Featured Research

from universities, journals, and other organizations

Key Interaction In Cholesterol Regulation Discovered

Date:
February 6, 2008
Source:
UT Southwestern Medical Center
Summary:
Researchers have determined the specific way in which a destructive protein binds to and interferes with a molecule that removes low-density lipoproteins, the so-called "bad" cholesterol, from the blood.

Researchers at UT Southwestern Medical Center have determined the specific way in which a destructive protein binds to and interferes with a molecule that removes low-density lipoproteins (LDL), the so-called "bad" cholesterol, from the blood.

Related Articles


"The practical benefit of this finding is that we can now search for new ways to lower cholesterol by designing targeted antibodies to disrupt this interaction," said Dr. Jay Horton, professor of internal medicine and molecular genetics and a senior author of the study, which appears online this week in the Proceedings of the National Academy of Sciences.

The protein, called PCSK9, has emerged as an important regulator of "bad" cholesterol in the blood, said Dr. Horton, whose research focuses in part on understanding the protein's function.

PCSK9 disrupts the activity of a key molecule called the low-density lipoprotein receptor, or LDLR. This molecule, which juts out from the surface of cells, latches on to "bad" cholesterol in the bloodstream and removes it by drawing it into the cells.

The PCSK9 protein also can latch on to 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 "bad" cholesterol remains in the bloodstream.

"You want to have LDL receptors to clear LDL from the blood -- that's a good thing," Dr. Horton said. "So you don't want to have PCSK9; it normally functions in a harmful way."

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. More than 25 million people worldwide take a class of drugs called statins to lower their cholesterol to within recommended healthy levels.

To determine exactly how PCSK9 and the LDLR physically interact, the researchers, led by Dr. Hyock Joo Kwon, an instructor in biochemistry, collaborated with Dr. Johann Deisenhofer, professor of biochemistry, an investigator with the Howard Hughes Medical Institute and a senior author of the study. Dr. Deisenhofer shared the 1988 Nobel Prize in Chemistry for his work in discovering the structure of a key protein involved in photosynthesis.

Using X-rays bounced off crystals made up of both PCSK9 and a portion of the LDLR protein, the researchers identified small regions of each protein that attach to each other. They then created a detailed structural model of the area.

"It looks like those portions are absolutely essential for the interaction to take place," Dr. Horton said.

The researchers are now designing antibodies and small chains of peptides -- the building blocks of proteins -- that have the ability to jam the interaction between LDLR and PCSK9.

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

While statin drugs work by increasing the number of LDL receptors on cells, a drug targeting PCSK9 might prevent the existing receptors from being degraded.

"These studies suggest that inhibiting PCSK9's action may be another route to lowering LDL cholesterol in individuals with high cholesterol," said Dr. Horton.

Other UT Southwestern researchers involved in the study were Dr. Thomas Lagace, postdoctoral researcher in molecular genetics, and graduate student Markey McNutt.

The work was supported by the Robert A. Welch Foundation, the Perot Family Foundation, the National Institutes of Health, HHMI, 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. "Key Interaction In Cholesterol Regulation Discovered." ScienceDaily. ScienceDaily, 6 February 2008. <www.sciencedaily.com/releases/2008/02/080204111808.htm>.
UT Southwestern Medical Center. (2008, February 6). Key Interaction In Cholesterol Regulation Discovered. ScienceDaily. Retrieved December 18, 2014 from www.sciencedaily.com/releases/2008/02/080204111808.htm
UT Southwestern Medical Center. "Key Interaction In Cholesterol Regulation Discovered." ScienceDaily. www.sciencedaily.com/releases/2008/02/080204111808.htm (accessed December 18, 2014).

Share This


More From ScienceDaily



More Health & Medicine News

Thursday, December 18, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Kids Die While Under Protective Services

Kids Die While Under Protective Services

AP (Dec. 18, 2014) As part of a six-month investigation of child maltreatment deaths, the AP found that hundreds of deaths from horrific abuse and neglect could have been prevented. AP's Haven Daley reports. (Dec. 18) Video provided by AP
Powered by NewsLook.com
UN: Up to One Million Facing Hunger in Ebola-Hit Countries

UN: Up to One Million Facing Hunger in Ebola-Hit Countries

AFP (Dec. 17, 2014) Border closures, quarantines and crop losses in West African nations battling the Ebola virus could lead to as many as one million people going hungry, UN food agencies said on Wednesday. Duration: 00:52 Video provided by AFP
Powered by NewsLook.com
When You Lose Weight, This Is Where The Fat Goes

When You Lose Weight, This Is Where The Fat Goes

Newsy (Dec. 17, 2014) Can fat disappear into thin air? New research finds that during weight loss, over 80 percent of a person's fat molecules escape through the lungs. Video provided by Newsy
Powered by NewsLook.com
Why Your Boss Should Let You Sleep In

Why Your Boss Should Let You Sleep In

Newsy (Dec. 17, 2014) According to research out of the University of Pennsylvania, waking up for work is the biggest factor that causes Americans to lose sleep. Video provided by Newsy
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:

Strange & Offbeat Stories


Health & Medicine

Mind & Brain

Living & Well

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