Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Newly discovered gene controls levels of ’bad’ cholesterol in mice

27.04.2004


Heart disease researchers at Rockefeller University have discovered the function of a gene associated with high cholesterol levels in humans.


GENE IN GREEN: This red and green photo shows that high levels of active Pcsk9 gene prevents LDL cholesterol from binding to the surface of liver cells. LDL cholesterol was labeled with red, glow-in-the-dark dye while the Pcsk9 gene was labeled with green. Green cells with high levels of Pcsk9 inside have little or no red border, which means that LDL cholesterol molecules are not bound to their surfaces. Cells without high levels of Pcsk9 inside appear red because red LDL molecules are bound to their surfaces.



Using mice as test subjects, the Rockefeller scientists determined that the gene, called Pcsk9, can decrease the number of receptors on liver cells that remove the "bad" LDL cholesterol from the blood.

"It’s very exciting to think that Pcsk9 might play a large role in the pathway to regulate the uptake of bad cholesterol from blood," said Kara Maxwell, the lead researcher of the study published this week in the journal Proceedings of the National Academy of Sciences. Maxwell is an M.D.-Ph.D. student in the Laboratory of Biochemical Genetics and Metabolism headed by Jan L. Breslow, M.D., the senior author of the study.


High levels of LDL cholesterol in the blood lead to heart attacks because the waxy LDL molecules build up inside the walls of arteries, causing damage to the blood vessels and leading to clots that block the follow of blood to the heart muscle.

Maxwell’s cholesterol study in mice is highly relevant to humans because mutant forms of the Pcsk9 gene have been linked to one form of autosomal dominant hypercholesterolemia, a group of genetic disorders characterized by excessive levels of cholesterol in the bloodstream.

To identify genes that regulate cholesterol levels in the blood in response to high cholesterol diets, Maxwell examined gene activity in mice that were fed normal diets and mice that were fed high-cholesterol diets. In this experiment she found a previously unknown gene, now called Pcsk9, that was expressed at a much lower level in mice that were fed high-cholesterol diets compared to mice that were fed normal diets.

Last year, a research team led by Nabil Seidah and Catherine Boileau at the Hospital Necker-Enfants Malades in France independently found that mutations in the Pcsk9 gene were linked to autosomal dominant hypercholesterolemia. But the function of Pcsk9 was not determined until now.

To find out what Pcsk9 does, Maxwell inserted the Pcsk9 gene into a virus that targets the liver and injected the virus into normal mice, where it made Pcsk9 protein inside liver cells.

With abnormally high levels of Pcsk9 in their livers, the mice developed high cholesterol. Four days after injection, the animals’ LDL levels were five times the normal level, and their levels of total cholesterol in the bloodstream had doubled. (Total cholesterol measures LDL plus HDL plus another type of cholesterol.)

Maxwell suspected that the Pcsk9 protein was raising LDL levels by acting on the liver cells’ LDL receptors, which snatch up LDL molecules from the blood.

To test this hypothesis, Maxwell injected the Pcsk9-carrying virus into a strain of mice that do not have LDL receptors because of a genetic defect. When Maxwell examined the special high-cholesterol mice after they had been injected with Pcsk9, she found that their cholesterol levels had not changed -- LDL levels did not increase as they had in normal mice. This suggests that Pcsk9 has no effect on cholesterol levels unless LDL receptor molecules are present.

In addition, Maxwell found that normal mice injected with the Pcsk9 lost their liver LDL receptors. This indicates that Pcsk9 directly affects LDL receptors.

"LDL receptors are the main way of getting LDL out of the blood," said Maxwell. "I think knowing that Pcsk9 modulates LDL receptors is important for understanding how LDL levels are regulated."

Maxwell and Breslow said it is unclear why Pcsk9 gene mutations cause high cholesterol in humans but this work in mice should help to figure this out.

"If the same mechanism Maxwell found in mice pertains to humans and we could inhibit Pcsk9 with drugs, this should increase the number of LDL receptors on cells and in this way lower LDL levels in the blood. This might offer another therapeutic approach to the high blood cholesterol levels that are a major risk factor for heart disease," said Breslow, a former president of the American Heart Association.

Out of all diseases, heart disease is the number one killer of Americans, followed by cancer. People with high levels of LDL, the "bad" cholesterol, and low levels of HDL, the "good" cholesterol are at high risk for developing heart disease.

"The question is, is your cholesterol at the right level?" said Breslow. "There are a huge number of people that fall into the category in which their LDL should be lowered. A lot can be done with diet and exercise but many people also need drugs."

The American Heart Association recommends that people maintain their total cholesterol level below 200 mg/dL, their LDL cholesterol below 130 mg/dL and their HDL cholesterol above 40 mg/dL.

Currently, about 105 million American adults have total cholesterol levels above 200 mg/dL. The average LDL cholesterol level among Americans is 140 mg/dL, which is higher than the recommended level.

Breslow is a pioneer in the genetics of heart disease. In 1992, his lab produced the first mouse model of heart disease by knocking out, or deleting, the apo E gene. The mouse provided the scientific community with the first small animal model to study heart disease in a controlled fashion that can render discoveries relevant for the human condition.


###
This research was supported by the National Institutes of Health. Maxwell is supported by a grant from the NIH’s Medical Scientist Training Program.


Joseph Bonner | Rockefeller University
Further information:
http://www.rockefeller.edu/pubinfo/042604.php

More articles from Health and Medicine:

nachricht Researchers identify cause of hereditary skeletal muscle disorder
22.02.2017 | Klinikum der Universität München

nachricht Second cause of hidden hearing loss identified
20.02.2017 | Michigan Medicine - University of Michigan

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

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

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Microhotplates for a smart gas sensor

22.02.2017 | Power and Electrical Engineering

Scientists unlock ability to generate new sensory hair cells

22.02.2017 | Life Sciences

Prediction: More gas-giants will be found orbiting Sun-like stars

22.02.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>