Scientists ID gene that regulates ‘bad’ cholesterol in mice
BY TIEN-SHUN LEE
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
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
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
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.”