“Good” cholesterol can sometimes be bad, study finds

Rare exception to simplistic cholesterol rule found in genetic analysis.

Beth Mole – Mar 11, 2016 3:50 pm | 94

When it comes to cholesterol, it is possible to have too much of a good thing.

High-density lipoprotein (HDL), the molecular packages that scavenge excess amounts of cholesterol from around the body and ferry it to the liver where it gets broken down, has long been considered “good” cholesterol. That’s in contrast to the “bad” low-density lipoprotein (LDL) cholesterol packages that deliver the waxy substance throughout the body where it’s used for the production of cellular products, such as membranes and hormones. Too much LDL—or not enough HDL—and cholesterol can end up getting stockpiled along blood vessels, which hampers blood flow and leads to coronary heart disease.

Thus, heart disease prevention efforts have largely revolved around lowering LDL and raising HDL. However, clinical trials and animal experiments that raise HDL levels have produced mixed results. And in a new study, researchers find that having naturally high levels of HDL can actually be bad.

In an analysis of patients’ genetic and health data, researchers found that a specific mutation was linked to having exceptionally high levels of HDL—as much as three times the normal amount in healthy individuals. Those with the mutation surprisingly seemed to have a higher risk of heart disease, the researchers reported in Science. The finding suggests that the general rule that high levels of HDL are always good should be tossed.

“Our results are consistent with a growing theme in HDL biology that steady-state concentrations of HDL [cholesterol] are not causally protective against [heart disease] and that HDL function and cholesterol flux may be more important than absolute levels,” the authors wrote.

Tracking the molecular workings of cholesterol cycling in the body, the researchers found that the mutation likely stymies HDL’s processing in the liver. The mutation affected a gene called SCARB1, which codes for a protein involved in recognizing and gathering HDL in the junking process. In petri dish experiments, researchers found that without this protein, HDL became overloaded with cholesterol but had nowhere to go with it. Without that clearing step, cholesterol could still build up in blood vessels despite plenty of HDL floating around.

Looking back at the patient data, researchers reported that people with a SCARB1 mutation were around 80 percent more likely to have coronary heart disease than a control group. The mutation also appeared to be specific to people of Ashkenazi Jewish descent, the researchers reported. But with only a few hundred people with the mutation, the statistical power was low and needs to be backed up with more data.

Still, the data adds more evidence that simple measures of HDL aren’t a perfect metric for assessing health. “Eventually we may want to perform genetic testing in persons with high HDL to make sure they don’t have mutations—like this one—that raise HDL but don’t protect against, or may even increase, risk for heart disease,” wrote senior author Daniel Rader, of the University of Pennsylvania.

Science, 2015. DOI: 10.1126/science.aad3517 (About DOIs).