The 67-year-old woman had sky-high high-density lipoprotein (HDL), the form of cholesterol long seen as protective against heart disease, and yet her arteries were lined with plaque. Her paradoxical case has helped motivate a team of scientists to show how high HDL can sometimes be a signal not of heart health, but of the opposite: a cholesterol system unable to siphon the fatty particles from circulation.

In the last 10 years, HDL particles have confounded scientists. The normal role of these bundles of protein and fat is to ferry cholesterol from the rest of the body to the liver, which eliminates it from the body. More of something good should mean better health, and people who naturally have higher HDL levels are usually better off. But drugs that increase HDL cholesterol have flopped in clinical trials, and genes that help raise it don’t seem to track with less heart disease. “Nothing with HDL’s ever simple,” says Jay Heinecke, a biochemist at the University of Washington, Seattle, who has studied it for years.

In this week’s issue of Science, Daniel Rader, a geneticist and lipidologist at the University of Pennsylvania, and his colleagues suggest that the amount of HDL is less important than how efficiently it gets moved from arteries into the liver. Rader’s inspiration was a mouse model developed by Monty Krieger at the Massachusetts Institute of Technology in Cambridge about 20 years ago. The mouse’s developers had deleted a gene called SCARB1, resulting in animals with startlingly high HDL and, just as startlingly, severely clogged arteries. “Mice actually get heart attacks,” Heinecke says. That’s because the system for moving cholesterol out of the body is broken in these mice.

Normally, HDL particles gather cholesterol from immune cells that line the arteries, and then deposit their load in the liver so that the cycle can begin again. The protein made by the SCARB1 gene, known as SR-B1, helps make that deposit happen. Mice without SR-B1 have HDL particles swollen with cholesterol, which struggle to draw more of it away from the arterial wall.

Rader wondered whether the same thing might be happening in some people. He and his colleagues began by sequencing genes in 852 people with very high HDL and more than 1000 controls. They found one person—the 67-year-old woman—who had no functioning copies of the SCARB1 gene and had more plaque on her arteries than an average woman her age. Her HDL was 152 mg/dl, well above the average of about 62 mg/dl among women in her age group. Eighteen others had just one functional copy of SCARB1 instead of the usual two, and most of them also had high HDL. Detailed studies of nine people with SCARB1 mutations, including the woman, suggested that as in the mice, their abundant HDL failed to transport cholesterol effectively through the body.

Rader then reached out to colleagues who had collected DNA on hundreds of thousands of people for studies of lipids and heart disease. Among them, he found another 284 people who had only one functioning copy of SCARB1. (No one else was like that first woman, with both copies missing.) Most of these people also had higher than average HDL. These people were also about 80% more likely than controls to have coronary artery disease—about the same increase in risk seen with traditional risk factors like diabetes and hypertension.

“This is a key indication of what people have suspected from animal studies,” says Alan Tall, an HDL researcher at Columbia University. It appears that HDL is higher “because the flux is blocked,” not because HDL is excelling at keeping cholesterol out of the arteries.

Still, because Rader could find so few people without fully functioning SCARB-1, and because the potential effects of the mutations on heart health appeared fairly modest, the link between faulty HDL transport and cardiac troubles is still tenuous, he and others say. And HDL’s behavior in a petri dish doesn’t necessarily reflect what it’s doing inside the body, suggests Jan Albert Kuivenhoven, who studies the genetics of lipid metabolism at the University Medical Center Groningen in the Netherlands. “We have no good ways to do the tests with HDL that can really tell what’s happening” in a person, Kuivenhoven says.

HDL remains extraordinarily complex, Rader and Kuivenhoven say. It’s possible that HDL-raising drugs failed in clinical trials because of the type of HDL the drugs produced—doctors detected more large HDL particles than expected. Overall, however, there’s little question that high HDL still tracks with a healthier heart for most people—except, Rader says, when it doesn’t.

Ultimately, he says, we’d like to be able to say, “Your HDL is high because X, and that’s good thing,” and in someone else, “Your HDL is high because of Y, and that’s a bad thing.” Now, he and others want to nail down exactly what those factors might be—and, potentially, how to head them off.