Name: How aging and lifestyle factors contribute to rising ApoB and LDL cholesterol levels
Uploaded: 2025-02-07T03:03:58.000Z
Duration: 9 min 13 s
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Relative clauses (Restrictive vs. nonrestrictive)

Let's pivot for a minute to talk a little bit about something you also touched on briefly, which was that when we're young, we have what's referred to as a physiologic level of ApoB or LDL cholesterol.

So the concentration of LDL cholesterol in a child is low.

We don't see this very often because we're not used to checking these things in kids, but occasionally you'll even notice it as a parent if your kid gets sort of a comprehensive blood test that their total cholesterol might be 60 milligrams per deciliter with an LDL cholesterol of 30 milligrams per deciliter and an HDL cholesterol of 25 milligrams per  I mean, they're very, very low levels of this.

Why is it that aging seems to be associated with a monotonic increase in lipoproteins?

And this is absent something that we could even get to later if we have time, which is what happens during menopause for women, which is more abrupt.

But just talk to me about ages, you know, 10 to 50.

Why does everybody seem to go the wrong way?

Well, a lot of, of course, is the multitude of things we subject our bodies to.

If you want to encompass that with the environment or a lifestyle, you quote, unquote, whatever, and you can throw probably whatever you want into that category of things that might cause your body to, as ApoB goes up, it's almost all related to your liver is losing the ability to clear these particles out of plasma.

It's not like you're overproducing 10 tons of them.

It can happen, but that's rarely a contributor to the high ApoB levels.

So scientifically, we have to zero in on what regulates clearance of these particles.

And the simplest thing is to say, well, the only way these ApoB particles get cleared is our liver produces something called an LDL receptor, which migrates to the surface of the liver cell that interacts with the blood flow, the plasma, and these LDL receptors are engineers to recognize any ApoB peptide that floats by it.

So if an LDL particle containing ApoB floats by an LDL receptor, it will get grabbed, and then it gets internalized into the LDL receptor, and it gets catabolized, and then the liver can take whatever cholesterol, triglycerides, fatty acids, blah, blah, blah, is in that molecule and use it for other purposes or somehow get rid of it in the biliary system if the liver doesn't need it.

So it's going to come down to what are these factors that I called, hey, environmental lifestyle that affects what we call LDL receptor expression, and it's a lot of things.

One of the things you mentioned before, insulin resistance would affect that, numerous components of the diet express, are you regulating LDL receptors or not, how much cholesterol your liver is being told it needs to put in the next VLDL particle, or more importantly, the HDL particle going out.

So lipid balance in the liver is regulated by a bunch of things called nuclear transcription factors, and they actually sense, hey, the liver needs some lipids or the liver's got too much lipids and we've got to get rid of it.

Those nuclear transcription factors migrate into the nucleus and the nucleolus of our cells, and they bind to specific parts of the DNA and tell our genes, produce this protein, produce that protein, this enzyme, that enzyme, this receptor, that receptor, that can go out and help restore sterile homeostasis to this human body.

So probably every adversarial thing you've been told in your life not to do, gain weight, don't eat this, don't eat that, are all affecting these nuclear transcription factors that are going to regulate clearance of these ApoB particles, and it's a long list of things that can probably do that.

It is interesting that, on average, more of the things that we do that are, quote-unquote, less healthy, whether it be gain weight, eat a certain way, tends to result in decreased hepatic clearance.

So on that topic, one of the questions you and I get asked all the time is, look, hey, doc, I kind of buy your thesis that ApoB is bad, I buy your thesis that mine is too high, and I buy your thesis that I should probably lower it.

I'd really like to start with my diet before I turn to pharmacology.

You know, typically, there's two things I tell patients here.

The first is, I think your two best levers nutritionally to reduce ApoB are lowering triglycerides and lowering saturated fat intake.

Now, of course, this assumes that you have high enough triglycerides that lowering them further will indeed lower ApoB, and it, of course, assumes you're eating a high enough amount of saturated fat that reducing it significantly will lower ApoB.

So let's assume for a moment that those things are true.

We're talking to a patient, Tom, whose ApoB is 100 milligrams per deciliter.

You know, you and I have just kind of, I don't want to say read him the riot act, but we've given him the education that says, look, you'd be a heck of a lot better off if you were at 60 milligrams per deciliter.

His triglycerides are sitting at about 162 milligrams per deciliter, and when we query his diet, we realize it's pretty high in saturated fat.

He's probably getting, you know, call it, I don't know, 40 or 50 percent of his calories from fat, and he's probably getting, you know, 50, 60 grams per day of saturated fat alone.

So in other words, he seems like a really ideal candidate if he's willing to switch more of his fat calories to monounsaturated and polyunsaturated or even just reduce fat altogether, and he's willing to take the dietary steps to reduce total calories and maybe even carbohydrates specifically to kind of bring down his triglycerides.

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 100 down to 60?

The saturated fat is a little easier to explain.

We have plenty of studies that show excess saturated fat, those genes that are regulating lipid or 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.

So in many, many people, exposure to saturated fat, the nuclear transcription factors realize, oh my God, fatty liver, fatty acid toxicity is going to occur to this liver.

We have to take our defensive mechanisms on that.

So what they 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.

Stop sending out the signal that will be translated into an LDL receptor.

So of course, if you eat saturated fat and your liver stops expressing LDL receptors, your ApoB is going to go through the roof.

What is the ApoB particle carrying?  And above the threshold concentration, it's going in the artery wall.

Typically, if that person does follow your advice and restricts the saturated fat, they will go back to some more increase in their LDL receptor expression.

The saturated fat in some people, too, also turn on the enzymes that induce cholesterol synthesis.

So now if the liver starts overproducing cholesterol, then the lipid pool is out of whack.

The same nuclear transcription factors go in and say, stop making the LDL receptors.

We don't want to pull in more cholesterol into this liver that's oversynthesizing cholesterol.

It's another whole story, as you know, Peter, why we don't necessarily tell people you have to restrict cholesterol in your diet.

And the absorption of sterols in your gut has nothing to do with the absorption of fatty acids in your gut.

Totally different mechanisms that pull them in.