[Rhonda]: I usually think of LDL cholesterol, the larger, buoyant LDL cholesterol, as something
that's important for cells that need to repair damage, to repair the cell membrane, those
growing cells.
What causes the formation of these smaller, dense LDL particles?
[Ron]: Well, it is true.
We think about, you know, LDL as if it's bad, and cholesterol is bad.
It, you know, gets in the arteries.
But, of course, cholesterol itself is vital for every aspect of human biology, ranging
from cell membrane function, as you point out, proliferation of cells, growth and the
health of cells, are dependent on cholesterol.
Most tissues, in fact, really, virtually all tissues in the human body, under normal conditions,
are capable of manufacturing their own cholesterol.
That's really an important system, which relates to some of the other work we are doing when
we start to manipulate cholesterol metabolism with the use of drugs like statins and also
with diet.
But the fundamental role of cholesterol is one that promotes health.
Where we get into trouble is when it exceeds the ability of cells to take cholesterol out
of the blood quickly through the liver, and it builds up in the blood and gets into the
arteries, is where it becomes pathologic.
But where do these particles come from?
That is something that we're very interested in.
The origin of LDL particles is in the liver.
The liver packages lipids, cholesterol, as well as other lipids, triglycerides and phospholipids
into this spherical particle that also has proteins, and so it's a combination of lipids
and proteins, and that's how we get the term lipoproteins, lipids and proteins complex
together, for the most part, in the form of triglyceride-rich, not cholesterol-rich, particles.
There are ways of unloading triglyceride from the liver.
Triglyceride is a fat that's used also for many positive features of our life, such as
energy storage and metabolism.
And in packaging these triglyceride-rich particles, there's some cholesterol that comes along
with it, and there are specific proteins that characterize these particles, as well.
There's different forms of these triglyceride-rich particles that are called very-low-density
lipoproteins or VLDL.
And the different forms of VLDL give rise to different forms of LDL.
That's one of the reasons that we have these different forms of LDL is that they can originate
from different precursors produced by the liver.
So cholesterol, in a sense, is a passenger on a train that is mainly delivering triglyceride,
but that triglyceride gets used by the body.
It gets hydrolyzed, it gets broken down into fatty acids, which are used for energy and
for energy storage, and muscle and in adipose tissue, very important metabolic players.
And as that process occurs through a lipase that breaks down the triglyceride, the particles
get smaller and smaller.
They lose their triglyceride, but they tend to retain most of their cholesterol.
So there's a shrinkage, where there's a big buoyant triglyceride-rich VLDL particle to
a smaller, more dense LDL particle, and to the extent that that process can continue
to occur during the excursion of lipoproteins in the blood, they can get smaller and smaller.
And that's how you finally wind up with the smaller LDL particles that we've been talking
about.
So the role of cholesterol in these particles is not a crucial feature of their biological
role.
As I say, most tissues can...in fact, all tissues, as I said, can make cholesterol.
Tissues don't make triglycerides.
So the triglyceride transport is a main feature, and most people don't understand that.
And the LDL is kind of a byproduct of that metabolic conversion that we've just described.
And LDL are used by tissues, you know, a gland uses LDL cholesterol, the gonads use cholesterol
to synthesize, for example, hormones that are made by those tissues.
So LDL does have a role, and the cholesterol does have a biological role, but it's not
a crucial one.
And so that's one of the issues that we have as humans versus almost all other species,
we don't have a very efficient way of removing LDL from the blood.
So our levels are much higher than almost any other species, certainly most other mammals.
You have to feed an enormous amount of cholesterol in order to get anything like what we have
in our blood.
So it's this inefficient removal of LDL that leads to the potential for accumulation in
the blood and ultimately arteries, and it's really the fundamental reason that we, as
a species, are so susceptible to heart disease risk.