Now let's

get into biochemically, what the heck is apoprotein little a and why does it cause such havoc? Why is it such a dangerous protein? There's a lot of great proteins that do wonderful things.

Why is this protein have the potential to do horrible things? Yeah.

And the funny thing is, in most people, that would be true.

But there is the oddball patient who has very high LP little a who nothing happens to them.

They just live their normal lives.

And this is a real enigma because say I got two people today with very high LP little a. likely they're both at terrible risk for something, but I don't know that with certainty.

you.

I just wanted to give an intro from where I'm coming from and why I wanted to have you on here because doing genetics, I'm seeing this and I'm Another, I'll bring up more things as I think of it and as you go that are on my mind as well around this, but let's delve in and talk about what is phytosterolemia? What are plant sterols and how do they build up? How do these genetics play this major part?

All right.

This is going to get a little bit ugly because we have to start with a little basic biochemistry, and I'll spell it out.

There are many organic molecules, carbon, hydrogen, oxygen, whatever.

That's what an organic molecule is.

And there are several subgroups of what type of organic molecules there are.

And the group that we're going to talk about today is called sterols, S-T-E-R-O-L-S.

Can I ask a quick question off of that, piggyback off of that? So you'll hear people say that their physician will tell them, okay, but your HDL is great here, even though the LDL is also high, the HDL is high, so you're fine.

Does the brain need to rely on any of the periphery's cholesterol? And if so, can ApoB and ApoA lipoproteins get in there and deliver cholesterol as needed?

Well, the quick answer to that, and then I'm going to elaborate, is what's going on with cholesterol in the brain, how much cholesterol is, uh, stored in the brain has zero to do with what is floating in the plasma.

So there are certain lipoproteins that we'll talk about that can work their way into the brain.

But the ApoB-containing particles, the vast-- which carry the vast majority of cholesterol, cannot.

They're much too big to pass through that w- what we call a blood-brain barrier, which is actually a barrier that separates the brain from the periphery, as we've taught.But I like to start to give you an idea about why has the brain got so much more cholesterol? Why is it storing it so much more than, say, the liver or any other organ in the body? Well, as, uh, we are in utero with mom, in the second and the third trimester, the fetal brain is already starting to de novo synthesize its cholesterol, 'cause it, evolution knows it's gonna need cholesterol because the brain probably has more cell membranes than any other tissue put together, especially our neurons.

Those cell membranes are kind of critical on do our neurons work or not.

Whether the neurons work or not is do we work or not normally or so.

So the one thing we haven't put together is what's the relationship between amyloid tau and cholesterol? There must be a link, right?

So without getting into how he's going to do that, can you explain why lowering triglycerides and lowering saturated fat intake, those two things could bring this guy from a hundred down to sixty?

Sure.

The saturated fat is, uh, a little easier to explain.

We have plenty of studies that show excess saturated fat, those nuclear transcription factors that are regulating lipid balance in the liver, and the liver is the master controller of lipid homeostasis in the body.

It works hand in hand with the intestine, but the liver is sort of the brains of the operation.

In many, many people, exposure to saturated fat, the nuclear transcription factors realize, "Oh my God, fatty acid toxicity is going to occur to this liver.

We have to take our defensive mechanisms on that." First thing they do is say, "My God, we don't want more lipids being pulled into the liver by these LDL receptors." So the nuclear transcription factors go into your DNA and say, "Stop making these LDL receptors.

[laughs]