
and apolipoproteins are directed outwards,
forming a shell around the completely nonpolar
lipids in the core.
These newly formed complexes are termed chylomicrons
and are lipoproteins.
Apolipoproteins comprise approximately 1%
of the chylomicron content.
As part of these transport complexes, apolipoproteins
have several important functions: In particular,
they stabilize lipoproteins through their
amphiphilic properties, that is, their hydrophilic
and lipophilic portions.
In addition, they activate various enzymes
responsible for modifying lipoproteins.
Also, they serve as ligands for binding to
This is particularly important because the
presence of specific apolipoproteins in a
transport complex determines which tissue
it’ll be absorbed by.
But, take note that lipoproteins in the bloodstream
can exchange apolipoproteins with one another.
This has important effects, as we’ll see
in just a moment.
Through exocytosis, the chylomicrons are transferred
from the enterocytes into the lymphatics,
and get into the bloodstream via the thoracic
In the blood, they start to degrade.
Initially, chylomicrons contain the apolipoproteins
A, B-48, C, and E. Although the apolipoprotein
names appear rather systematic, they have
a purely historical basis.
Unfortunately, they don’t provide much information
on their occurrence, structure, or function.
While the lipoproteins circulate in the blood,
they gradually release lipids that are eventually
absorbed by the body’s tissues and exchange
apolipoproteins with one another: The lipoprotein
composition is, therefore, changing constantly.
They’re distinguished and characterized
by an important physical attribute: their
The lipoprotein density, that is, their mass
per volume, depends primarily on their share
of proteins: The more apolipoprotein in the
particle, the higher its density.
In addition to chylomicrons, which have the
lowest protein content and, therefore, have
the lowest density of all particles, there
are very low-density lipoproteins, intermediate-density
lipoproteins, low-density lipoproteins, and
The HDL and the majority of VLDL particles
are produced in the liver and secreted into
Here, IDL and LDL particles are formed during
the breakdown of VLDL.
Now, let’s go back to the breakdown of chylomicrons:
The process begins with the uptake of the
apolipoproteins ApoE and ApoC-II from HDL
particles by the chylomicrons.
ApoC-II activates lipoprotein lipase, in short,
Lipoprotein lipase is an enzyme that cleaves
free fatty acids from triglycerides via hydrolysis.
These free fatty acids are used to supply
the surrounding tissues or are further transported
bound to albumin.
LPL is primarily located in the vascular endothelium
of cardiac or skeletal muscles and adipose
LPL breaks down almost all triglycerides in
chylomicrons, building free fatty acids.
The remaining particles are extremely rich
They transfer the apolipoprotein ApoA to HDL,
forming a chylomicron remnant.
This is taken up by the liver, using ApoE
receptors, and broken down again.
Chylomicron remnants are presented here as
fragments to illustrate their relationship
In fact, like chylomicrons, they’re spherical
particles with both a hydrophobic core and
hydrophilic outer layer.
The HDL particles mentioned originate from
They’re the smallest and most protein-rich
lipoproteins in the body.
Almost half of their mass consists of apolipoproteins.
They pass on a portion of their ApoE and ApoC-II
proteins to other lipoproteins.
In HDL, the remaining ApoC-II proteins activate
the enzyme LPL, leading to the cleavage of
triglycerides and the release of free fatty
acids, just as for chylomicrons.
In addition, another enzyme is activated,
namely lecithin cholesterol acyl transferase,
in short, LCAT.
This enzyme converts cholesterol molecules
located on the lipoprotein surface into cholesterol
These completely nonpolar and hydrophobic
cholesterol esters migrate into the lipoprotein
As a result, the concentration of cholesterol
in the outer layer decreases and the HDL particle
can absorb cholesterol from the surrounding
environment, such as cholesterol deposits
in blood vessels.
HDL then transports the cholesterol to the
liver, where it can be used for bile acid
Cholesterol can’t be cleaved or degraded
in the body and needs to be excreted via the
So, HDL reduces the risk of developing atherosclerosis
by absorbing cholesterol and transporting
it to the liver, therefore having an important
Now onto VLDL particles: Like HDL particles,
VLDL particles are also produced in the liver.
Their function is to transport the triglycerides
and cholesterol produced by the liver to tissues
via the bloodstream.
They contain the apolipoproteins ApoE and
VLDL particles also absorb ApoE and ApoC-II
from HDL particles in the blood.
Consequently, the enzymes LPL and LCAT are
IDL particles are formed, though only temporarily
and in low concentrations.
Due to the two enzymes’ progressive activity
as well as the transfer of ApoE and ApoC-II
to HDL, the IDL particles are finally converted
ApoB-100 remains completely preserved during
the conversion of VLDL to LDL via IDL.
LDL particles are mainly reabsorbed by the
liver via ApoB.
Almost half of the LDL particle's content
is cholesterol, making it the lipoprotein
with the highest cholesterol content of all
The cholesterol, which stems mainly from the
liver, is required physiologically, for example,
as a membrane component or for hormone synthesis.
It reaches the cells via lipoproteins.
However, long-lasting excess cholesterol favors
the development of atherosclerosis.
In this respect, with its high cholesterol
content, LDL is also called the "bad cholesterol".
Another risk factor is lipoprotein(a), in
short, Lp(a), which can be classified as an
LDL, according to its density, but contain
Lp(a) levels are primarily influenced by genetics
and can lead to a higher atherosclerosis risk
within a family.
In contrast, HDL, which helps remove deposits
from blood vessels, is known as the "good
We’ll learn more about this in the other
episodes of this course.
At this stage, we’d like to wrap things
up with a short quiz on lipoproteins.