Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Study reveals potential new target for cholesterol-lowering drugs

30.03.2005


Mice lacking a key protein involved in cholesterol regulation have low-density lipoprotein, or "bad" cholesterol, levels more than 50 percent lower than normal mice, and researchers suggest that inhibiting the same protein in humans could lead to new cholesterol-lowering drugs.



In a study to be published in the Proceedings of the National Academy of Sciences and available online this week, researchers at UT Southwestern Medical Center deleted the Pcsk9 gene in mice. The gene, present in both mice and humans, makes the PCSK9 protein, which normally gets rid of receptors that latch onto LDL cholesterol in the liver. Without this degrading protein, the mice had more LDL receptors and were thus able to take up more LDL cholesterol from their blood.

"The expression of LDL receptors is the primary mechanism by which humans lower LDL cholesterol in the blood," said Dr. Jay Horton, associate professor of internal medicine and molecular genetics and senior author of the study. "This research shows that in mice, deleting the PCSK9 protein results in an increase in LDL receptors and a significant lowering of LDL cholesterol."


High LDL cholesterol is a major risk factor for heart disease, heart attack and stroke because it contributes to the buildup of plaque that clogs the walls of arteries. Nearly 25 million people worldwide take a class of drugs called statins to lower their cholesterol to within recommended healthy levels.

On average, mice lacking the Pcsk9 gene, called knockout mice, had blood LDL cholesterol levels of 46 milligrams per deciliter, while wild-type mice had levels around 96 mg/dl, a difference of 52 percent.

Dr. Horton’s research is consistent with findings from another recent UT Southwestern study showing that humans with mutations in their PCSK9 gene, which prevented them from making normal levels of PCSK9 protein, had LDL cholesterol levels 40 percent lower than individuals without the mutation. That study, based on data gathered from nearly 6,000 participants in the Dallas Heart Study, was published in February in Nature Genetics. The research was led by Dr. Helen Hobbs, director of the Dallas Heart Study and of the Eugene McDermott Center for Growth and Development, and Dr. Jonathan Cohen, associate professor of internal medicine.

"The lower cholesterol levels of humans with mutations in PCSK9, combined with the results of our studies in mice, suggest that variations in the levels of the PCSK9 protein significantly affect blood cholesterol levels, and compounds that inhibit this protein may be useful for the treatment of high cholesterol," Dr. Horton said.

Dr. Horton and his colleagues also gave their knockout mice statins, which further enhanced the clearance of LDL cholesterol from their blood. The findings suggest new drugs targeting PCSK9 may be able to act in conjunction with statin drugs to further lower LDL cholesterol levels. Dr. Horton said cholesterol-lowering drugs based on blocking PCSK9 might be effective on their own as well, providing another option for individuals unable to take statins.

Statins increase the activity of a protein called SREBP-2, which activates the creation of more LDL receptors; however, Dr. Horton’s previous studies found that SREBP-2 also boosts the activity of the PCSK9 protein, which degrades those receptors.

"We looked at these competing effects and thought that if we removed the PCSK9 component completely, we would get a further increase in LDL receptors, and that’s what happened," he said.

The competing systems may have evolved to keep the body’s cholesterol levels fine-tuned and to minimize big swings in cholesterol content in normal cells, Dr. Horton said. Too much or too little cholesterol can damage or kill cells. He and his colleagues next will try to determine just how the PCSK9 protein degrades the LDL receptors.

Dr. Horton said the current study’s results also are important because many researchers thought there might be no new ways to exploit the LDL receptor pathway as a means of lowering LDL cholesterol.

"Our research, and that of Dr. Hobbs and her colleagues, further emphasize the importance of the LDL receptor in cholesterol regulation," Dr. Horton said.

UT Southwestern researchers Dr. Michael Brown, director of the Erik Jonsson Center for Research in Molecular Genetics and Human Disease, and Dr. Joseph Goldstein, chairman of molecular genetics, shared the 1985 Nobel Prize in physiology or medicine for their discovery of the LDL receptor.

Other UT Southwestern researchers who participated in the PNAS study were Dr. Shirya Rashid, molecular genetics postdoctoral research fellow; Dr. David Curtis, surgery postdoctoral researcher; Dr. Rita Garuti, visiting senior fellow; Norma Anderson, molecular genetics senior research associate; Drs. Yuriy Bashmakov, Young-Ah Moon and Yiu Kee Ho, assistant professors of molecular genetics; and Dr. Robert E. Hammer, professor of biochemistry.

The research was supported by the National Institutes of Health and the Perot Foundation.

Amanda Siegfried | EurekAlert!
Further information:
http://www.utsouthwestern.edu

More articles from Life Sciences:

nachricht Scientists uncover the role of a protein in production & survival of myelin-forming cells
19.07.2018 | Advanced Science Research Center, GC/CUNY

nachricht NYSCF researchers develop novel bioengineering technique for personalized bone grafts
18.07.2018 | New York Stem Cell Foundation

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Future electronic components to be printed like newspapers

A new manufacturing technique uses a process similar to newspaper printing to form smoother and more flexible metals for making ultrafast electronic devices.

The low-cost process, developed by Purdue University researchers, combines tools already used in industry for manufacturing metals on a large scale, but uses...

Im Focus: First evidence on the source of extragalactic particles

For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.

To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...

Im Focus: Magnetic vortices: Two independent magnetic skyrmion phases discovered in a single material

For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.

Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...

Im Focus: Breaking the bond: To take part or not?

Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.

A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...

Im Focus: New 2D Spectroscopy Methods

Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.

"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Leading experts in Diabetes, Metabolism and Biomedical Engineering discuss Precision Medicine

13.07.2018 | Event News

Conference on Laser Polishing – LaP: Fine Tuning for Surfaces

12.07.2018 | Event News

11th European Wood-based Panel Symposium 2018: Meeting point for the wood-based materials industry

03.07.2018 | Event News

 
Latest News

A smart safe rechargeable zinc ion battery based on sol-gel transition electrolytes

20.07.2018 | Power and Electrical Engineering

Reversing cause and effect is no trouble for quantum computers

20.07.2018 | Information Technology

Princeton-UPenn research team finds physics treasure hidden in a wallpaper pattern

20.07.2018 | Materials Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>