Cardiologist Dr. Paul D. Thompson, MD, uses simple comparisons to show how inherited genes for liver receptors and particle proteins push blood cholesterol up, and why a protein called PCSK9 has become a target for newer injectable and oral cholesterol-lowering medicines.
Inherited High Cholesterol: LDL Receptors, Apolipoprotein B, and PCSK9
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- Cholesterol levels run in families
- How the liver clears LDL cholesterol
- Inherited LDL receptor problems
- Apolipoprotein B as a zip code
- PCSK9 and the medicines that block it
- Full Transcript
Cholesterol levels run in families
High cholesterol is definitely genetic, according to cardiologist Dr. Paul D. Thompson, MD. Answering Dr. Anton Titov, MD, he explains the inheritance by pretending to be the liver, where cholesterol is made.
How the liver clears LDL cholesterol
LDL receptors on liver cells are the starting point of his explanation. A person gets one gene for this receptor from the mother and another from the father. As LDL cholesterol, which he calls the ugly cholesterol, floats by in the blood, the receptors grab it and pull it into the liver.
He says this has two good effects. The blood cholesterol level goes down, and the liver cell senses that it has enough cholesterol and stops making more.
Inherited LDL receptor problems
Dr. Thompson describes inherited LDL receptor problems as one reason cholesterol levels can be high. His explanation focuses on reduced removal of LDL cholesterol from the blood when the liver's receptor system does not work properly.
This is why, he says, so much of a person's cholesterol level is genetic.
Apolipoprotein B as a zip code
Apolipoprotein B adds another inherited factor, which Dr. Thompson admits makes the picture more complex. He compares cholesterol particles to envelopes in the mail that need to know where to go. The apolipoprotein on the particle works like a zip code, and on the bad cholesterol particles that zip code is apolipoprotein B.
If a parent passes on a faulty apolipoprotein B gene, the particle cannot reach the receptor as well, because the receptor and the apolipoprotein B do not recognize each other.
PCSK9 and the medicines that block it
PCSK9 is the final piece of his explanation, which he considers important for patients taking these medicines to understand. An LDL receptor normally goes into the liver and comes back out, and he says it would like to make that trip about 150 times. PCSK9 can bind the receptor on the liver surface, and when the receptor, its cholesterol and PCSK9 all go into the liver, the receptor does not come back.
Dr. Thompson notes that there are now medicines that block PCSK9 before it can grab the receptor. He says these are injectable, and that Merck had just recently released an oral medicine at the time of the interview. He calls them wonderful medicines for people with a genetic defect or, as he tells patients, for those who picked the wrong parents.
Full Transcript
Dr. Anton Titov, MD: Is high cholesterol genetic - does it run in families?
Dr. Paul D. Thompson, MD: Definitely. Cholesterol is definitely genetic. Now let me explain to you how this happens.
Dr. Paul D. Thompson, MD: Let us pretend I am your liver, okay? I am your liver. So what happens in the liver?
Dr. Paul D. Thompson, MD: You make cholesterol. On your liver cells, you also have these cholesterol receptors. You get one gene for a cholesterol receptor from mom.
Dr. Paul D. Thompson, MD: You get another gene for the cholesterol receptor from dad. As cholesterol floats by, as LDL cholesterol, the ugly cholesterol, floats by, these LDL receptors grab it and they pull it into the liver. Now two good things happen.
Dr. Paul D. Thompson, MD: One is that the LDL receptor grabbed the LDL cholesterol and pulled it into the liver, so the cholesterol level in the blood went down. But the other thing that happens, number two, is that the liver cell says, "Hey, I have got enough cholesterol. I am going to take the day off.
Dr. Paul D. Thompson, MD: I do not need to make any more cholesterol." Now let us suppose you pick the wrong parents, and one cholesterol receptor gene was not passed on.
Dr. Paul D. Thompson, MD: That means about half of your liver cells will have the good cholesterol receptor gene, and about half of the liver cells will have no LDL cholesterol gene. So what happens is your cholesterol level is higher. Why?
Dr. Paul D. Thompson, MD: Because you do not have as many grabbers pulling LDL cholesterol out of the blood, and because those liver cells that do not have the receptor say, "Hey, I got to make more cholesterol. I do not have enough cholesterol here in my blood." So so much of your cholesterol level is genetic.
Dr. Paul D. Thompson, MD: Now, it is a little bit more complex than I made it, because there are other things that can happen. On the cholesterol particle itself, there is what we call an apoprotein. And that apoprotein tells the particle where to go.
Dr. Paul D. Thompson, MD: I say it is like the mail, right? If you send a letter, that envelope has a zip code on it. The cholesterol particles are like envelopes.
Dr. Paul D. Thompson, MD: They contain stuff, and they need to know where to go. So they have a zip code as well. And that zip code is called an apolipoprotein.
Dr. Paul D. Thompson, MD: The apolipoprotein on the bad cholesterols is called apolipoprotein B. That is the zip code. And if you were born with a bad ApoB, if one of your parents gave you a bad apoprotein B gene, it cannot get to the receptor as well, because the ApoB does not recognize the receptor.
Dr. Paul D. Thompson, MD: The receptor does not recognize the ApoB. Now, one of them makes it complex, but it is important for your patients who take this drug to know. The LDL receptor goes into the liver, and it comes back out.
Dr. Paul D. Thompson, MD: An LDL receptor would like to go around about 150 times. But it can be bound. The LDL receptor can be bound on the surface of the liver by something called PCSK9.
Dr. Paul D. Thompson, MD: So this PCSK9 grabs the receptor. The receptor grabs the cholesterol. They all go into the liver.
Dr. Paul D. Thompson, MD: And you know what happens? They disappear. The LDL receptor does not come back, because that thing, the PCSK9, bound it.
Dr. Paul D. Thompson, MD: So we also have medicines now that do this. They block PCSK9 before PCSK9 can grab the receptor. Okay?
Dr. Paul D. Thompson, MD: Those are injectable, and also Merck has just recently released an oral medicine. So we have wonderful medicines to treat these things if you have a genetic defect of some sort, or, as I say to patients, if you happen to have picked the wrong parents.