[Rhonda]: Yeah.
You mentioned the generation of the small LDL particles, the small, dense LDL particles,
which, you know, through normal biology for these LDL particles are donating triglycerides
to cells and make them smaller and smaller.
I've done a lot of reading directed from Mark Shigenaga, he'd, you know, talked about some
very interesting mechanisms and directed me into the literature on the role of inflammation
and inflammation in the production of VLDL.
So, as inflammation goes up, VLDL production is increased.
And, at least in a couple of studies that I've read in literature, it seems to be implied
the reason for that is that inflammation increases the release of endotoxin, which is a lipopolysaccharide
from, you know, bacterial cell walls in the gut that gets released, and it binds to lipoproteins,
to all lipoproteins, and it's sort of like an adaptive response to make sure we don't
get sepsis or some sort of a toxic infection.
And so I've done, you know, some reading on a few studies that have shown that, you know,
endotoxin does bind lipoproteins.
And I'm wondering if you've looked into that at all or what role the endotoxin in binding
these lipoproteins seems to play in keeping the smaller dense lipoproteins in the circulation
longer or... [Ron]: Okay, all right.
That's a very interesting topic, and I'll just take a step back regarding the role of
inflammation in lipoprotein metabolism because that's something that is not widely appreciated.
We know that inflammation is an important feature of many chronic diseases including
heart disease.
The artery wall inflammation really is the major factor that converts a relatively benign
cholesterol deposit into a much more nasty and dangerous form that can cause blood clots
and rupture and plaque formation that blocks arteries.
Inflammation is a key feature of that.
So inflammation is really an important feature of many aspects of the processes we're talking
about.
But biologically, again, inflammation is not designed to cause heart attacks, it's designed
to help us with host defense.
So there's a very interesting argument that has been made that a part of the physiological
driver for VLDL secretion by the liver, the production of these triglyceride-rich particles,
is really not a nutritional role, although I think it does have an important nutritional
role.
But perhaps, even as importantly, it may serve an important role in host defense.
And so I'll come to the LPS question at the end of this little discussion because a really
interesting sort of corollary of that is, what role do lipoproteins have in the host
defense mechanism?
And what's intriguing and it's sort of like a biological fact that we don't want to make
too much out of, but I think it's very intriguing, is that the liver constantly makes the major
protein that forms the backbone of these VLDL and multiple VLDL particles called ApoB, apoprotein
B. It's a very big protein that is biologically ancient, it goes back to lobsters, and it's
a very important and complicated protein that gives the integrity to lipoprotein particle.
It helps keep all the fat contained and allows the fat to be soluble in the bloodstream.
That's the secret of lipoprotein particles is that there is a soluble protein that helps
to keep the fat from forming droplets like you see in chicken soup.
It helps to dissolve the fat in a way.
Anyway, the ApoB protein is constantly synthesized by the liver.
It's under a tonic stimulation.
It's not much regulated, it's just continually being produced and degraded, which seems like
a very inefficient process.
But one of the thoughts that has intrigued me and others is that the regulation of ApoB
and the particles that are formed on ApoB, the VLDL particles, is really to get these
particles out in a hurry when they're needed, because VLDL, it's a huge particle relatively
speaking to most other biological proteins.
Its molecular weight can be in tens of millions as opposed to, you know, 50,000.
So it takes a lot of work for the liver to make one of these VLDL particles.
And what the liver doesn't want to do is spend hours making a VLDL particle if it needs to
come out in a hurry.
But why would it need to come out in a hurry?
Well, one of the arguments is it may be because it contains components, which it does, that
help promote inflammation in the circulatory system.
Why would that be important?
Well, because when you have an organism, that'd be the parasite or another infectious agent
in the vascular system, malaria or parasites, trypanosomas, whatever you care to mention,
viruses, one way the body has of eliminating them is by setting up an inflammatory response
and an immune response related to that.
And VLDL carry pro-inflammatory proteins, they carry also pro-thrombotic proteins.
They actually are a very efficient delivery system, sort of like a fire truck that carries
a lot of things that we can use to fight a lot of infection.
Now, biologically, in our current era of antibiotics and antisepsis, that function has sort of
faded, but the rapidity of this response and the fact that it's regulated, not by production
of ApoB, but by degradation, suggests that this is designed to come out in a hurry.
And so degradation of ApoB is inhibited when there's lipid to be released.
So the ability of the liver to secrete ApoB and the lipids associated with VLDL is increased
when there is this additional lipid production that occurs, and that lipid production is
stimulated by cytokines.
So it comes back to the body having a foreign agent in it, that foreign agent, these days,
is more likely to be a plaque in the artery rather than a bacterial agent, but the response
is the same.
So as we got cytokines, we got inflammation, those come to the liver.
And one of the early studies that got me interested in this aspect of things is that we showed,
in collaboration with people at UCSF, that cytokines, such as TNF-alpha in particular,
but interferon, as well, stimulate the production of VLDL secretion by the liver.
And so, again, infectious agent, inflammatory signals, cytokines are produced, increasing
lipid synthesis, reducing the degradation of ApoB, allowing the rapid export of these
VLDL particles, all of that occurs in minutes.
And so that's the sort of thing you want the fire engine to get out of that fire station
in a hurry.
And so it's an intriguing argument that is consistent with the notion that inflammation
is a key regulator of lipoprotein metabolism in a positive way, historically, evolutionary-wise,
but in an adverse way in our current environment.