U-M researchers find new way to clear cholesterol from the blood

April 10, 2013, University of Michigan

Researchers at the University of Michigan have identified a new potential therapeutic target for lowering cholesterol that could be an alternative or complementary therapy to statins.

Scientists in the lab of David Ginsburg at the Life Sciences Institute inhibited the action of a gene responsible for transporting a protein that interferes with the ability of the liver to remove cholesterol from the blood in mice. Trapping the destructive protein where it couldn't harm receptors responsible for removing cholesterol preserved the liver cells' capacity to clear plasma cholesterol from the blood, but did not appear to otherwise affect the health of the mice.

In the research, published April 9 in the online journal eLife, scientists found that mice with an inactive SEC24A gene could develop normally. However, their plasma cholesterol levels were reduced by 45 percent because vesicles from liver cells were not able to recruit and transport a critical regulator of called proprotein convertase subtilisin/kexin type 9. PCSK9 is a secretory protein that destroys the liver cells' receptors of – LDL, the so-called ""—and prevents the cells from removing the LDL.

"Inhibiting SEC24A or PCSK9 may be an alternative to statins, and could work together with statins to produce even greater effects," said Xiao-Wei Chen of the Ginsburg lab, the first author on the paper. "Also, they might be effective on patients who are resistant to or intolerant of statins."

Initial studies of anti-PCSK9 therapies in humans have shown that eliminating PCSK9 can lower cholesterol dramatically and work with statins like to lower it even further. The Ginsburg lab's research points to a new area for study: rather than inhibiting PCSK9 itself, perhaps future therapies could block the transport mechanism that allows the destructive protein to reach the LDL receptors.

The paper, "SEC24A deficiency lowers through reduced PCSK9 secretion," explains the mechanism by which cells transport PCSK9. Vesicles transport proteins in the cell; the Ginsburg lab's research focused on a specialized type of vesicle packaged by the Coat Protein Complex II, which regulates the metabolism of cholesterol, among many other things. These selectively transport cargo proteins including PCSK9.

Without those LDL receptors (LDLR), are not able to remove LDLs from the bloodstream, so protecting the LDLR from PCSK9 would allow the receptors to continue to remove cholesterol.

"Without SEC24A, much of the PCSK9 couldn't make its way out of the cells to destroy the LDLR, which then clears cholesterol from the blood," Chen said.

The part of the vesicle that selects which proteins to transport is SEC24. By blocking SEC24A gene, the researchers disabled the vesicle's selection of PCSK9. The destructive protein remained trapped within the cells, leaving the LDLR intact and enabling the liver to clear the body of cholesterol that otherwise could accumulate in arteries.

"We have no reason at this point to expect that this strategy will be any better than anti-PCSK9 therapy for treating high , but it would be another alternative approach, and it's hard to predict which drugs will work the best and be the safest until we actually try them out in people," Ginsburg said.

Ginsburg is a research professor at the Life Sciences Institute, where his laboratory is located. He is also the James V. Neel Distinguished University Professor and the Warner-Lambert/Parke-Davis Professor in the Division of Molecular Medicine and Genetics, Department of Internal Medicine and departments of Human Genetics and Pediatrics at the U-M Medical School and a Howard Hughes Medical Institute Investigator.

Explore further: Monthly shot lowers cholesterol 66 percent: study

More information: elife.elifesciences.org/content/2/e00444

Related Stories

Monthly shot lowers cholesterol 66 percent: study

March 26, 2012
A monthly injection of an experimental drug made by the US biotech firm Amgen reduced patients' cholesterol by up to 66 percent, according to a small study described at a US cardiology conference.

Injection lowers cholesterol in preliminary human trial

November 14, 2011
Patients unable to control their cholesterol levels with medications may someday be able to lower their "bad" cholesterol with a shot, according to research presented at the American Heart Association's Scientific Sessions ...

Antibody injection lowers LDL, adding to effectiveness of statin therapy

March 26, 2012
A novel monoclonal antibody identified in a new study dramatically lowered circulating LDL cholesterol by 40 percent to 72 percent, a development with potential to provide a new option for patients who are resistant to cholesterol-lowering ...

Recommended for you

Starting periods before age of 12 linked to heightened risk of heart disease and stroke

January 15, 2018
Starting periods early—before the age of 12—is linked to a heightened risk of heart disease and stroke in later life, suggests an analysis of data from the UK Biobank study, published online in the journal Heart.

'Decorated' stem cells could offer targeted heart repair

January 10, 2018
Although cardiac stem cell therapy is a promising treatment for heart attack patients, directing the cells to the site of an injury - and getting them to stay there - remains challenging. In a new pilot study using an animal ...

Exercise is good for the heart, high blood pressure is bad—researchers find out why

January 10, 2018
When the heart is put under stress during exercise, it is considered healthy. Yet stress due to high blood pressure is bad for the heart. Why? And is this always the case? Researchers of the German Centre for Cardiovascular ...

Two simple tests could help to pinpoint cause of stroke

January 10, 2018
Detecting the cause of the deadliest form of stroke could be improved by a simple blood test added alongside a routine brain scan, research suggests.

Heart-muscle patches made with human cells improve heart attack recovery

January 10, 2018
Large, human cardiac-muscle patches created in the lab have been tested, for the first time, on large animals in a heart attack model. This clinically relevant approach showed that the patches significantly improved recovery ...

Place of residence linked to heart failure risk

January 9, 2018
Location. Location. Location.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.