Season 1 Episode 6: High Density Lipoprotein

For decades, HDL — the so-called “good cholesterol” — has been celebrated as the body’s knight in shining armor. Patients brag about their high HDL levels like it’s a shield against heart disease. But is HDL truly the hero we once thought? 

In this episode of LipidCurious, we’ll separate myth from science and uncover the real story of HDL: 

1.  Why is HDL called the “good cholesterol” — and is that nickname really fair?
2. What exactly is reverse cholesterol transport, and why does it matter? 
3. Why did drugs that raise HDL fail to improve cardiovascular outcomes? 

We’ll also explore clinical twists: how HDL can become dysfunctional in high-triglyceride states, and why extremely high HDL might not always be protective.

Bonus: The Visual Guide for this episode is waiting for you — click here. For the full collection of visuals across episodes, visit the Podcast page.

Download the Free LipidCurious Starter Kit here

Questions or feedback? Reach out at hello@lipidcurious.com 

Disclaimer: This podcast is for educational purposes only. It is NOT medical advice.

Transcript

SEASON 1, EPISODE 6: HIGH DENSITY LIPOPROTEIN

Hi everyone, Today we’re talking about one of the most beloved — and misunderstood — characters in lipidology: HDL, the so-called “good cholesterol.”

For decades, HDL has been celebrated as the knight in shining armor of cardiovascular disease prevention. Patients often brag about their high HDL numbers like they’re a ticket to immortality. But reputations can be misleading. Does HDL really deserve all that credit? Let’s find out.

Welcome to LipidCurious — the podcast dedicated to demystifying lipids for medical boards and real-world clinical practice.
I’m your host, Dr. Vishnu Priya Pulipati — a board-certified Endocrinologist and Lipidologist.

This is Season 1, Episode 6 — HDL & Reverse Cholesterol Transport.

Here’s what we’ll cover together:

• Why is HDL called the “good cholesterol” — and is that nickname really fair?
• What exactly is reverse cholesterol transport, and why does it matter?
• Why did drugs that raise HDL fail to improve cardiovascular outcomes?

You’ll find a bonus visual handout in the show notes, and if you want everything in one place — head to www.lipidcurious.com. There you’ll find the full visual set for Season 1 plus the free Starter Kit: a collection of practical clinical guides, cheat sheets, and quick references you can actually use in your clinical practice.

And as always — this podcast is for educational purposes only, not medical advice.

Alright, let’s dive in. 

Why is HDL called the “good cholesterol”?

HDL — High-Density Lipoprotein — is a small, dense, protein-rich particle. Its signature protein, ApoA-I, defines its structure and function. 

In the 1970s, researchers proposed HDL hypothesis which suggested that people with low HDL were more likely to develop heart diseases. Population studies, including the landmark Framingham study, have consistently linked higher HDL to lower risk cardiovascular risk. That simple observation earned HDL the nickname “the good cholesterol.”

The idea was intuitive. HDL appeared to be a cleanup crew, sweeping up excess cholesterol from artery walls and hauling it back to the liver for disposal. 

So, if HDL was protective, the logic was simple: let’s raise it. And so began decades of research and drug development aimed at boosting HDL cholesterol levels.

But here’s the twist: raising HDL cholesterol on paper didn’t consistently lower heart attacks or strokes. That was the first clue that HDL’s reputation as “good cholesterol” was an oversimplification.

Here’s the nuance: HDL-C — the lab number — tells us how much cholesterol is being carried inside HDL particles. It says nothing about whether those particles are functional. So a high HDL number doesn’t guarantee protection. 

What really matters is HDL function — its ability actually to remove cholesterol and deliver it back to the liver. And in certain conditions, like diabetes, kidney disease, or inflammation, HDL particles can even become dysfunctional or harmful. 

What is reverse cholesterol transport, and why does it matter?

Reverse cholesterol transport is HDL’s most important job. Think of it as the body’s cleanup system for cholesterol. 

Most cells can’t break cholesterol down once they’ve got it. So, when cholesterol starts piling up in the wrong places, like inside macrophages in artery walls, the body needs a way to get it out. That’s where HDL steps in.

I’ll walk you through the main steps here; the detailed enzymes and transporters are in the visual guide at lipidcurious.com.

Here’s the journey in plain terms:

Step 1: The liver and intestines secrete ApoA-I, an empty protein scaffold.

Step 2: ApoA-I interacts with transporters like ABCA1 on macrophages. These transporters load cholesterol onto it, forming nascent HDL particles. I like to picture these as flat pita breads starting to fill up.

Step 3: As the particle travels, the enzyme LCAT packages cholesterol into the core, reshaping the pita into a round, mature HDL sphere.

Step 4: From there, HDL has two ways back to the liver: 

• Direct delivery through the SR-B1 receptor. 
• Indirect delivery, where HDL swaps cargo with ApoB particles like VLDL or LDL through CETP. Those particles then return cholesterol to the liver via LDL receptors.

Final Step: Once in the liver, cholesterol can be turned into bile acids or secreted directly into bile — and eventually leaves the body through the intestines.

Why does this matter? Because without RCT, foam cells build up in arteries, plaques grow, and cardiovascular risk escalates.

Now, That’s the textbook version of how HDL does its job. But in real life, things are rarely that clean. So let me share a clinical wrinkle — one that shows up all the time in practice.

In the setting of high triglycerides, the story gets complicated. CETP starts trading cholesterol esters from HDL for triglycerides from VLDL and chylomicrons. HDL becomes triglyceride-rich and cholesterol-poor. Then lipoprotein lipase trims these overloaded HDL particles down, leaving them small, dense, and dysfunctional. And here’s the kicker: those small HDL particles don’t hang around. The kidney filters them out, ApoA-I gets broken down, and overall HDL levels drop. This pattern — high triglycerides, low HDL, and small dense LDL — is the hallmark of atherogenic dyslipidemia. 

Why drugs that raise HDL often fail

We’ve all heard it in clinic: “My HDL is 90, so I must be heart-attack proof!”

But here’s the catch — association is not causation. Low HDL is a marker of higher risk, but high HDL doesn’t guarantee protection. And clinical trials made that painfully clear.

Niacin was one of the first big bets. It raised HDL by 20–30%. But in large trials like AIM-HIGH and HPS2-THRIVE, adding niacin to statins didn’t reduce cardiovascular events. Worse, it caused more side effects.

CETP inhibitors looked even more promising. Torcetrapib raised HDL by more than 70%. But instead of preventing disease, it increased blood pressure, worsened outcomes, and raised mortality — leading to the trial’s termination. Other CETP inhibitors like dalcetrapib and evacetrapib also failed. Anacetrapib showed modest benefit, but most of that was from lowering LDL, not raising HDL.

So why the failure?

• Function matters, not concentration. Raising the number doesn’t guarantee effective reverse cholesterol transport.
• Mechanisms can misfire. Some drugs such as Torcetrapib produced larger but dysfunctional HDL particles, which is actually linked to increased CVD risk.
• Off-target effects. Torcetrapib raised blood pressure, wiping out potential benefits.
• The real villains are ApoB particles. LDL, VLDL, IDL — these are the true drivers of atherosclerosis. That’s why statins, PCSK9 inhibitors, and other ApoB-lowering therapies consistently reduce events, while HDL-raising drugs don’t.
• Extremely high HDL may not be good. In some studies, HDL above 90 or 100 mg/dL was linked to increased mortality, creating a U-shaped curve of risk. A paradoxically high HDL may be a marker for genetic or environmental factors affecting cardiovascular health. 

So the clinical lesson is clear: HDL is important, but the lab number is not the whole story. Our focus should remain on lowering ApoB-containing lipoproteins, improving metabolic health, and interpreting the entire lipid profile in context.

And the HDL story isn’t over. Research is ongoing into HDL function, subtypes, and therapies.

Did you know that in some infections and autoimmune diseases, HDL actually flips — from anti-inflammatory to pro-inflammatory? Instead of calming the fire, it adds fuel to it. That’s how complex this particle really is.

Take-home points

• HDL’s “good cholesterol” reputation comes from early observational studies, but that label oversimplifies a much more complex story.
• HDL’s true value lies in its function — reverse cholesterol transport — not in the cholesterol number reported on a lab panel.
• In practice, lowering ApoB-containing lipoproteins remains the proven path to reducing risk; HDL is important, but it’s not the main target.

Our journey with HDL is far from over. HDL remains fascinating and complex, but don’t be fooled by the number.

Thanks for tuning in to LipidCurious. If today’s episode was helpful, share it with a friend or colleague. I’d love to hear your suggestions, feedback, or just want to connect, you can always reach me at hello@lipidcurious.com. Be sure to subscribe or follow, so you don’t miss what’s next. And don’t forget — you can download the free Starter Kit and season 1 visual guide at www.lipidcurious.com

Until next time — stay curious, and stay confident.
Signing off, Dr. Pulipati.

Bonus: The Visual Guide for this episode is waiting for you — click here. For the full collection of visuals across episodes, visit the Podcast page.

Download the Free LipidCurious Starter Kit here

Questions or feedback? Reach out at hello@lipidcurious.com