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 Rainbow colors reveal cell history: Uncovering β-cell heterogeneity
22.09.2017 | DFG-Forschungszentrum für Regenerative Therapien TU Dresden

nachricht The pyrenoid is a carbon-fixing liquid droplet
22.09.2017 | Max-Planck-Institut für Biochemie

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: The pyrenoid is a carbon-fixing liquid droplet

Plants and algae use the enzyme Rubisco to fix carbon dioxide, removing it from the atmosphere and converting it into biomass. Algae have figured out a way to increase the efficiency of carbon fixation. They gather most of their Rubisco into a ball-shaped microcompartment called the pyrenoid, which they flood with a high local concentration of carbon dioxide. A team of scientists at Princeton University, the Carnegie Institution for Science, Stanford University and the Max Plank Institute of Biochemistry have unravelled the mysteries of how the pyrenoid is assembled. These insights can help to engineer crops that remove more carbon dioxide from the atmosphere while producing more food.

A warming planet

Im Focus: Highly precise wiring in the Cerebral Cortex

Our brains house extremely complex neuronal circuits, whose detailed structures are still largely unknown. This is especially true for the so-called cerebral cortex of mammals, where among other things vision, thoughts or spatial orientation are being computed. Here the rules by which nerve cells are connected to each other are only partly understood. A team of scientists around Moritz Helmstaedter at the Frankfiurt Max Planck Institute for Brain Research and Helene Schmidt (Humboldt University in Berlin) have now discovered a surprisingly precise nerve cell connectivity pattern in the part of the cerebral cortex that is responsible for orienting the individual animal or human in space.

The researchers report online in Nature (Schmidt et al., 2017. Axonal synapse sorting in medial entorhinal cortex, DOI: 10.1038/nature24005) that synapses in...

Im Focus: Tiny lasers from a gallery of whispers

New technique promises tunable laser devices

Whispering gallery mode (WGM) resonators are used to make tiny micro-lasers, sensors, switches, routers and other devices. These tiny structures rely on a...

Im Focus: Ultrafast snapshots of relaxing electrons in solids

Using ultrafast flashes of laser and x-ray radiation, scientists at the Max Planck Institute of Quantum Optics (Garching, Germany) took snapshots of the briefest electron motion inside a solid material to date. The electron motion lasted only 750 billionths of the billionth of a second before it fainted, setting a new record of human capability to capture ultrafast processes inside solids!

When x-rays shine onto solid materials or large molecules, an electron is pushed away from its original place near the nucleus of the atom, leaving a hole...

Im Focus: Quantum Sensors Decipher Magnetic Ordering in a New Semiconducting Material

For the first time, physicists have successfully imaged spiral magnetic ordering in a multiferroic material. These materials are considered highly promising candidates for future data storage media. The researchers were able to prove their findings using unique quantum sensors that were developed at Basel University and that can analyze electromagnetic fields on the nanometer scale. The results – obtained by scientists from the University of Basel’s Department of Physics, the Swiss Nanoscience Institute, the University of Montpellier and several laboratories from University Paris-Saclay – were recently published in the journal Nature.

Multiferroics are materials that simultaneously react to electric and magnetic fields. These two properties are rarely found together, and their combined...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

“Lasers in Composites Symposium” in Aachen – from Science to Application

19.09.2017 | Event News

I-ESA 2018 – Call for Papers

12.09.2017 | Event News

EMBO at Basel Life, a new conference on current and emerging life science research

06.09.2017 | Event News

 
Latest News

Rainbow colors reveal cell history: Uncovering β-cell heterogeneity

22.09.2017 | Life Sciences

Penn first in world to treat patient with new radiation technology

22.09.2017 | Medical Engineering

Calculating quietness

22.09.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>