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 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 cell membrane. The finding is reported in Nature Chemical Biology.
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," senior author said.
Until now, scientists believed cholesterol was in both layers of the membrane, senior author 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 percent of the outer layer of the membrane, they found, and only about 3 percent 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 amount.
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," senior author said.
Researchers 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, senior author 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 We have many unpublished data indicating that cholesterol is involved in a wide variety of cellular processes and regulation," author said.
Lipids like cholesterol are "very nasty molecules to work with," author 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," senior author 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.
http://news.uic.edu/researchers-zero-in-on-cholesterols-role-in-cells
http://www.nature.com/nchembio/journal/vaop/ncurrent/full/nchembio.2268.html
Is cholesterol, a signaling molecule?
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