Nav: Home

Researchers zero-in on cholesterol's role in cells

January 17, 2017

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 cell membrane.

The finding is reported in Nature Chemical Biology.

"Cholesterol is a lipid that gets bad press because of its association with cardiovascular disease," says Wonhwa Cho, professor of chemistry at UIC, who led the research. "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. A cholesterol deficiency can cause several diseases, and the substance is the starting material for making the body's dozen or so steroid hormones.

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 the message.

"But cholesterol is there all the time," he said. The membrane contains up to 90 percent of a cell's total cholesterol, and cholesterol makes up about 40 percent 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 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," 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 said.

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.
-end-
Co-authors on the study are Shu-Lin Liu, Ren Sheng, Li Wang, Ewa Stec, Matthew J. O'Connor, Seohyoen Song and Daesung Lee of the UIC department of chemistry; Rama Kamesh Bikkavilli, Robert A. Winn and Irena Levitan of the UIC College of Medicine; Jae Hun Jung, Kwanghee Baek and Kwang-Pyo Kim of Kyung Hee University in Korea; and Kazumitsu Ueda of Kyoto University in Japan.

The research was supported by grants from the National Institutes of Health (GM68849 and GM110128 to Cho, and HL-073965 and HL-083298 to Levitan) and from the Japan Society for the Promotion of Science (25221203 to Ueda).

University of Illinois at Chicago

Related Cancer Articles:

Radiotherapy for invasive breast cancer increases the risk of second primary lung cancer
East Asian female breast cancer patients receiving radiotherapy have a higher risk of developing second primary lung cancer.
Cancer genomics continued: Triple negative breast cancer and cancer immunotherapy
Continuing PLOS Medicine's special issue on cancer genomics, Christos Hatzis of Yale University, New Haven, Conn., USA and colleagues describe a new subtype of triple negative breast cancer that may be more amenable to treatment than other cases of this difficult-to-treat disease.
Metabolite that promotes cancer cell transformation and colorectal cancer spread identified
Osaka University researchers revealed that the metabolite D-2-hydroxyglurate (D-2HG) promotes epithelial-mesenchymal transition of colorectal cancer cells, leading them to develop features of lower adherence to neighboring cells, increased invasiveness, and greater likelihood of metastatic spread.
UH Cancer Center researcher finds new driver of an aggressive form of brain cancer
University of Hawai'i Cancer Center researchers have identified an essential driver of tumor cell invasion in glioblastoma, the most aggressive form of brain cancer that can occur at any age.
UH Cancer Center researchers develop algorithm to find precise cancer treatments
University of Hawai'i Cancer Center researchers developed a computational algorithm to analyze 'Big Data' obtained from tumor samples to better understand and treat cancer.
More Cancer News and Cancer Current Events

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Anthropomorphic
Do animals grieve? Do they have language or consciousness? For a long time, scientists resisted the urge to look for human qualities in animals. This hour, TED speakers explore how that is changing. Guests include biological anthropologist Barbara King, dolphin researcher Denise Herzing, primatologist Frans de Waal, and ecologist Carl Safina.
Now Playing: Science for the People

#534 Bacteria are Coming for Your OJ
What makes breakfast, breakfast? Well, according to every movie and TV show we've ever seen, a big glass of orange juice is basically required. But our morning grapefruit might be in danger. Why? Citrus greening, a bacteria carried by a bug, has infected 90% of the citrus groves in Florida. It's coming for your OJ. We'll talk with University of Maryland plant virologist Anne Simon about ways to stop the citrus killer, and with science writer and journalist Maryn McKenna about why throwing antibiotics at the problem is probably not the solution. Related links: A Review of the Citrus Greening...