So from your perspective, what is changing with lipids prior to that fasting insulin starting to increase?

And it's so important because the sooner we diagnose insulin resistance, the sooner we can take measures to improve insulin sensitivity, which is obviously crucial to many aspects of healthcare, so.

And we just cannot wait for glycemic abnormalities, either a fasting, even a postprandial glucose.

By the time they start to go up, you've probably been insulin resistant for many, many years, and the damage that insulin resistance does occurs long before the glycemic abnormalities.

It continues to get worse, of course.

So of course, and many people check insulin levels.

I always did, and I think that's an another important signal for you.

Curehydration.com

Just so we're clear on our operational definitions here, can you remind people what the difference is between primary and secondary prevention?

Yeah.

It's evolved over time.

People who are docs who started out in, uh, when I did in, as [chuckles] I said, in the Dark Ages, there was primary and secondary prevention.

A patient coming into the office had not had a heart attack, a bypass, or a stroke.

Had they had any of those, then we'd say, "Oh my God, we gotta prevent the next heart attack, bypass, or stroke." That would be classic secondary prevention.

And anything before, "Oh, I haven't had a heart attack yet, Doc." "All right.

I'd love to sh- to go through the statistics and the data with you, but before I do that, can I ask Tom to tell us what a typical weekend on call was like for him at age thirty-five, how many people he admitted to the ICU with a myocardial infarction?

So why, in the short amount of time we've got, why don't you tell us what we need to know about w- where we are with HDL and how we look at it?

Yes, and [laughs] indeed, as you know, it's a complex topic, but, uh, and HDL is different from all of the other lipoproteins in our plasma 'cause the apoprotein that surrounds the other lipid-carrying, uh, particles is apolipoprotein B.

We have the very low density, intermediate density, low density, post, uh, prandial we have chylomicrons coming out of the intestine.

So that is one group of lipoproteins.

They originally were called beta lipoproteins before they even knew what apoB was, because they migrate it with beta proteins in the serum.

So the any non-apoB containing lipoprotein is in this high-density lipoprotein classification, and the structural peptide that, um, d- uh, ch- is different on an HDL than the apoB, it's its apoprotein A1 is the structural protein.

So HDL particles can actually carry from one to several, four, and rarely five copies of apoA1 per particle.

ApoB lowering, yes.

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 what's your, your feeling about, uh, where we are with HDL now?

Well, we know a lot, [chuckles] a real lot, but I still think we're in our infancy on truly understanding all of the things that, uh, the good Lord gave us HDL particles for, to do and everything.

So, and, uh, our...

Part of the difficulty was the only way we've ever measured, uh, w- something about HDLs was to measure the mass of cholesterol that they're carrying per deciliter or per liter if you're using moles, uh, millimoles or so.

And the early studies, which are all epidemiologic, Mr.

Fit, Framingham, going way back to, uh, the several stu- all suggested that, wow, we're noticing that there's a higher risk of atherosclerotic events in people who have low HDL cholesterol, and we don't see as many events if the people have normal or even higher levels of HDL cholesterol.

Hence, epidemiologically, it sort of made sense.

Yeah.

Mm.

And when estrogen goes bye-bye, your insulin resistance is happy to take over.

So very common.

And this is e-even in men, insulin resistance is part of the aging process, so it's not only all hormonal.

There are other factors a-at play.

So, uh, that's certainly one.

I, I got into it a little bit last time.

Um, I only know-

So let's start with the basics to kind of give our listeners and our community some context to some of the discussions that we're going to have today and moving forward.

Sure.

Well, the first thing is absolutely to define what the heck is a lipid.

Uh, you know, biochemistry is full of a lot of molecules, all of which perform various functions or so, and many of them in the animal kingdom.

And certainly cholesterol is one of the lipids that is absolutely crucial for human life in certain amounts.

Beyond that, it can cause harm.

Too low, it can cause harm.

You mentioned they're absorbed into the gut lumen with specific enzymes and carrier molecules, but let's talk a little bit more about how we go from talking about phospholipids, phospholipid bilayers, triglycerides, esters, et cetera, until we're actually talking about the transportation system in the body.

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]