The findings shed light on how cholesterol is transported through the cells of the body and suggest a possible therapeutic target for Niemann-Pick type C disease (NP-C), an inherited neurodegenerative disorder characterized by abnormally high cholesterol levels in every organ.
“What we’ve shown is that very quickly after administration of this compound, the huge pool of cholesterol that has just been accumulating in the cells is suddenly released and metabolized normally,” said Dr. John Dietschy, professor of internal medicine at UT Southwestern and senior author of the study appearing online this week and in an upcoming issue of the Proceedings of the National Academy of Sciences. “With just one dose, you excrete a large portion of this pool of cholesterol.”
Cholesterol in the body comes from dietary sources and is also made by the body itself. It is essential for many biological processes, including the construction and maintenance of cell membranes. Cholesterol normally is transported through cells and is excreted by the body.
People with Niemann-Pick type C have a genetic mutation that causes excessive amounts of cholesterol to accumulate in compartments within cells called lysosomes. This cholesterol accumulation leads to liver disease, neurodegeneration and dementia. There is no specific level at which cholesterol levels become abnormal, but the vast majority of children diagnosed with NP-C die before they are 20 years old and many before age 10. Late onset of neurological symptoms such as clumsiness, mild retardation and delayed development of fine motor skills can lead to longer life spans, but few people diagnosed with NP-C reach age 40.
In the current research, researchers injected a single dose of a cholesterol-binding agent known as CYCLO into 7-day-old mice with the Niemann-Pick mutation. Shortly after administration, the mice that received CYCLO began to process cholesterol just as their healthy counterparts did. After 49 days, the mice treated with a single injection continued to show substantially lower tissue cholesterol levels than the untreated mice, as well as improved liver function and decreased eurodegeneration.
Dr. Dietschy, who has been studying cholesterol metabolism for nearly 50 years, cautioned that the findings in no way represent a Niemann-Pick disease cure.
“The key idea is that we appear to have overcome the transport defect in the lysosome that is brought about by the genetic defect or mutation,” Dr. Dietschy said. “We do not yet understand what is happening at the molecular level, but it is clear that this compound somehow overcomes the genetic defect that causes individuals to accumulate cholesterol.”
The next step in Dr. Dietschy’s investigation is to determine the concentration of CYCLO needed to trigger the cholesterol’s release. Researchers also hope to determine in animals the additional lifespan CYCLO administration provides, as well as how long the drug’s affects lasts.
“By treating at seven days, we eliminated approximately one-third of the accumulated cholesterol almost immediately,” Dr. Dietschy said. “Now we want to see what happens if we give it every week. Can we maintain low cholesterol levels? That’s what we’re looking at now.”
Other UT Southwestern researchers involved in the research were Dr. Benny Liu, lead author of the study and postdoctoral researcher in internal medicine; Dr. Stephen Turley, professor of internal medicine; Dr. Dennis Burns, professor of pathology; Anna Miller, student research assistant; and Dr. Joyce Repa, assistant professor of physiology.
The work was funded by the U.S. Public Health Service, the Harry S. Moss Heart Trust, the Ara Parseghian Medical Research Foundation and the Dana’s Angels Research Trust.
Visit http://www.utsouthwestern.org/digestive to learn more about clinical services in digestive disorders, including liver disease, at UT Southwestern. Visit http://www.utsouthwestern.org/pediatrics to learn more about UT Southwestern’s pediatrics clinical services.
Dr. John Dietschy -- http://www.utsouthwestern.edu/findfac/professional/0,2356,11822,00.html
Kristen Holland Shear | Newswise Science News
International team discovers novel Alzheimer's disease risk gene among Icelanders
24.10.2016 | Baylor College of Medicine
New bacteria groups, and stunning diversity, discovered underground
24.10.2016 | DOE/Lawrence Berkeley National Laboratory
Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.
"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...
In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.
A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...
By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.
"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...
COMPAMED has become the leading international marketplace for suppliers of medical manufacturing. The trade fair, which takes place every November and is co-located to MEDICA in Dusseldorf, has been steadily growing over the past years and shows that medical technology remains a rapidly growing market.
In 2016, the joint pavilion by the IVAM Microtechnology Network, the Product Market “High-tech for Medical Devices”, will be located in Hall 8a again and will...
'Ferroelectric' materials can switch between different states of electrical polarization in response to an external electric field. This flexibility means they show promise for many applications, for example in electronic devices and computer memory. Current ferroelectric materials are highly valued for their thermal and chemical stability and rapid electro-mechanical responses, but creating a material that is scalable down to the tiny sizes needed for technologies like silicon-based semiconductors (Si-based CMOS) has proven challenging.
Now, Hiroshi Funakubo and co-workers at the Tokyo Institute of Technology, in collaboration with researchers across Japan, have conducted experiments to...
14.10.2016 | Event News
14.10.2016 | Event News
12.10.2016 | Event News
24.10.2016 | Power and Electrical Engineering
24.10.2016 | Life Sciences
24.10.2016 | Life Sciences