Cholesterol is a lipid that gets bad press because of its
association with cardiovascular disease. Scientists have long puzzled over cholesterol. It's biologically
necessary; it's observably harmful - and nobody knows what it's doing
where it's most abundant in cells: in the cell membrane.
Now, for the first time, chemists at the University of Illinois at
Chicago have used a path-breaking optical imaging technique to pinpoint
cholesterol's location and movement within the membrane. They made the
surprising finding that, in addition to its many other biological roles,
cholesterol is a signaling molecule that transmits messages across the
‘Treating cells with a statin dramatically lowered the level of cholesterol in the inner layer, leading to suppression of cell growth activity. This suggests a new way to treat cancer through pharmacological modulation of the cellular cholesterol level.’
The finding is reported in Nature Chemical Biology
Wonhwa Cho, professor of
chemistry at UIC, who led the research, said, "It's been very well studied,
but not much is known about its cellular function. What is its role? Is
it a bad lipid? Absolutely not - for example, the brain is about half
lipid, and cholesterol is the richest lipid in the brain," he said.
cholesterol deficiency can cause several diseases, and the substance is
the starting material for making the body's dozen or so steroid
Cho's earlier studies showed cholesterol interacts with many
regulatory molecules - mostly cellular proteins - but it was never
thought to be one.
"We knew it could play an important role in cell regulation - for
example, in proliferation or development," he said. "We know that
high-fat diets, which boost cholesterol levels, have been linked to an
elevated incidence of cancer. How, is not fully understood," Cho said.
One of the biggest problems conceptually, he said, is that a
regulatory or signaling lipid should exist only transiently to transmit
"But cholesterol is there all the time," he said. The membrane
contains up to 90% of a cell's total cholesterol, and cholesterol
makes up about 40% of the membrane lipids.
Cholesterol lends stability to the membrane, which is actually a
double layer of lipid - or fat - molecules. The cholesterol gathers into
"rafts," which were thought to serve as platforms from which other
signaling molecules might operate.
"But in this paper, we showed that a single cholesterol molecule can itself be the signal trigger," Cho said.
Until now, scientists believed cholesterol was in both layers of the
membrane, Cho said, "maybe more in the inner layer. But we, for the
first time, measured cholesterol levels in the inner and outer layers
simultaneously in real time, in living cells. And we showed that
cholesterol is predominantly in the outer layer."
Cholesterol makes up about 40% of the outer layer of the
membrane, they found, and only about 3% of the inner layer. In
response to a specific cell stimulus, the amount in the inner layer more
than doubles, and the level in the outer layer drops by the same
They also found that, while in normal cells the concentration of
cholesterol in the inner layer is low, in cancer cells it's much higher.
"We checked this in many different cell lines," Cho said.
The new study sheds some light on the positive side effect of statin
drugs lowering cancer risk. Cho and his coworkers found that treating
cells with a statin dramatically lowered the level of cholesterol in the
inner layer, leading to suppression of cell growth activity. This
suggests a new way to treat cancer through pharmacological modulation of
the cellular cholesterol level, Cho said.
"I think we're just scratching the surface of the regulatory role of
cholesterol. We have many unpublished data indicating that cholesterol
is involved in a wide variety of cellular processes and regulation," he
"Lipids like cholesterol are "very nasty molecules to work with," Cho
says, "because they can't be dissolved in water like most biological
molecules. This makes quantitative techniques very challenging."
"We had to devise a new strategy," he said. Six years ago, he and
his colleagues developed an optical imaging technology that allows
direct quantification of lipids in living cells. They tagged a
lipid-binding protein molecule with a fluorescent sensor that changes
color when it binds lipid. The color-change indicates the ratio of bound
to free lipid, letting them determine how much of the lipid is at a
given location in the cell membrane.