Featured Research

from universities, journals, and other organizations

Where 'Bad' Cholesterol Levels Are Controlled

Date:
April 22, 2009
Source:
UT Southwestern Medical Center
Summary:
Researchers have found that a protein responsible for regulating "bad" cholesterol in the blood works almost exclusively outside cells, providing clues for the development of therapies to block the protein's disruptive actions.

Researchers at UT Southwestern Medical Center have found that a protein responsible for regulating "bad" cholesterol in the blood works almost exclusively outside cells, providing clues for the development of therapies to block the protein's disruptive actions.

"The fact that it works mostly extracellularly provides more opportunities to develop different kinds of therapies," said Dr. Jay Horton, professor of internal medicine and molecular genetics and co-author of the study, which is available online and appears in the April 17 issue of the Journal of Biological Chemistry.

The protein, called PCSK9, disrupts the activity of a key molecule called the low-density lipoprotein receptor, or LDLR. This molecule, which is made and secreted in the liver, latches onto the LDL receptor. This binding, however, triggers a chain of biochemical reactions that leads to the destruction of the LDL receptor. With fewer receptors available, more of the so-called "bad" cholesterol remains in the bloodstream.

Dr. Horton said these new findings show that PCSK9 principally acts as a secreted protein to cause the degradation of LDL receptors. "Therefore, approaches to block the protein's activity in the blood should be successful in reducing plasma cholesterol levels," he said.

Too much LDL cholesterol in the blood 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. Up to 30 million people worldwide take a class of drugs called statins to lower their cholesterol to within recommended healthy limits.

To determine whether PCSK9 works inside or outside the cell, the researchers designed peptides – the building blocks of proteins – to jam the interaction between PCSK9 and the LDL receptor. They then added the peptides to a cultured cell medium to see if they could block the activities of PCSK9. The peptides prevented the secreted PCSK9 from binding to the surface of the LDL receptors.

Dr. Horton said the fact that PCSK9 performs its destructive duties outside cells provides more opportunities for drug development.

"It's much easier to design inhibitors of PCSK9 function to work outside a cell than to develop a small molecule that works inside a cell," he said.

The researchers also discovered how a mutation in the LDL receptor causes a condition called hypercholesterolemia in some people. The mutation increases the binding of the LDL receptor to PCSK9, leading to excessive degradation of the receptor and extremely high cholesterol levels. Dr. Horton said degradation is bad news for LDL receptors.

"You want as many of these receptors as possible to clear the LDL from your blood," he said.

Dr. Horton's previous studies have shown that mice lacking PCSK9 have LDL cholesterol levels less than half those of normal mice.

Studies by other UT Southwestern researchers have found that people with mutations in the PCSK9 gene, which prevented them from making normal levels of the PCSK9 protein, had LDL cholesterol levels 28 percent lower than individuals without the mutation and were protected from developing coronary heart disease. That research was led by Dr. Jonathan Cohen, professor of internal medicine, and Dr. Helen Hobbs, director of the Eugene McDermott Center for Human Growth and Development.

Dr. Horton said it's now up to pharmaceutical companies to develop drugs that will block these PCSK9 activities. "Our work paves the way for a more active pursuit of antibody and peptide approaches to block the destructive actions of PCSK9," he said.

Other UT Southwestern researchers involved in the current study were senior author Dr. Thomas Lagace, former postdoctoral researcher in molecular genetics; lead author Markey McNutt, graduate student; Dr. Hyock Joo Kwon, assistant professor of biochemistry; Dr. Chiyuan Chen, postdoctoral researcher in molecular genetics; and Justin Chen, summer student research fellow.

The work was supported by the Perot Foundation, the National Institutes of Health, the UT Southwestern Medical Scientist Training Program and the Canadian Institutes of Health Research.


Story Source:

The above story is based on materials provided by UT Southwestern Medical Center. Note: Materials may be edited for content and length.


Cite This Page:

UT Southwestern Medical Center. "Where 'Bad' Cholesterol Levels Are Controlled." ScienceDaily. ScienceDaily, 22 April 2009. <www.sciencedaily.com/releases/2009/04/090417084004.htm>.
UT Southwestern Medical Center. (2009, April 22). Where 'Bad' Cholesterol Levels Are Controlled. ScienceDaily. Retrieved August 28, 2014 from www.sciencedaily.com/releases/2009/04/090417084004.htm
UT Southwestern Medical Center. "Where 'Bad' Cholesterol Levels Are Controlled." ScienceDaily. www.sciencedaily.com/releases/2009/04/090417084004.htm (accessed August 28, 2014).

Share This




More Health & Medicine News

Thursday, August 28, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Mini Pacemaker Has No Wires

Mini Pacemaker Has No Wires

Ivanhoe (Aug. 27, 2014) — Cardiac experts are testing a new experimental device designed to eliminate major surgery and still keep the heart on track. Video provided by Ivanhoe
Powered by NewsLook.com
After Cancer: Rebuilding Breasts With Fat

After Cancer: Rebuilding Breasts With Fat

Ivanhoe (Aug. 27, 2014) — More than 269 million women are diagnosed with breast cancer each year. Many of them will need surgery and radiation, but there’s a new simple way to reconstruct tissue using a patient’s own fat. Video provided by Ivanhoe
Powered by NewsLook.com
Blood Clots in Kids

Blood Clots in Kids

Ivanhoe (Aug. 27, 2014) — Every year, up to 200,000 Americans die from a blood clot that travels to their lungs. You’ve heard about clots in adults, but new research shows kids can get them too. Video provided by Ivanhoe
Powered by NewsLook.com
Radio Waves Knock out Knee Pain

Radio Waves Knock out Knee Pain

Ivanhoe (Aug. 27, 2014) — Doctors have used radio frequency ablation or RFA to reduce neck and back pain for years. But now, that same technique is providing longer-term relief for patients with severe knee pain. Video provided by Ivanhoe
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
 
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:  

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:  

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile iPhone Android Web
Follow Facebook Twitter Google+
Subscribe RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins