By Nic Fleming of Nature magazine
The movement of cholesterol in and out of cells takes much longer than previously thought, according to new measurements of the phenomenon in artificial cell membranes. The findings could lead to a better understanding of the movement of cholesterol in the body and might someday help improve treatments for some serious neurological diseases.
Most people worry about the negative effects of too much cholesterol, but this lipid is essential for cells. Cholesterol forms part of the lipid bilayer membrane that surrounds each cell in the body. It also insulates nerve fibers, aids the transport of chemical signals, and is used in the production of hormones. Problems with cholesterol's movement across cell membranes have been linked to Alzheimer's disease and other severe neurodegenerative disorders.
Understanding the causes of these conditions and how best to treat them has been hampered by inconsistencies in the measurements of cholesterol's motion reported in previous research. Timescales for cholesterol "flipping" from one layer of the membrane to the other vary from several hours to a few milliseconds, and timings for its movement between cells also vary from tens of minutes to hours.
These differences might be related to the fluorescent chemical tags and other substances used to track cholesterol in such studies. To avoid adding such chemicals, Sumit Garg at Argonne National Laboratory in Argonne, Illinois, and his colleagues used bombardment with neutrons--neutral subatomic particles--to follow cholesterol movement. The researchers began with a mix of cholesterol-enriched and cholesterol-free bubbles of artificial lipid membrane, known as vesicles, which mimic the cell membrane bilayer. The vesicles were dispersed in water and zapped with a beam of neutrons.
The researchers adjusted conditions so that only neutron scattering by cholesterol was visible. This allowed the team to track cholesterol as it flipped from one layer of the lipid membrane to the other, or as it moved out of one vesicle membrane and into that of another. The measurements were carried out using neutrons from research reactors at the Laue-Langevin Institute (ILL), a nuclear research facility in Grenoble, France, and at the National Institute of Standard and Technology (NIST) in Gaithersburg, Maryland.
The results show that the movement of cholesterol both within the membrane and from one vesicle to another was slower than measured in most previous studies--transfer of half the cholesterol from the enriched vesicles to the cholesterol-free vesicles took on the order of a few hours.
The team then repeated the experiments with the addition of cyclodextrin, a ring-shaped glucose molecule used in many previous measurements of cholesterol transport. They found that the chemical sped up cholesterol movement by an order of magnitude.
Slow but sure
"This is the first complete accurate measurement of pure cholesterol transport," says team member Lionel Porcar at the Laue-Langevin Institute. "Most of the other studies tell us about fluorescent cholesterol, which is not what we have in our bodies."
The research is fundamental, but it could help to develop future treatments. Some researchers believe that changes to cholesterol distribution in the brain can lead to the accumulation of amyloid-beta plaques that seem to be central to an early onset of Alzheimer's disease. Animal and cell-culture studies strongly suggest that cholesterol helps to modulate amyloid-beta production, although how it does so is not understood. Porcar and his colleagues believe that understanding the movement of cholesterol in and out of cells is an important step in mapping its relationship to the Alzheimer's and other related illnesses. "Once we understand the mechanism, that will have a lot of potential application for diseases," he says.
The new measurement alone won't be enough to settle the debate, however. "The very slow flip rate is very surprising and would certainly be significant if we could be confident in the result," says Frederick Maxfield at the Weill Cornell Medical College, New York, who questions whether the model used by the researchers correlates accurately with the way cholesterol moves in the body. "This will undoubtedly spur further investigation," he adds. "We need to keep exploring new methodologies such as this to get a complete picture."
This article is reproduced with permission from the magazine Nature. The article was first published on July 19, 2011.