Good riddance for bad cholesterol - May 14, 2004 - The Rockefeller University Scientist

Even cholesterol is bound by the basic laws of economics. When the inventory of fatty, artery-clogging molecules in your bloodstream is too high — that’s the case for 105 million Americans — the best options are to either reduce supply or increase demand.

Dietary changes, exercise and statin drugs are ways to lower the bloodstream’s supply of cholesterol. Now, Rockefeller researchers are pursuing another approach — getting rid of cholesterol in the bloodstream by increasing demand for it in the liver.

A gene recently identified in mice by Jan L. Breslow’s Laboratory of Biochemical Genetics and Metabolism suggests that increasing the number of LDL cholesterol receptors in the liver can help eliminate more LDL, the “bad” form of cholesterol that is a risk factor for heart attacks and strokes. LDL receptors snatch up LDL into liver cells, depleting the bloodstream’s inventory of it.

It was Kara Maxwell, a graduate student in Breslow’s lab, who first identified the LDL-regulating gene. Her initial experiment, which compared gene activity in mice that were fed normal diets to mice that were fed high-cholesterol diets, found that the previously unknown gene, now named Pcsk9, was expressed at a much lower level in the mice eating high-cholesterol food.

To find out what Pcsk9 does, Maxwell inserted the gene that codes for this protein into a virus that targets the liver and injected the virus into normal mice, where it made Pcsk9 protein inside liver cells. The blood vessels of the mice were quickly flooded with cholesterol; four days after injection, the animals’ LDL levels were five times the normal level, and their levels of total cholesterol in the bloodstream had doubled.

Maxwell suspected that the Pcsk9 protein was raising LDL levels by decreasing the number of LDL-snatching LDL receptors on the surface of liver cells. To test this hypothesis, she injected the Pcsk9-carrying virus into a strain of mice that do not have LDL receptors because of a genetic defect. Their cholesterol levels did not change — with no LDL receptors to eliminate, there was no room for further increase in LDL cholesterol.

Another experiment, in which Maxwell injected Pcsk9 into normal mice, confirmed that the protein reduced the number of LDL receptors in their livers.

“LDL receptors are the main way of getting LDL out of the blood,” says Maxwell. “Knowing that Pcsk9 modulates LDL receptors is critical to our understanding of how LDL levels are regulated.”

The results of the mice studies, published last month in Proceedings of the National Academy of Sciences, are highly relevant to humans because mutant forms of the Pcsk9 gene have been linked to people with one form of autosomal dominant hypercholesterolemia, a group of genetic disorders characterized by excessive levels of cholesterol in the bloodstream. (This finding, discovered last year by a group in France, did not identify the function of Pcsk9.)

“If the same mechanism Maxwell found in mice pertains to humans, and we could inhibit Pcsk9 with drugs, this should increase the number of LDL receptors on cells and in this way lower LDL levels in the blood. This might offer another therapeutic approach to the high blood cholesterol levels that are a major risk factor for heart disease,” says Breslow, the university’s Frederick Henry Leonhardt Professor and a former national president of the American Heart Association.

High levels of LDL cholesterol in the blood lead to heart attacks because the waxy LDL molecules build up inside the walls of arteries, causing damage to blood vessels and leading to clots that block the flow of blood to the heart muscle.

“The question is, is your cholesterol at the right level?” says Breslow.

“There are a huge number of people that fall into the category in which their LDL should be lowered. A lot can be done with diet and exercise but many people also need drugs.”

May 14, 2004