[Ron]: So where does LPS come in?
Well, these particles that are secreted, as I mentioned, will get smaller and smaller.
LPS produced through this infectious inflammatory signal does bind to these particles.
Their binding to VLDL and LDL is partly, I think, a protective mechanism to sequester
the LPS.
Again, this is somewhat hypothetical, but it's a plausible scenario, which requires
a lot more study to really get the molecular basis of this interaction understood.
But from a physiological standpoint, there is evidence that if you increase the clearance
of LDL from the blood through drugs like statins, which lower LDL by...
We can talk about this perhaps later, the role of LDL receptors in the liver is crucial
to regulating LDL in the blood, because LDL receptors, particularly in the liver, remove
LDL from the blood.
So it has been shown that if you increase LDL receptor activity and increase LDL uptake
from the blood, you can lower LPS levels.
So it's consistent with the idea that one of the protective mechanisms, in addition
to the secretion of these inflammatory molecules that can kill bugs, one of the other ways
that we are protected from the effects of sepsis by lipoprotein metabolism is probably
through the transport and ultimate removal of LPS by these particles.
HDL does that to some extent, as well.
As I mentioned, all lipoproteins are capable of binding LPS.
Where that comes from, what's the molecular basis for this, and what regulates that binding,
I think is an important question that we really need to have more work on.
[Rhonda]: I agree.
And also, whether or not, you know, the binding of these LPS to these lipoproteins stimulates
more of an inflammatory response.
[Ron]: Right, right.
And the other thing you mentioned, which I'll come back to, is that the smaller particles,
and, in fact, this is an important feature of these smaller particles that I didn't mention
earlier, that may actually be one of the more important reasons that they're associated
with heart disease risk, is they have less affinity for the LDL receptor.
That's been shown by us and by others, that as the particle shrinks to a smaller size,
the region of the particle that is recognized by the LDL receptor, which is actually a region
of the ApoB protein, that is the receptor recognition site for the whole particle, gets
to be obscured, it gets to be less exposed.
And that's one reason we think that these particles are less capable of being removed
from the blood by the liver.
There are other features of these particles that contribute to that, including changes
in other proteins that may inhibit receptor-mediated uptake of the smaller LDL.
So they hang around longer, and that may be one of the more important reasons that they're
bad, is not because, partly because of the binding to the artery wall, the oxidation,
all of that is important, but the fact that they're circulating so much longer gives them
much more opportunity to interact with the arteries and undergo transformations that
can be pro-inflammatory themselves.
And the ability of LPS to stick to the VLDL means that some of that LPS remains on the
particle as it gets smaller and smaller.
And if that particle isn't being cleared rapidly, the LPS will be circulating even longer, and
it may be part of the whole process by which this contributes to atherosclerosis.
[Rhonda]: And I think that makes perfect sense, and that's a really elegant way of explaining
it.