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 medicine.
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 treated.
In this episode, we'll start with an overview of fat metabolism, followed by looking at
the structure and physiological function of blood lipids.
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
in water.
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
process.
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 termed micelles.
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 particular way.
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 components.
Now, let’s delve into dietary fat absorption: Fatty acid esters from food are enzymatically
cleaved in the stomach and duodenum by lipases and esterases.
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
esters form.
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 lipoprotein receptors.
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 duct.
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
density.
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 high-density lipoproteins.
The HDL and the majority of VLDL particles are produced in the liver and secreted into
the blood.
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, LPL.
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
tissue.
LPL breaks down almost all triglycerides in chylomicrons, building free fatty acids.
The remaining particles are extremely rich in cholesterol.
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
to chylomicrons.
In fact, like chylomicrons, they’re spherical particles with both a hydrophobic core and
hydrophilic outer layer.
The HDL particles mentioned originate from the liver.
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
esters.
These completely nonpolar and hydrophobic cholesterol esters migrate into the lipoprotein
core.
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
formation.
Cholesterol can’t be cleaved or degraded in the body and needs to be excreted via the
bile acids.
So, HDL reduces the risk of developing atherosclerosis by absorbing cholesterol and transporting
it to the liver, therefore having an important protective effect.
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 ApoB-100.
VLDL particles also absorb ApoE and ApoC-II from HDL particles in the blood.
Consequently, the enzymes LPL and LCAT are activated.
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 to LDL.
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 lipoproteins.
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 apolipoprotein a.
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
cholesterol".
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.