Ep 217 The High Stakes of Cholesterol

Summary

This Podcast Will Kill You, Ep 217: The High Stakes of Cholesterol

Hosts: Erin Welsh, Ph.D., & Erin Allmann Updyke, MD, Ph.D.
Date: July 28, 2026
Podcast Network: Exactly Right and iHeartPodcasts

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Episode Overview

In this rich, science-focused episode, Erin Welsh and Erin Allmann Updyke delve deep into the complex biology, history, and controversy surrounding cholesterol. Tackling one of the most famous and misunderstood molecules in medicine, the hosts explain what cholesterol actually is, its essential role in the body, why its “bad” reputation is sometimes very much deserved, and how scientific thinking about cholesterol’s connection to heart disease evolved over the past century. The episode prominently features a moving firsthand account of living with familial hypercholesterolemia, setting the stage for a compassionate and nuanced medical discussion.

Erin Welsh [07:06]: "LDL is just one part of the cholesterol story. Atherosclerosis, just one part of... the story we're gonna be talking about this week—the role of cholesterol in our bodies overall and the role of cholesterol in disease."

Erin Allmann Updyke [07:32]: "What do we do about it? It won't just be statins, but it will be focused on, like, how do we lower cholesterol? And why would we lower cholesterol?"

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Key Discussion Points & Insights

1. Firsthand Story: Living With Familial Hypercholesterolemia ([01:58]–[06:40])

• Speaker: Tori, lived experience of hereditary high cholesterol
• Summary:
  • Tori describes growing up in a family with a history of early heart attacks and strokes (grandfather, father, and sister).
  • Diagnosed with high cholesterol as a teen; lifestyle changes insufficient for improvement.
  • Required genetic testing to access statin medication.
  • Family’s anxiety and fear are pervasive, especially after losing her sister suddenly at age 25.
  • Describes daily anxieties, the burden of medication, dietary restrictions, and open discussion within her family.

Tori [04:39]: "It's just kind of this, like, constant worry that this might happen and a lot sooner than you think."

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2. Cholesterol: Biology & Its Role in the Body ([13:38]–[25:57])

What Is Cholesterol?

• Cholesterol is an essential lipid molecule (a sterol) needed by all animal life.
• Key roles:
  • Provides structure to cell membranes.
  • Backbone for steroid hormones (estrogen, testosterone, cortisol).
  • Needed for vitamin D and bile acid production.
• Plants/fungi have similar sterols (phytosterols, ergosterol).

Erin Allmann Updyke [15:07]: "One of the biggest things that sterols like cholesterol, for us animals, does is provide shape and structure to our cell membranes."

Cholesterol Production & Transport

• Humans make most of their cholesterol in the liver.
• We also absorb some from dietary sources.
• Cholesterol travels in the blood in lipoprotein “packages”:
  • VLDL (very low-density lipoprotein): Sent out by the liver.
  • LDL (low-density lipoprotein): Formed from VLDL, delivers cholesterol to cells (“bad” cholesterol).
  • HDL (high-density lipoprotein): Transports cholesterol from cells back to the liver (“good” cholesterol).

Erin Allmann Updyke [19:14]: "Our liver takes the cholesterol that it makes... and sends it out in a box that we call VLDL. Eventually becomes a smaller box... LDL. These are the packages our cells are taking up and using for cholesterol."

Why Cholesterol Becomes a Problem

• High LDL levels can lead to its buildup in the blood vessel walls, provoking an immune/inflammatory response.
• Over time, this results in atherosclerosis: plaque buildup leading to hardened, narrowed arteries and increased risk of heart attack or stroke.
• The key factor is how much LDL is circulating uncollected by cells—this can be due to genetics (e.g., number/function of LDL receptors) or diet/lifestyle factors.

Erin Allmann Updyke [26:20]: "If that's high levels in your bloodstream, then sometimes... especially LDL packages, are small and sticky... can get stuck along the walls of our blood vessels..."

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3. Epidemiology & Numbers: Risk, Guidelines, and Lifespan ([29:20]–[36:16])

Risk Factors & Cutoffs

• Cholesterol rises with age (mechanisms not fully understood).
• Diet: High saturated fats raise both total and LDL cholesterol.
• Physical activity can increase HDL, lower LDL.
• Guidelines:
  • LDL < 100 mg/dL = ideal.
  • 160–190 mg/dL = very high risk.
  • Total cholesterol < 200 mg/dL preferred.

Erin Allmann Updyke [32:40]: "Ideal levels of LDL cholesterol would be less than 100 mg/dL in your blood. But... levels above 100 are associated with higher risk."

Impacts Beyond the Heart

• High LDL also associated with:
  • Stroke
  • Chronic kidney disease
  • Peripheral arterial disease
  • Higher risk of Alzheimer’s disease
  • Potential links with cancer

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4. Cholesterol’s Evolution and Reputation ([39:47]–[68:29])

Cholesterol through Evolution

• The need for flexible, stable cell membranes arose after the Great Oxygenation Event ~2.5 billion years ago.
• Cholesterol synthesis and utilization critical in early animal evolution; context-specific advantages may now, in modern lifestyles, turn disadvantageous.
• Modern abundance of dietary fats and sedentary lives exacerbate risk.

Erin Welsh [47:56]: "Our relationship with cholesterol... you can't really paint it with a broad brush. It's super complicated, both at a population level and an individual level."

The History & "Cholesterol Wars"

• 1910s: Discovery of cholesterol in atherosclerotic plaques; animal (rabbit) studies show high cholesterol causes vascular lesions—but early skepticism due to species differences and unrealistic dosing.
• 1950s–70s:
  • John Goffman at UC Berkeley invents methods to measure different lipoproteins—finds not all cholesterol is the same (“atherogenic index”).
  • Persistent skepticism in scientific/medical circles—correlation vs. causation, what counts as “high.”
  • Famous epidemiological studies resolve much of this:
    • Seven Countries Study (Ancel Keys): Correlation between dietary fats, cholesterol, and fatal heart attacks at population level.
    • Framingham Heart Study: Shows that high cholesterol precedes heart disease on an individual level.

Erin Welsh [55:24]: "The next phase... brings us to UC Berkeley... John Goffman... suspected that there might be something to the cholesterol atherosclerosis link... You need to give different weight to the different lipoproteins in predicting the risk of cardiovascular disease."

Erin Welsh [63:26]: "Where the Seven Countr[y] Study showed the relationship between blood cholesterol and heart disease at a population level, the Framingham Heart study demonstrated it in the individual."

Mechanisms Unveiled: Familial Hypercholesterolemia & the LDL Receptor

• Familial hypercholesterolemia (FH): Early cases showed severe disease, led to search for mechanism.
• 1973: Brown & Goldstein's Nobel-winning work reveals affected patients lack LDL receptors, so LDL accumulates in the blood.
• Understanding receptor biology opens new avenues (statins, PCSK9 inhibitors, etc.) and cements the link between blood cholesterol and vascular disease.

Erin Welsh [66:15]: "The cells of people with familial hypercholesterolemia lacked receptors... to scoop up the LDL from the bloodstream... LDL just kept piling up, piling up, circulating and circulating with nowhere to go."

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5. Debates, Doubters, and Legacy ([68:29]–[71:14])

• Statins and other drugs transformed heart disease from something you managed to a condition you could treat or even prevent.
• Yet controversy (“cholesterol wars”) about “how low to go,” the significance of diet, drugs, and individual risk continues to this day.
• Next episode: the story of statins.

Erin Allmann Updyke [68:02]: "It is so interesting, Erin, how much like... it is really hard to find someone who doesn't at least agree that high levels of cholesterol put you at high risk for heart disease, and yet... there's still so much [debate] about what you do about it or... what your diet effect might be."

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Notable Quotes & Memorable Moments

• “Cholesterol is the Bill Buckner of cell biology.”
  — Erin Welsh [39:47]; a playful baseball analogy highlighting cholesterol's essential function and its outsized infamy due to its "one bad play."

• “You could see this. You could see this. You also could see this.”
  — Erin Welsh [08:45]; the hosts’ banter as they promote their Quarantini recipes and website, exemplifying their warm, irreverent chemistry.

• On the episode’s complexity:

  • Erin Allmann Updyke [16:02]: "It really does, because I'm not even done. The backbone of cholesterol... is also the prec of our steroid hormones..."

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Timestamps: Important Segments

| Segment | Timestamps | |----------------------------------------------|--------------| | Firsthand account (Tori) | 01:58–06:40 | | What cholesterol is, roles in the body | 13:38–18:46 | | Lipoproteins: VLDL, LDL, HDL explained | 18:46–21:27 | | How cholesterol causes disease/atherosclerosis| 21:27–29:16 | | Age, diet, hard numbers for risk | 29:16–34:32 | | Associated diseases beyond heart attack | 34:32–36:16 | | Evolutionary biology/historical context | 39:47–47:55 | | Cholesterol wars, epidemiology | 54:28–63:53 | | Familial hypercholesterolemia; LDL receptor | 64:35–66:54 |

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Further Resources & Reading

• Papers and reviews on cholesterol biology, the historical debate, epidemiological studies, and the molecular mechanisms are highlighted and linked on the podcast’s website.

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Tone & Style

The episode blends clear, authoritative scientific explanation with warm, playful banter and deep empathy for patients and listeners living with chronic disease. Both Erins bring humor and analogy (from salad dressing to baseball) to make complex biomedical concepts accessible and memorable.

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Next Episode Teaser

The story continues: next week will focus on statins—how they work, their impact, and the continuing debate over cholesterol and strategies for lowering it.

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End of Summary

Transcript

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[Erin Welsh]

The firsthand account for this episode features a story involving the death of a family member. Some listeners might find this upsetting, so please listen with discretion.

[Tori (Personal Story Speaker)]

Hi, I'm Tori, and I have familial hypercholesterolemia. I think growing up, I always knew my dad was different because he like walked with a limp and he spoke weirdly. He couldn't like, write or do anything, but I didn't know why. And then I remember When I was 10 years old, my mom requesting that I get my cholesterol checked at a doctor's appointment. And they're like, she's 10. I think it was when they sat me down and told me that my dad had had a heart attack, which turned into a stroke when I was a baby. And so that's why things were a little different. And then that the same thing happened to his Father. His father was 45. My dad was 47 when he had his heart attack. And then they told me what causes it and why they're worried that I could have it. When I was 14, my cholesterol was 232, which not good. And they told me like, oh, diet and exercise come back in a year. And it was 231. And so we were like, this is something more. It's not just lifestyle. But then the pandemic happened and, and there was like so much going on. But I finally got like tested again and they were like, we can't put you on statin unless you have a geneticist prove that this is something. So I had to go to geneticist and I have a fun little chart that's like, she's missing something. That's now what I live with. I'm on statin for the past two years. My cholesterol is 197, still a little high. But last July I was taking a nap and I got like shook awake by my brother in law and I hear like sobbing in the background. And I remember being told, we have to go to the hospital right now. And I check my phone and there's a text from my mom that says, your sister's heart stopped and the name of the hospital they were at. And so we speed over there and when we get there, the chaplain tells us that there was nothing they could do. She was only three weeks away from her 26th birthday. It was kind of a huge shock and kind of be like, oh, this is real. This is like real real, you know, so yeah, that's something that I live with. And the constant back of my mind, I don't really know how to talk about it unless it's like, fun fact, my DNA is missing, you know, but it always comes up where I'm like, oh, I don't eat red meat. Oh, I can't have that. I can't do this. I have to take my pills. I have a plethora of pills that I take every morning and night for a bit. My twin had to wear a heart monitor because they now have afib. I bedazzled it for them. It is something that's discussed openly. I think that fear has gotten really largely into my mom's head. And she's like, you have to take this, this and this, and are you doing like your exercises and stuff like that. And so I think it is just very established that this is a fear. It's a huge part of my life. And then it's a huge part of my anxiety where it's like, this could be it. But I think just realizing that this is going to be the rest of my life, and it may not be as long as, you know, others. And my dad was lucky to survive his heart attack. His father and my sister were not. So it's just kind of this, like, constant worry that this might happen and a lot sooner than you think.

[Erin Welsh]

Tori, thank you so much for taking the time to chat with us and share your story.

[Hulu Series Promoter]

We.

[Erin Welsh]

We deeply, deeply appreciate it.

[Erin Allman Updike]

We do. Thank you so much.

[Erin Welsh]

Hi, I'm Erin Welsh.

[Erin Allman Updike]

And I'm Erin Allman Updike.

[Erin Welsh]

And this is this podcast, Will Kill youl.

[Erin Allman Updike]

And today we're talking about cholesterol.

[Erin Welsh]

Today and next week. Cholesterol and next week.

[Erin Allman Updike]

Cause it's kind of a big deal, so it's gonna take a while.

[Erin Welsh]

A pretty big deal. It's a pretty big deal.

[Audiobook Narrator/Host (possibly Ray Porter or Kal Penn)]

Yeah.

[Erin Welsh]

We decided to divide this up into two different episodes because the first is really about cholesterol, because, you know, LDL is just one part of the cholesterol story. Atherosclerosis, just one part of the. And so that's the story that we're gonna be talking about this week. So the role of cholesterol in our bodies overall and the role of cholesterol in disease.

[Tori (Personal Story Speaker)]

Yeah.

[Erin Welsh]

And then next week, we're talking statins.

[Erin Allman Updike]

We're talking what do we do about it?

[Erin Welsh]

What do we do about it? It won't just be statins, but it will be focused on, like, how do we lower cholesterol? And why would we lower cholesterol?

[Tori (Personal Story Speaker)]

And why.

[Erin Welsh]

Yeah.

[Erin Allman Updike]

And how low can we go? Just kidding. That is, like, a very small part.

[Erin Welsh]

But, yeah, I was gonna say there is a low that is too low. Correct.

[Hulu Series Promoter]

Yeah.

[Erin Allman Updike]

Yes, we do need it.

[Erin Welsh]

There's. There's a lot of good material to cover. So let's just get through the rest of this intro.

[Erin Allman Updike]

Let's do our next to say that

[Erin Welsh]

it's not exciting, but, like, you know, we want to get to the meat of it. It's quarantin each time. Disaster. What are we drinking this week?

[Erin Allman Updike]

We're drinking plaque attack.

[Erin Welsh]

Plaque attack.

[Erin Allman Updike]

Are we attacking plaque? Is plaque attacking us? A little bit of both.

[Narrator/Announcer]

Yeah.

[Erin Welsh]

Plac Attack is a delicious Bev. It has blueberries and lemon juice and sparkling water and a little bit of simple syrup and some mint to make it nice and refresh.

[Tori (Personal Story Speaker)]

Yeah.

[Erin Allman Updike]

Has nothing to do with your cholesterol, but it is delicious. We'll post the full recipe on our website, this podcast with Kelly.com and all of our social media channels too. So are you following us there? Because then you could see the this.

[Erin Welsh]

You could see this. You could see this. You also could see this. If you go to our website, this podcast will kill you.com, which features not just pictures of Quarantini recipes and still maybe videos from past ones. Working on that still. Still. But you can also find things like transcripts. You can find our show notes. You can find links to bookshop.org affiliate page, music by bloodmobile about us page Merch Patreon Submit your firsthand account form Contact us form. I got there in the end.

[Erin Allman Updike]

You did. You really nailed it and I don't think you missed a single thing.

[Erin Welsh]

Thanks for saying that.

[Erin Allman Updike]

That's all we got, right? We can just.

[Tori (Personal Story Speaker)]

Yeah, I think so.

[Erin Allman Updike]

Rate, review, subscribe, do those things.

[Erin Welsh]

And also I'll just throw it out there, you know. Thank you to everyone who has ever suggested an episode topic. It's really helpful. We love getting topic ideas from you all and feedback from you all and so keep it up. We love it.

[Erin Allman Updike]

Also, thank you to everyone who has submitted firsthand accounts. We, we really do read them all and sometimes it might take us like, I don't know, two or three years

[Erin Welsh]

to reach out to you.

[Erin Allman Updike]

That doesn't mean even longer.

[Erin Welsh]

At times I wonder what our record is. Yeah, more than three years.

[Erin Allman Updike]

But thank you. We, we, we really do appreciate it and like being able to hear all of your stories and share your stories. It's, it's what makes this podcast, in our opinion. So thank you.

[Erin Welsh]

Absolutely. Well, let's take a quick break and then get into the story of cholesterol.

[Narrator/Announcer]

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[Hulu Series Promoter]

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[Narrator/Announcer]

It's Alice's first case on the job and she's already already bitten off more than she can chew.

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While Alice believes justice is achieved through law enforcement, Catherine has lost all faith in the legal system.

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[Hulu Series Promoter]

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[Narrator/Announcer]

streaming on Hulu and Hulu on Disney plus for bundle subscribers terms apply.

[Erin Allman Updike]

Goodbye.

[Kal Penn]

Hey everyone, it's Cal Penn. I'm the host of Irsay The Audible and iHeart Audiobook Club. This week on the podcast, I am sitting down with Ray Porter, the narrator of Andy Weir's audiobook project Hail Mary Massive sci fi adventure about survival and science and what happens when you wake up alone, very far from Earth.

[Audiobook Narrator/Host (possibly Ray Porter or Kal Penn)]

I really had to make a decision because I caught myself getting that frog in my throat and starting to get teary as I'm narrating some of these sections and it's like, okay, yo yo, yo, is this indulgent? And I really thought about it. I was like, no. At this point it would kind of be betraying the trust the author and the listener have in telling this story if I don't go through it. But there's places in this book that deeply, emotionally affected me and I left it on the mic. That's great because it served the story. People will say like, oh my God, I cried at the end. It's like, yeah, dude, me too.

[Kal Penn]

Listen to Earsay, the Audible and iHeart Audiobook Club on the iHeartradio app or wherever you get your podcasts.

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[Erin Allman Updike]

My goal for you today is that in the next, I don't know, 20 minutes or so, okay, you will understand what on earth cholesterol actually is and what our bodies are supposed to be using it for. And then what your doctor actually means when they talk about your quote unquote, cholesterol and why those levels matter for your health.

[Erin Welsh]

All right, Love this.

[Erin Allman Updike]

Okay, so cholesterol itself is a type of lipid molecule, and we think of lipids as fats. Technically, fats are just triglycerides, but whatever. Think of them as fats. And it's specifically a type of lipid called esterol, like cholesterol. Okay. Cholesterol is just a string of carbons and hydrogens and one oxygen that's formed in these little rings. There's like, four rings together, so it's a pretty rigid molecule. And cholesterol is an essential molecule for all animal life. And really, nearly all kinds of life on earth need things like cholesterol. So plants, they don't make cholesterol, really, but they do make a whole bunch of other very similar compounds called phytosterols. Phytosterols. Phytosterols. Anyways, I'll accept both, thank you. And fungi make their cell membranes out of something called ergosterol.

[Tori (Personal Story Speaker)]

Okay.

[Erin Allman Updike]

Sterol also. And one of the biggest things that sterols, like cholesterol, for us animals, does is provide shape and structure to our cell membranes. So cholesterol molecules are interspersed throughout all of our cell membranes, like the outside of our cells, which is called our plasma membrane. And then also, all of our organelles inside of our cells also have membranes that also have cholesterol within them. And what this does is provide just the right amount of rigidity and structure without being, like, too solid.

[Tori (Personal Story Speaker)]

Okay.

[Bank of America Advertiser]

Right.

[Erin Allman Updike]

Cholesterol molecules are also moved back and forth across these cell membranes. They interact with proteins both inside and outside membranes, and they serve as signaling molecules that helps our cells communicate, like, within the cells, like, between organelles, and then also between cells themselves. It's kind of a big deal.

[Erin Welsh]

It does a lot of things.

[Erin Allman Updike]

It really does, because I'm not even done. The backbone of cholesterol, those ring structures of carbons and hydrogens are also the prec of our steroid hormones. So that's estrogen, testosterone, cortisol, all of them. And vitamin D and our bile acids, which we learned in our gallbladder episodes. Pretty freaking important. So suffice to say, we need cholesterol in order to be alive, Right?

[Erin Welsh]

Totally.

[Erin Allman Updike]

Where do we get it from? Let me tell you. We make our own cholesterol, and most all of our cells can make cholesterol. Like, all of our cells are capable of it, but it's a pretty energy intensive process. So the vast majority of cholesterol that we actually use in our body is made in our liver. And then we also get cholesterol and other fats and fatty acids that we also need from our diet. So we absorb it through our intestine and then that gets transported to our liver. So while our cells can make their own cholesterol, they're generally not making quite enough of it, which is why our liver makes so much, something like more than 50% of the cholesterol that our cells use, which means that we have to be able to deliver cholesterol from our liver and our intestine to everywhere else in our body.

[Tori (Personal Story Speaker)]

Yeah.

[Erin Allman Updike]

And our body uses blood to transport stuff around.

[Tori (Personal Story Speaker)]

Okay.

[Erin Welsh]

It's the super highways of the body.

[Erin Allman Updike]

Ex. And so while cholesterol is integral to life, when it ends up causing problems, which is obviously what we're gonna focus on for this episode, is when that cholesterol starts building up in high amounts in places that it shouldn't, that is where we can end up seeing cholesterol cause disease. And so to understand how that happens, we have to understand how it is that our body is moving cholesterol around from our liver to our cells, et cetera, and how our cells are cycling that ch, because then we can understand how this might build up in places that it shouldn't. Now, lipids, a key thing to understand about them, including cholesterol and all of our other fatty acids, is that they are not water soluble.

[Tori (Personal Story Speaker)]

Right.

[Erin Allman Updike]

Everyone who's tried to make salad dressing knows this. And what that means is that in order to move cholesterol around our bloodstream, it's not just going to be free floating because it won't do that. Well, yeah, so we actually move our cholesterol around our body in little packages called lipoproteins.

[Tori (Personal Story Speaker)]

Okay.

[Erin Allman Updike]

Now, we have a bunch of different kinds of lipoproteins. Lipo, fat, protein, protein. And they all serve different functions. Most of our cholesterol is made in our liver, right? So our liver takes the cholesterol that it makes and along with other fatty acids and connects it to a protein and sends it out in a box that we call vldl, or very low density lipoprotein.

[Tori (Personal Story Speaker)]

Right?

[Erin Allman Updike]

So it sends that package out and that is the type of cholesterol package that our cells are going to end up using along the way in our bloodstream, this VLDL gets broken down a bit and eventually becomes a smaller box of cholesterol and other fats that we call LDL or low density lipoprotein. Right?

[Erin Welsh]

Okay.

[Erin Allman Updike]

So VLDL and ldl, these are the lipoproteins. These are the packages of cholesterol that our cells are taking up and using for cholesterol.

[Erin Welsh]

Okay. So these are the things that our liver is making to say, here you go, here's. You said you needed some cholesterol to make your cell membranes or make some hormones or whatever. Here's this package. Starts out VLDL turns into ldl. Our cells take that up.

[Erin Allman Updike]

Our cells are like, awesome. I got this. They grab onto it, they bring it inside of them. Protein, cholesterol, fatty acids and all in a little package. Right?

[Tori (Personal Story Speaker)]

Right.

[Erin Allman Updike]

Now once it's in our cells, our cells can either use it or they can store it for later. If they're like, I want to have a little extra, or they might get way too much of it and then they have to send it back out into our bl. Cells are going to export extra cholesterol. They do it in a package called hdl, or high density lipoprotein.

[Narrator/Announcer]

Okay.

[Erin Allman Updike]

And that is the cholesterol that's being transported from our cells back to our liver so that our liver can recycle it or excrete it into bile acids or whatever our liver is going to do with it.

[Erin Welsh]

That makes sense. So this is LDL being the ldl, you know, quote unquote bad cholesterol, quote unquote bad.

[Erin Allman Updike]

Cuz this is what's going from our liver out to our cells floating around in bloodstream. And it's small and it is sticky, so it can get stuck in places in our bloodstream, but it's also what our cells need to take it up and use it. And then HDL is what's going from our cells back to our liver to be recycled.

[Erin Welsh]

Okay, what's the relationship between. Maybe this is jumping ahead, like the relationship between VLDL and ldl. What decides how much your liver is making? If high LDL is, how does that. What's that feedback cycle like?

[Erin Allman Updike]

Oh, this is a really, really good question, Aaron. The balance between how much of the different types of cholesterol packages that we have, vldl, ldl, hdl, whatever it is. It depends on a lot of different things. It depends on how much your liver is making. And some of that is just genetic.

[Audiobook Narrator/Host (possibly Ray Porter or Kal Penn)]

Yeah.

[Erin Allman Updike]

Some of that might have to do with your dietary factors. We know that, like diets that are high in fat, especially saturated fat, increase the total amount of all these types of cholesterol in Your bloodstream, all these different cholesterol packages. We don't know why, though. It also is going to depend on how good your cells are at taking this cholesterol out of your bloodstream. And one of the main things that determines that is how many, what are called LDL receptors you have on your cells. These are like Velcro mitts that grab on to those LDL packages of cholesterol really efficiently and pull them into the cells so that those cells can use them. But if you don't have as many LDL receptors or your LDL receptors are not as functional as someone else's, or they just get saturated because you end up with so much of that LDL cholesterol package floating, all your receptors are full, then you're going to have more of that LDL cholesterol in your body. And what determines how much HDL cholesterol you have is even more unknown because there's definitely like a big genetic factor there. But we don't know, like, why is it that some people's cells are exporting more HDL and others aren't?

[Erin Welsh]

And the VLDL LDL is just sort of like, that's just a natural progression.

[Erin Allman Updike]

It's a progression. Yeah. And, and again, it, it, it is going to vary person to person, like how quickly that VLD into LDL within your bloodstream while it's like bumping around. But it's all very like, person dependent. There's not like a lot of specificness.

[Erin Welsh]

So it's so tricky because. Yeah, there are so many different drivers of ldl.

[Erin Allman Updike]

Right.

[Erin Welsh]

Like why? Why? Okay, this is getting in a little bit to the evolution question of this, but, like, why would it be more beneficial to have more LDL receptors or fewer receptors? Why would it be better to stor cholesterol rather than utilize it?

[Erin Allman Updike]

Such great questions. I don't have answers.

[Erin Welsh]

Okay. I had a feeling you were gonna say that.

[Erin Allman Updike]

You know, I never do. But no, those are, those are all really good questions because that is really the, the determinant of whether cholesterol is going to become a problem.

[Tori (Personal Story Speaker)]

Yeah.

[Erin Allman Updike]

Is if it is building up in the wrong places or at the wrong times. And there are actually a whole bunch of diseases that I'm not going to get into any detail on today that are where cholesterol is building up not outside of our cells, not in our bloodstream, but actually inside of our cells. So you can get buildup of fats and, and cholesterol after that cholesterol has been taken up into our cells. If you can't export it.

[Tori (Personal Story Speaker)]

Right.

[Erin Allman Updike]

So, for example, there's a genetic disorder called Niemann Pick disease.

[Erin Welsh]

Okay.

[Erin Allman Updike]

And this is where you have a defective, basically, exporter.

[Tori (Personal Story Speaker)]

Right.

[Erin Allman Updike]

Molecule.

[Jacob Goldstein]

And so you would.

[Erin Welsh]

You would have really low HDL levels,

[Erin Allman Updike]

low HDL levels, and just low cholesterol levels overall, because you're still taking up cholesterol from your bloodstream, but then you can't get rid of it, and now your cells are too full of cholesterol.

[Hulu Series Promoter]

Right.

[Erin Allman Updike]

So that's going to be really detrimental. There are other ones as well, and I. I'm not going to get into deep detail, because the way that we to worry about the buildup of cholesterol for most people is when it builds up in our bloodstream, because that is when we see increased risk of a number of different diseases, but especially atherosclerosis, which is the fancy name for when cholesterol builds up in your blood vessels.

[Erin Welsh]

Okay, so cholesterol, meaning these packages, These LDL packages, specifically?

[Erin Allman Updike]

Well, yes. So here's what happens when you have high levels of these LDL packages, or not just LDL packages, but other, like vldl, like other cholesterol packages that are not hdl.

[Tori (Personal Story Speaker)]

Okay.

[Bank of America Advertiser]

Okay.

[Erin Allman Updike]

Non HDL cholesterol. If that's high levels in your bloodstream, then sometimes. Because many of those particles, especially LDL packages, are small and sticky.

[Tori (Personal Story Speaker)]

Yeah.

[Erin Allman Updike]

In our blood vessels, especially maybe at, say, bifurcations, like somewhere where your blood vessels split or a curvature or a place where you got damaged for some reason or another. Those molecules can get stuck along the walls of our blood vessels, and they get just underneath the first layer of cells into the wall of our blood vessel. And once they are there, those packages kind of disintegrate. And then you do have just free cholesterol molecules in the wall of our blood vessel. And our immune system is like, whoa, dude, you're not supposed to be here. You're only supposed to be inside of cells or attached to your little protein package. What the heck are you doing here? So our immune system triggers a huge inflammatory response, and then that cycle basically can kind of continue. More cholesterol gets stuck because there's inflamma in the wall of your blood vessel that triggers more inflammatory markers to come in. And then over time, you get this buildup of actual free cholesterol, not just these packages, but, like cholesterol floating underneath the wall of your blood vessel.

[Erin Welsh]

Okay.

[Erin Allman Updike]

And then as these plaques build up and our body is trying to respond to it, eventually we build this kind of fibrous cap over it. Our smooth muscle cells build a cap, and eventually they calcify. And that's all our body's response to try and stop this thing that's in the walls of our blood vessels from taking over, essentially.

[Erin Welsh]

Okay, so it's essentially a numbers game in that, you know, we. We can throw things like the LDL receptors in there. We can throw. But ultimately it comes down to how much LDL is in your bloodstream that is not being taken up by cells for whatever reason. And that just associated with more of these little clogs, these little sort of sticking to the walls of your arteries, and then that cholesterol leaking out into the actual lining, causing inflammation and an immune response, which then leads to hardening and plaques, et cetera, and problems down the line.

[Erin Allman Updike]

Exactly.

[Erin Welsh]

Or immediately.

[Erin Allman Updike]

Yeah, or immediately. Yeah. So those problems could be that the plaque gets so big that it actually blocks the vessel entirely, or it could be that the plaque gets big and then becomes unstable and a chunk of it breaks off, travels farther down, and blocks smaller arteries.

[Tori (Personal Story Speaker)]

Okay. Okay.

[Erin Allman Updike]

That's cholesterol and how it causes atherosclerosis. That's as short as I could make it.

[Erin Welsh]

Aaron, tell me about the relationship between LDL and things like age, things like diet. I know you mentioned saturated fats, but, like. And you said we don't know the mechanism. And then also some hard numbers here. Like, what levels are we talking about? And what is important to consider? Like, what is that if you have high ldl? Is that a snapshot in time? How long has it been high?

[Erin Allman Updike]

Oh, these are really fun questions. Um, so, yeah, in general, your total amount of cholesterol, and when we're measuring your total cholesterol, we're measuring all these different types of packages. Right. We're measuring the HDL packages, We're measuring the LDL packages, We're measuring all the packages. It is going to go up as we get older.

[Narrator/Announcer]

Why?

[Erin Allman Updike]

I don't know.

[Erin Welsh]

Okay, okay.

[Erin Allman Updike]

Are. Is it because our LDL receptors that are taking this up are getting less efficient or not being recycled as easily? I don't have a perfect answer for you, but cholesterol does go up as we get older. So that is one of the biggest risk factors for atherosclerosis in general is just age, and we can't do anything about that. You also asked about diet and other things that are going to influence it. Diet can have. And. And not just diet. Also, like, physical activity levels and what types of especially fats. So saturated fat vs unsaturated fat vs dietary cholesterol vs how many carbohydrates you're getting. All of that is going to affect your body's cholesterol levels and all the.

[Narrator/Announcer]

The.

[Erin Allman Updike]

The different, like, ratios of these different packages that we have. And we don't fully understand the exact mechanisms of how this happens, but what we do know is that diets that are higher in saturated fats tend to increase both your total amount of cholesterol and specifically your LDL cholesterol levels.

[Narrator/Announcer]

Okay.

[Erin Allman Updike]

But not your HDL cholesterol levels.

[Erin Welsh]

Your body maintains a fairly consistent ability to produce hdl, and so HDL is independent of LDL levels.

[Erin Allman Updike]

Yeah.

[Tori (Personal Story Speaker)]

Okay.

[Erin Allman Updike]

Yeah. They're not directly connected. Okay. There are things that you can do that will sort of shift their proportions. Right. Increasing physical activity is actually one of those that ends up increasing the amount of HDL and lowering the amount of ldl. But there are lots of other things that might just affect one versus the other. HDL is one of the harder ones because it's just really. We don't fully understand, like, how do we. We know that having higher levels of HDL is protective against heart disease.

[Erin Welsh]

Right.

[Erin Allman Updike]

But we don't know why.

[Erin Welsh]

Exactly.

[Erin Allman Updike]

We don't know exactly what levels it's at, and we don't really have a lot to. To do to try and increase somebody's hdl, for example.

[Erin Welsh]

Okay.

[Erin Allman Updike]

Isn't that interesting?

[Erin Welsh]

And so go ahead.

[Erin Allman Updike]

And you asked about hard numbers. Yeah.

[Tori (Personal Story Speaker)]

Right.

[Erin Welsh]

Yes, yes, yes.

[Erin Allman Updike]

Now, these are going to depend a little bit on which guidelines that you're looking at and things like that. But, like, right now, the general consensus is that, quote, unquote, ideal levels of LDL cholesterol would be less than 100 milligrams per deciliter in your blood.

[Tori (Personal Story Speaker)]

Okay.

[Erin Allman Updike]

Does that mean that if you have more than 100, you're going to have plaque buildup and you're going to have a high risk of heart attack? No, absolutely not. But we know that levels above a hundred are associated with higher risk than levels below a hundred. And we know that it's not quite like a linear relationship, but it is definitely an increasing risk with increasing LDL levels above 100.

[Erin Welsh]

Yes.

[Tori (Personal Story Speaker)]

Right. Okay.

[Erin Allman Updike]

Okay. So especially as those levels get to be above 160 or 190 milligrams per deciliter, then we are looking at that very. That that is considered a very high level of LDL in the bloodstream.

[Tori (Personal Story Speaker)]

Okay.

[Erin Allman Updike]

And total cholesterol, again, it's going to vary usually under 200 or even under 160 would be considered ideal total cholesterol. And that's going to be, again, a measure of your LDLs, your HDLs, and all the other types of lipoprotein cholesterol packages.

[Tori (Personal Story Speaker)]

Okay.

[Erin Allman Updike]

Okay.

[Erin Welsh]

And so when people talk about lifestyle modifications for managing cholesterol levels, is that mostly geared towards decreasing LDL with the kind of beneficial side effect of also hopefully increasing hdl? If it's something like exercise or certain types of food that have an impact

[Erin Allman Updike]

on both, that's exactly what it is.

[Tori (Personal Story Speaker)]

Yes.

[Erin Allman Updike]

Yeah. It's all about dietary intervention. So decreasing saturated fats, increasing whole grains and plant based proteins that have higher amounts of unsaturated fats, and then increasing physical activity.

[Tori (Personal Story Speaker)]

Okay.

[Erin Allman Updike]

Now, atherosclerosis or heart disease. Cardiovascular disease, which are not all exactly the same thing, but I'm using them interchangeably. That is not the only thing that's associated with high levels of cholesterol or high levels of LDL cholesterol. Right. There are a lot of other things that are associated. And even when we hear the term cardiovascular, you might think that's only your heart. And yes, I'm talking about heart attack, I'm talking about heart disease, but I'm also talking about stroke. I'm also talking about chronic, chronic kidney disease, peripheral artery disease, and there's a whole range of other diseases that the more that we look for associations between high levels of LDL and other diseases, we find them liver disease. There's also strong associations between certain types of lipoproteins and an increased risk of Alzheimer's disease. And even though that's only like a strong association with one type of this, like, lipoprotein cholesterol package, it does look like lowering total amounts of LDL cholesterol can also lower the risk of Alzheimer's disease. Right. So there are these other associations. There's some thought that there's associations with cancer, and we just don't know the exact mechanisms of all of this. But high levels of LDL cholesterol are associated with this increased inflammatory response and this buildup of cholesterol, especially in the arteries in your blood vessels. So that's cholesterol. Aaron, There's a lot more detail, but I gotta be done. You know,

[Erin Welsh]

it's a strange. It's a strange beast. Yeah, yeah, yeah.

[Erin Allman Updike]

So can you tell me? You know, I don't even know. I don't even know.

[Erin Welsh]

You don't even know. You know, we'll find somewhere to begin. I think I can. I can make that happen.

[Narrator/Announcer]

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Goodbye.

[Kal Penn]

Hey everyone, it's Kal Penn. I'm the host of Irsay, the Audible and iHeart Audiobook Club. This week on the podcast, I am sitting down with Ray Porter, the narrator of Andy Weir's audiobook project, Hail Mary, massive sci fi adventure about survival and science and what happens when you wake up alone, very far from Earth.

[Audiobook Narrator/Host (possibly Ray Porter or Kal Penn)]

I really had to make a decision because I caught myself getting that frog in my throat and starting to get teary as I'm narrating some of these sections and it's like, okay, yo, yo, yo, is this indulgent? And I really thought about it. I was like, no. At this point it would kind of be betraying the trust the author and the listener have in telling this story if I don't go through it. But there's places in this book that that deeply, emotionally affected me and I left it on the mic. That's great because it served the story. People will say like, oh my God, I cried at the end. It's like, yeah, dude, me too.

[Kal Penn]

Listen to Irsay, the Audible and iHeart audiobook club on the iHeartradio app or wherever you get your podcasts.

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[Erin Welsh]

Cholesterol is vital. It is an essential part of all animal life. Without cholesterol, we wouldn't survive. Yet these crucial functions have been overshadowed by its role in the development of cardiovascular disease. You could say that cholesterol is the Bill Buckner of cell biology.

[Erin Allman Updike]

Bill Buckner.

[Erin Welsh]

Do you know who that is?

[Erin Allman Updike]

Why do I know that name? I'm so embarrassed.

[Erin Welsh]

Okay, okay, okay.

[Erin Allman Updike]

This is, this is a basketball reference.

[Erin Welsh]

Baseball. This might be a stretch.

[Tori (Personal Story Speaker)]

Yeah, okay, give it to me.

[Kal Penn]

But once I.

[Erin Welsh]

Once I landed on it, I was like, I can't let this go. I'm gonna force this analogy.

[Erin Allman Updike]

Okay, so Bill Buckner.

[Erin Welsh]

Bill Buckner was a major league baseball player. Really a well rounded player. Over 2, 700 hits in over his career, which spanned over 21 seasons, which is huge.

[Narrator/Announcer]

Really.

[Erin Welsh]

It was someone that you wanted on your team.

[Erin Allman Updike]

Okay, great player.

[Erin Welsh]

But in the 1986 World Series, while playing first base for the Red Sox, it was the bottom of the 10th inning and in Game 6, and he missed a ground ball. It went right through his legs.

[Bank of America Advertiser]

Oof.

[Erin Welsh]

Brutal, right?

[Erin Allman Updike]

Brutal.

[Erin Welsh]

The error clinched the game for the Mets and they went on to win the next game, making them World Series champs. And this is like Boston, right? So like Boston sports fans are known to be incredibly forgiving and understanding.

[Erin Allman Updike]

They will never forget.

[Erin Welsh]

Yeah, no, I think, I think after the Red Sox won In the 2000s, there was like, you know, okay, we forgive you, Bill Buckner type of a thing. But it only took almost 20 years.

[Erin Allman Updike]

I have to know, Aaron, did you like, already know this about Bill Buckner? How did you.

[Erin Welsh]

I have felt so. Compassion. Such compassion for Bill Buckner. I think I saw it on some sports special when I was like in high school or something, and I was just like, I was heartbroken because he was so reviled after this happened. And it was one mistake, first of all, I mean, I could go into this. It was also like the Pitchers had already blown the lead. It was game six, so they still had had one more game that they could have won. But somehow all of this came down to Bill Buckner.

[Erin Allman Updike]

You need a guy to.

[Erin Welsh]

Yeah, he was the scapegoat for sure, but that, so that, that missed ball, the, the Buckner play, it overshadowed his otherwise really impressive career and it's mostly what he's known for. So Bill Buckner, cholesterol, same thing, same thing. Both, you know, admirable, should be appreciated for more than. They are well rounded, but they're overshadowed by this bad reputation. The only difference between the two that I could discern is that Bill Buckner is undeserving of the hate that he got, whereas cholesterol has earned its bad reputation, at least in certain contexts.

[Erin Allman Updike]

I, I love this. This is a. I will never forget.

[Erin Welsh]

Get this analogy. I'm so glad cholesterol and Bill Buckner. I don't think it's going to help anyone studying for a test, but hopefully it'll bring more appreciation for Bill Buckner. Okay, so. But today what I want to do is tell you how cholesterol earned this bad reputation. Our story begins around two and a half billion years ago with the Great oxygenation event.

[Erin Allman Updike]

Oh, that's not the first time that we've gotten to start this podcast this way. And I just love it.

[Erin Welsh]

It's. I just, I'm like, man, I really. We should just do an episode on that. I think it was our hemochromatosis episode when I talked about it and the importance of iron. But then something.

[Erin Allman Updike]

You talked about it more recently.

[Erin Welsh]

Yeah, yeah.

[Erin Allman Updike]

Dunno, dunno.

[Erin Welsh]

But what happened during the Great oxygenation event? There was a sharp, sudden rise.

[Erin Allman Updike]

Boogers. Was it boogers?

[Erin Welsh]

I think it was mucus.

[Erin Allman Updike]

It might have been.

[Erin Welsh]

That sounds right. Yeah.

[Erin Allman Updike]

I don't know. Sorry.

[Erin Welsh]

Whatever. However it happened. But there was a sharp, sudden rise in oxygen in the atmosphere that was caused by photosynthesizing cyanobacteria. And it had an enormous impact on life on this planet. Although we air breathers don't think of oxygen as harmful, it's actually quite toxic if you're not used to it, which at the time of the event described most of the anaerobes that were living on Earth. And so in respons to the accumulating oxygen, many organisms died out like it was probably one of the greatest extinction events in our planet's history. But other organisms evolved mechanisms that protected them against oxidative damage, or they developed strategies to take advantage of this molecule. This New molecule like for instance, aerobic respiration. Cholesterol synthesis, which requires oxygen, evolved after the great oxygenation event and it dramatically changed things. So you touched on this a bit. But in those early eukaryotes, cholesterol was incorporated into cell membranes which made for more stable and less permeable barriers. It protected them from oxidative stress. It allowed them to signal across cells within cells, and it just kind of helped to organize things which ultimately allowed for greater complexity, even multicellularity. Because then you're having like, oh, here's a little organell can have, here's a little whatever. We're not doing open floor concept anymore. We are walling off, walling ourselves off, 100% off. So now establishing that, so now fast forwarding to humans. By the time that our species came onto the scene, cholesterol synthesis had been around for billions of years and the uses of cholesterol had expanded. It became a precursor for hormones involved in stress reproduction, metabolism. It was essential for staying warm as temperatures dropped and helped to provide enough energy for foraging. It was involved a lot in like energy balance. And we weren't just making it ourselves, we were also getting it from our diet, which helped to free up energy that could be used for cognitive processing and social behavior. Being able to hold on to cholesterol that we got in our diets was really beneficial, particularly because food, food could become scarce. And so in some populations, living in certain environments and under certain food availabilities, traits emerged that altered the ways that our bodies dealt with cholesterol. So for instance, it's thought that like, being able to utilize fats rapidly and efficiently would have been really helpful in cold environments when you needed to keep yourself warm and have enough energy for foraging. And so there might have been a particular pattern of cholesterol regulation that emerged in the living under these conditions.

[Erin Allman Updike]

Interesting.

[Hulu Series Promoter]

Right.

[Erin Welsh]

And so it's, it's sort of thought that like the way today that we regulate cholesterol would have been very helpful in the past, but in today's context, it's not really serving us well. We're not faced with these same challenges most of the time.

[Erin Allman Updike]

Well, and we just also have exposure to much higher levels of dietary fats and things that we would not have had exposure to thousands, hundreds of thousands of years ago.

[Erin Welsh]

Exactly, yeah, yeah. And so it's again sort of like this context specific, something that evolved that was really beneficial under one context in modern times maybe isn't as much, you know, much of the world lives a sedentary lifestyle and Consumes a diet rich in animal fats, saturated fats, and sugars, where either these types of foods are the ones that are the most readily available. And so, given that the most damaging impacts of high cholesterol tend to happen later in our life, things like heart attack and stroke, it's not really surprising that high cholesterol seems to be a problem for so many of us. Right. It's just this sort of constellation of different factors going on.

[Tori (Personal Story Speaker)]

Right.

[Erin Welsh]

But again, our relationship with cholesterol, you can't really paint it with a broad brush. It's super complicated, Both at a population level as well as an individual level. Context really does matter with cholesterol. And this rich inner life of cholesterol is what makes it so challenging to understand and to communicate its health impacts. Like, as important as cholesterol is in maintaining healthy physiology, it's also responsible for some major issues. And scientists have suspected this darker side of cholesterol for over a century.

[Audiobook Narrator/Host (possibly Ray Porter or Kal Penn)]

Wow.

[Erin Welsh]

Yeah. So since its discovery in the late 1700s and its naming in 1815. Cholesterol. Yeah. Quite a long time.

[Erin Allman Updike]

Yeah, yeah.

[Erin Welsh]

Cholesterol has inspired a great deal of fascination, and over a dozen scientists have been awarded a Nobel prize for their research on cholesterol.

[Narrator/Announcer]

Wow.

[Erin Welsh]

Yeah.

[Erin Allman Updike]

Just for cholesterol.

[Erin Welsh]

Gold mine. Really is. Yeah. In case you were curious, cholesterol comes from cholesterine, which was the name given to it in 1815 by Michel Chevreul, who had isolated the stuff from human gallstones. So C H O L E is bile and stereo. Solid.

[Erin Allman Updike]

Solid bile. Okay, interesting.

[Erin Welsh]

So when did people start to suspect cholesterol's role in atherosclerosis? The first clue that we have comes from 1910 with a paper by German chemist A. Windhouse reporting that his patients with atherosclerosis in autopsies, he found that their aortas were just chock full of cholesterol. Like, much more so than his patients who did not have the disease. The second clue arrives a few Years later, in 1913, when Russian experimental pathologist N.N. anichkao showed that when he fed rabbits basically pure cholesterol dissolved in sunflower oil, they quickly developed lesions in their blood vessels that looked a whole lot like human atherosclerosis. The rabbits who were fed on a normal diet did not develop those same lesions. Curious.

[Tori (Personal Story Speaker)]

Very curious.

[Erin Welsh]

And he was inspired to do this not because of windows paper, but because of other previous work investigating whether too much protein was toxic and caused premature ag.

[Erin Allman Updike]

Interesting.

[Erin Welsh]

Yeah. Which was kind of the. The idea at the time. And so there were these studies where rabbits were fed on a super protein rich diet and the rabbits developed what looked like human atherosclerosis. And so Anichka wanted to know what it was like, was it the protein? What is it about the protein or that diet specifically that caused the lesions? And so he narrowed it down. Down to cholesterol.

[Erin Allman Updike]

Yeah, fascinating.

[Erin Welsh]

Yeah. And so on the surface, Anichka's results showing that a diet high in cholesterol led to atherosclerosis, like lesions. That's some pretty compelling stuff to our modern eyes.

[Jacob Goldstein]

Yeah.

[Erin Welsh]

In reality, it did not resonate with the scientific community of the time.

[Erin Allman Updike]

It never does, does it, Erin?

[Erin Welsh]

Never does. That's okay. You know, like there were things, three main reasons for this hesitance.

[Tori (Personal Story Speaker)]

Okay.

[Erin Welsh]

So the first was that when other people tried to replicate his results in different animals. No dice. Wasn't happening.

[Tori (Personal Story Speaker)]

Okay.

[Erin Welsh]

Even when a. Nichkow himself tried with a dog, he could not produce the lesions. And so he reasoned that it might be because dogs, as omnivores, are more accustomed to eating cholesterol rich diets and so have evolved to excrete or convert excess cholesterol.

[Erin Allman Updike]

Oh, interesting.

[Erin Welsh]

It turned out to be right about that, which is cool. Rabbits, being herbivores, don't have that same cholesterol.

[Narrator/Announcer]

Right.

[Erin Allman Updike]

They're not usually eating cholesterol, so they're not equipped to manage it.

[Erin Welsh]

Yeah. But I don't think other people made this connection. And so they were like, just. I think it's just something about these rabbits because I think they also couldn't do it in other animals like rats, maybe. Anyway.

[Tori (Personal Story Speaker)]

Okay.

[Erin Welsh]

What they were missing also was that this was a two stage process. You had to have a high cholesterol diet followed by a corresponding rise in blood cholesterol levels to get atherosclerosis. If you didn't have that second step, if your diet was super high in cholesterol, but you didn't actually have high circulating blood cholesterol, then you. Atherosclerosis probably wasn't going to develop because you were lacking the little. The ability to make those plaques.

[Erin Allman Updike]

You ate it, but then it didn't get stuck in your blood. Didn't you get stuck?

[Tori (Personal Story Speaker)]

Stuck, Right.

[Erin Allman Updike]

And never made it there for one reason or another.

[Erin Welsh]

Somehow excreted or processed in a different way.

[Erin Allman Updike]

Never absorbed it. Whatever, Whatever. Just really grody poops.

[Erin Welsh]

Just. Yeah, Real, real rough. Real rough. But the second reason that his results were met with skepticism was the blood cholesterol levels that he was Inducing in these rabbits were staggering. It was like 500 to 1,000 milligrams per deciliter and above of.

[Erin Allman Updike]

Of total cholesterol.

[Erin Welsh]

Total cholesterol? Yeah. Which is like, way higher than it. Than it gets for most humans.

[Erin Allman Updike]

Yeah. If I saw that, I would be. When I get to the three hundreds, I'm like, we need to do something. Thank you.

[Erin Welsh]

Oh, just wait till later. I don't know if it can't, but.

[Tori (Personal Story Speaker)]

But.

[Erin Welsh]

So it was kind of like, well, yeah, enough of anything is deadly. But, like, that's just not realistic. We're not. This is not what we're seeing. Later, though, he showed that even small rises. So not 500 to 1000 range, but small rises still led to atherosclerosis, like lesions in these rabbits. It just took longer to develop than the couple of weeks or whatever it was. And then one last thing. The third thing that held him back was the prevailing view of atherosclerosis. At the time when his work was being published, atherosclerosis was seen as an inevitable part of the aging.

[Erin Allman Updike]

Interesting.

[Erin Welsh]

Something that took decades to develop. And so how on earth could these rabbits showing these atherosclerotic lesions within months or weeks of eating lots of cholesterol? How could that be a reasonable model for human disease? It just didn't seem plausible.

[Erin Allman Updike]

Doesn't make sense.

[Tori (Personal Story Speaker)]

Yep.

[Erin Welsh]

Interesting that skeptical sentiment followed Anichka for decades as the senescence hypothesis of atherosclerosis proved particularly stubborn to dislodge. For his part, Anichka pursued this line of research for 50 years. Like, he was, like, singularly focused on, like, I want to understand cholesterol and what's going on here till the end of his career. And I. I just wrote this little comment here. I wonder, too, whether global politics came into play, because there's, like, cold war stuff. He was friends with Stalin, apparently. And so I'm wondering if there was just sort of like, well, we're going to distrust you.

[Tori (Personal Story Speaker)]

Right.

[Erin Allman Updike]

You're not a person that we want to hear from.

[Erin Welsh]

Yeah, okay.

[Tori (Personal Story Speaker)]

Yeah.

[Erin Welsh]

I don't know. I didn't see that anywhere. That was just my own little speculation. But in any case, the next phase of the cholesterol atherosclerosis story brings us to UC Berkeley in the mid 20th century.

[Erin Allman Updike]

Oh, wow. A long time later.

[Jacob Goldstein]

Yeah.

[Tori (Personal Story Speaker)]

Yeah.

[Erin Welsh]

About 40. 40 years or so. 50 years.

[Erin Allman Updike]

Okay.

[Erin Welsh]

Yeah. So there. Young physician science, John Goffman found himself drawn to cardiovascular disease, in particular the relationship between diet, blood, cholesterol, and atherosclerosis and he had come across Anichka's work, but rather than dismissing it like so many other people, he suspected that there might be something to the cholesterol atherosclerosis link. God, it's so hard to say that over and over again. But to get at the heart of that link, Pun intended. I literally wrote pun intended here he. Nothing better than a planned joke. But he was like, well, I have to better understand the dynamics of cholesterol in the blood. Because by this point in time, researchers had recognized that there were these compounds called lipoproteins that circulated in the blood. They carried cholesterol, and they came in different forms. So he was like, there might be. We can't just say cholesterol. We have to be more detailed than that to understand what's going on.

[Erin Allman Updike]

Which cholesterol package are we talking about?

[Erin Welsh]

Yeah, exactly. And so people had recognized different lipoproteins, but they didn't know what they did and how their concentrations affected health.

[Erin Allman Updike]

Interesting.

[Erin Welsh]

Unclear. Goffman was really the first to clarify their role, and he did this through a complicated and sophisticated technique. The long and the short of it is that he was able to take a sample and reliably sort and measure the different types of lipoproteins in the blood. And when he applied this technique to the question that interested him the most, what caused atherosclerosis? He found that not all lipoproteins had the same impact. And he proposed that we shouldn't be looking at total cholesterol. That's an incomplete picture. That's too broad of a picture, really. You need to give different weight to the different lipoproteins in predicting the risk of cardiovascular disease. So in other words, he came up with the atherogenic index. He was like, we need to figure this out and have these specific numbers. And he applied this index to a small sample of patients, and he showed that there was a strong association between certain ratios of lipoproteins and the risk of heart attack. As a fun little aside here, his wife, Dr. Helen Goffman, published what was probably the first Heart healthy cookbook in 1951. I think, because of this research was like, wow, don't eat saturated fats, basically. Goffman's research, though, really transformed the field. He bears the title the father of clinical lipidology.

[Bank of America Advertiser]

Wow.

[Erin Welsh]

I know.

[Erin Allman Updike]

Gotta love it. Gotta love it when we get a father.

[Erin Welsh]

Yeah, we have. We have another father in the next episode. The father of statins. Yeah. But his central hypothesis linking certain cholesterol carrying lipoproteins with heart disease. Once again, it met with resistance. Understandably so, to a degree. So first of all, he didn't have a mechanistic explanation as to why this would cause disease. That would have to wait for a few decades. And secondly, his sample sizes were fairly small. They weren't prospective, meaning you couldn't draw firm conclusions about causality, like which came first? Was it cholesterol or heart disease? Did you have heart disease and that is what caused your high cholesterol?

[Tori (Personal Story Speaker)]

Right.

[Erin Welsh]

So doubt lingered and things were getting heated. The quote unquote cholesterol wars that began in the 1950s reached new heights in the 1970s. Oh, yeah, cholesterol wars. Decades long.

[Erin Allman Updike]

More than salt wars, honestly.

[Erin Welsh]

Very. Like I would say, more contentious than salt war. Course interesting in my reading of it.

[Erin Allman Updike]

Yeah, tell me all about it, Aaron.

[Erin Welsh]

Yeah, okay. So while some physicians and scientists had grown convinced that high blood cholesterol caused heart disease, others argued that it was the other way around. And they took issue with high. Where do you draw the line? What does high mean? Okay, yeah, yeah, okay. So in medicine, one common cutoff for deciding this is 95%. So, for example, if 95% of people have cholesterol less than a particular value, anything above that is considered abnormal. The problem with this is that you're assuming any cholesterol value less than 95% is normal. Non pathogenic.

[Tori (Personal Story Speaker)]

Right.

[Erin Welsh]

But average doesn't always equate to normal. In the 1940s, 95% of the US population had blood cholesterol below 2 8.

[Erin Allman Updike]

280.

[Erin Welsh]

280. We know today that, yeah, that heart attacks occur with levels much lower than that. In fact, most occur between 200 and 280. But since that was the standard cutoff at the time, doctors didn't consider a cholesterol level of, say, 250 to be worrisome because it was considered normal.

[Erin Allman Updike]

And this is total cholesterol. There's still total cholesterol?

[Tori (Personal Story Speaker)]

Yes. Okay.

[Erin Welsh]

It took several strong epidemiological studies to turn that thinking around and say, like, actually, average doesn't always equate to. To normal. Healthy.

[Tori (Personal Story Speaker)]

Right.

[Erin Welsh]

So one of these studies I actually touched on in a previous episode, our Dietary Guidelines episode, Ancel Keys Seven Countries Study. So, in the 1950s, as a refresher, Keys and his colleagues conducted a wide ranging study across seven countries, examining relationships between diet, blood cholesterol and mortality due to coronary heart disease. The results were striking. At one end of the spectrum, you had Japan with an Average blood cholesterol level of 160 and less than five fatal heart attacks per 1,000 men.

[Tori (Personal Story Speaker)]

Okay.

[Erin Welsh]

On the other end, you've got Finland with an average blood cholesterol of 260 and 70 fatal heart attacks per 1,000. Yeah. And other countries kind of followed the same trend, just like, fell right on along along that plot line with blood cholesterol and saturated fat consumption positively related to fatal heart attacks.

[Narrator/Announcer]

Yep.

[Erin Welsh]

Again, it was compelling stuff. But again, like many other studies, it showed correlation and it didn't prove causation. And so a lot of people remained unconvinced. The next study turned all but the most stubborn skeptics into believers.

[Tori (Personal Story Speaker)]

Okay.

[Erin Welsh]

In 1950, researchers enrolled 28,000 residents of Framingham, Massachusetts.

[Audiobook Narrator/Host (possibly Ray Porter or Kal Penn)]

Love it.

[Erin Allman Updike]

Framingham.

[Erin Welsh]

Framingham. The Framingham study is one of the most. It's one of the most long term and valuable and informative public health studies ever put together.

[Erin Allman Updike]

It's incredible.

[Erin Welsh]

It's incredible.

[Tori (Personal Story Speaker)]

Yeah.

[Erin Welsh]

They measured things like blood cholesterol, blood pressure, smoking, diabetes, and family history of disease. And they followed these residents for years. It is still ongoing, recording any disease events as they occurred, including in offspring.

[Erin Allman Updike]

Now including in offspring. They've enrolled offspring. Like, it is a huge deal type of study that's been ongoing for so

[Erin Welsh]

long, the amount of information we've gained. Really cool. Really?

[Hulu Series Promoter]

Yeah.

[Tori (Personal Story Speaker)]

Powerful.

[Erin Welsh]

Okay. But what this allowed them to do, what the study allowed them to do, was establish a sequence. High cholesterol preceded heart attack. And then they could also calculate risk. What is high cholesterol? How much does smoking combined with high cholesterol impact risk? Things like that. They could create these sort of calculations and say, what are the factors that increases your risk of heart attack or stroke?

[Narrator/Announcer]

Yeah. Where?

[Erin Welsh]

The seven country study showed the relationship between blood cholesterol and heart disease at a population level, The Framingham Heart study demonstrated it in the individual. So this person had high cholesterol, and then they experienced a heart attack. It was sort of that directional relationship.

[Tori (Personal Story Speaker)]

Right.

[Erin Welsh]

The link between high cholesterol and coronary heart disease could not be ignored.

[Kal Penn]

No.

[Tori (Personal Story Speaker)]

No.

[Erin Welsh]

Which, of course, didn't prevent people from doing so. The wars continued. Erin.

[Hulu Series Promoter]

Wow.

[Erin Welsh]

But it's increasingly those cholesterol doubters were becoming a tiny but vocal minority. Other studies, such as dietary intervention studies, helped to build the case against cholesterol. But there was still one important facet missing, and that was a mechanism. So since at least the late 1800s, physicians had noticed a condition that ran in some families where people developed large deposits of lipids under their Skin. Members of these families were very prone to develop severe cardiovascular disease at early ages, with some experiencing heart attacks in the first 10 years of life.

[Kal Penn]

Gosh.

[Erin Welsh]

And by the early 1970s, researchers had established that very high blood cholesterol was a key feature of this, hence the name familial hypercholesterolemia. But they weren't sure what caused it or its role in disease development particularly. They were like, okay, there's clearly a genetic link, but, like, what's the mechanism here? What is this, that mutation that leads to these high cholesterol levels?

[Erin Allman Updike]

Exactly. What is going on that is causing this person's cholesterol to be so high and then resulting in negative health outcomes like, what's. Why, why, why, why?

[Erin Welsh]

In 1973, the key to the puzzle was unlocked by two researchers, Michael Brown and Joseph Goldstein, who, over the course of their 50 year collaboration, would be compared to Rogers and Hammerstein, which is.

[Erin Allman Updike]

Yeah, Erin, can we work together for 50 years? Yes.

[Tori (Personal Story Speaker)]

Yes.

[Erin Welsh]

I was like, can that be us? I want that to be us.

[Kal Penn]

Please.

[Erin Welsh]

Thank you.

[Erin Allman Updike]

I don't think we'll ever create something as good as Rogers and Hammerstein, though. Let's be.

[Tori (Personal Story Speaker)]

Let's be real.

[Erin Welsh]

Or the LDL receptors.

[Brilliant Tutor Advertiser]

Goldstein.

[Erin Welsh]

Yeah, yeah. But Brown and Goldstein, they were fascinated by the mystery of familial hypercholesterolemia, and they wanted to figure out what caused such high levels of LDL in the blood in affected individuals. Because that was really one of the key features of this was high ldl. As they discovered. It wasn't that there was too much LDL being produced. It was that too little LDL was being taken up by the cells.

[Erin Allman Updike]

Ah, I love this so much, Darren.

[Erin Welsh]

So the cells of people with familial hypercholesterolemia lacked receptors that would allow them to scoop. Scoop up the LDL from the bloodstream. So they didn't have those little Velcro hands, right? They didn't have enough Velcro hands.

[Tori (Personal Story Speaker)]

Not enough Velcro hand.

[Erin Welsh]

And so LDL just kept piling up, piling up, circulating and circulating with nowhere to go. And over time, it just. Again, it's a numbers game. It's gonna lodge into the blood vessel walls, it's gonna cause a blockage, inflammation, plaques, et cetera, et cetera. Yeah. This discovery, Brown and Goldstein's discovery of the LDL receptor, it transformed the field.

[Narrator/Announcer]

Wow.

[Erin Welsh]

So much so that it earned them a Nobel Prize in 1985. Because not only did it explain why people with familial hypercholesterolemia develop Cardiovascular disease. It clarified how our cells regulate cholesterol, specifically ldl, and why disease happens when that regulation goes awry. So it was a major, major step forward in solidifying the cholesterol heart disease link. And it was opened these different pathways to treatment.

[Erin Allman Updike]

Ding, ding, ding.

[Erin Welsh]

Can we do something about this receptor?

[Erin Allman Updike]

For instance,

[Erin Welsh]

did it end the cholesterol wars? Not necessarily. It really didn't. The debate continued, but it had lost a lot of steam. The advent of cholesterol lowering drugs like statins changed the conversation by turning cardiovascular disease from a disease to manage into one to treat, treat, even prevent potentially. But as we'll see next week, their use has also been met with a hefty amount of skepticism. And so the cholesterol wars really continue through today.

[Erin Allman Updike]

It is so interesting, Aaron, how much like it is really hard, I think to find someone who doesn't at least agree that high levels of cholesterol put you at high risk for heart disease.

[Tori (Personal Story Speaker)]

Yeah.

[Erin Allman Updike]

And yet there still is so much like about what you do about it or what we shouldn't do about it or what your diet effect might be like. It's oh, I can't wait for next week.

[Erin Welsh]

Yeah. There's a lot more to cover next week when it comes to the story of statins and how the role that they have played in changing our approach to managing and preventing heart disease. Also, how the heck do statins work? Do you want to know the answers to these questions? I want to tell you that. Tune in next week.

[Erin Allman Updike]

Should we tell people if they want to just learn more about what we've already talked about?

[Erin Welsh]

Yes, absolutely we should. I have a lot of sources for this.

[Erin Allman Updike]

I bet you do, Erin.

[Erin Welsh]

I'm shouting out. So there was a. If you wanted to learn more about sort of cholesterol in oxygen and the great oxygenation event and why it plays a role. There's a paper called the Evolution of Cholesterol Rich Membrane as Oxygen Adaptation the Respiratory System as a Model by Zuniga, Hertz and Patel from 2019. I liked that one. And then there's an excellent series by Steinberg from 2004. It's a five part series called An Interpretive History of the Cholesterol Controversy. Controversy. I can't speak today, Erin. It's a five part series. Check it out. Good stuff.

[Erin Allman Updike]

You did a good job, I think.

[Erin Welsh]

Thanks.

[Erin Allman Updike]

I also had a number of papers for this episode. I think probably my three favorites that cover a lot of ground. One was from 2020 by Luo et al. From Nature Reviews Molecular Cell Biology it was called Mechanisms and Regulation of Cholesterol Homeostasis. So this is just like how our bodies are using cholesterol. There was another older one by Maxfield and Tabas from 2005 in nature called Role of Cholesterol and Lipid Organization in Disease. And Then one from 2019 by Holmes and Allah Corpella from Nature Reviews Cardiology, just titled what is LDL Cholesterol? So that was a good one too. But they have a bunch more and you can check them all out from like these ones from this episode, but also from all of our other episodes on our website. This podcast with Killy.under the episode Indeed.

[Erin Welsh]

Thank you again so much, Tori, for sharing your story with us. It means a lot.

[Erin Allman Updike]

It really does. Thank you.

[Erin Welsh]

Thank you also to Blood Mobile for providing the music for this episode and all of our episodes.

[Erin Allman Updike]

Thank you to Liana and Tom and Mark and Jessica and Christine. Everyone. Everyone. Exactly right.

[Hulu Series Promoter]

Yes.

[Erin Allman Updike]

We really appreciate everything that you do for us.

[Hulu Series Promoter]

We do.

[Erin Welsh]

Thank you to you listeners for listening, watchers, for watching. Anyone who subscribes, participates, does anything with this podcast, interacts in any way. We truly appreciate it.

[Erin Allman Updike]

We do. Thank you. And as always, a special shout out to our patrons for your support over on Patreon. It means so much to us, truly. Thank you, truly.

[Erin Welsh]

Thank you. Until next time, wash your hands, you filthy animals.

[Jacob Goldstein]

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[Kal Penn]

hey, everyone, it's Kel Penn. I'm inviting you to join the best sounding book club you've ever heard with my podcast, Hearsay, The Audible and iHeart Audiobook Club. Every episode, I nerd out with amazing guests and dive into the best new audiobooks available on Audible. It's the book club for your ears. Listen to Earsay, the Audible and iHeart Audio Radio Book Club on the iHeartradio app or wherever you get your podcasts.

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[Erin Allman Updike]

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[Erin Welsh]

All right, we're gonna need a plan here.

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[Audiobook Narrator/Host (possibly Ray Porter or Kal Penn)]

Oh, that's actually really simple.

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