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 Nitric oxide-scavenging hydrogel developed for rheumatoid arthritis treatment
06.06.2019 | Pohang University of Science & Technology (POSTECH)

nachricht Infants later diagnosed with autism follow adults’ gaze, but seldom initiate joint attention
24.05.2019 | Schwedischer Forschungsrat - The Swedish Research Council

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: MPSD team discovers light-induced ferroelectricity in strontium titanate

Light can be used not only to measure materials’ properties, but also to change them. Especially interesting are those cases in which the function of a material can be modified, such as its ability to conduct electricity or to store information in its magnetic state. A team led by Andrea Cavalleri from the Max Planck Institute for the Structure and Dynamics of Matter in Hamburg used terahertz frequency light pulses to transform a non-ferroelectric material into a ferroelectric one.

Ferroelectricity is a state in which the constituent lattice “looks” in one specific direction, forming a macroscopic electrical polarisation. The ability to...

Im Focus: Determining the Earth’s gravity field more accurately than ever before

Researchers at TU Graz calculate the most accurate gravity field determination of the Earth using 1.16 billion satellite measurements. This yields valuable knowledge for climate research.

The Earth’s gravity fluctuates from place to place. Geodesists use this phenomenon to observe geodynamic and climatological processes. Using...

Im Focus: Tube anemone has the largest animal mitochondrial genome ever sequenced

Discovery by Brazilian and US researchers could change the classification of two species, which appear more akin to jellyfish than was thought.

The tube anemone Isarachnanthus nocturnus is only 15 cm long but has the largest mitochondrial genome of any animal sequenced to date, with 80,923 base pairs....

Im Focus: Tiny light box opens new doors into the nanoworld

Researchers at Chalmers University of Technology, Sweden, have discovered a completely new way of capturing, amplifying and linking light to matter at the nanolevel. Using a tiny box, built from stacked atomically thin material, they have succeeded in creating a type of feedback loop in which light and matter become one. The discovery, which was recently published in Nature Nanotechnology, opens up new possibilities in the world of nanophotonics.

Photonics is concerned with various means of using light. Fibre-optic communication is an example of photonics, as is the technology behind photodetectors and...

Im Focus: Cost-effective and individualized advanced electronic packaging in small batches now available

Fraunhofer IZM is joining the EUROPRACTICE IC Service platform. Together, the partners are making fan-out wafer level packaging (FOWLP) for electronic devices available and affordable even in small batches – and thus of interest to research institutes, universities, and SMEs. Costs can be significantly reduced by up to ten customers implementing individual fan-out wafer level packaging for their ICs or other components on a multi-project wafer. The target group includes any organization that does not produce in large quantities, but requires prototypes.

Research always means trying things out and daring to do new things. Research institutes, universities, and SMEs do not produce in large batches, but rather...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

SEMANTiCS 2019 brings together industry leaders and data scientists in Karlsruhe

29.04.2019 | Event News

Revered mathematicians and computer scientists converge with 200 young researchers in Heidelberg!

17.04.2019 | Event News

First dust conference in the Central Asian part of the earth’s dust belt

15.04.2019 | Event News

 
Latest News

Concert of magnetic moments

14.06.2019 | Information Technology

Materials informatics reveals new class of super-hard alloys

14.06.2019 | Materials Sciences

New imaging modality targets cholesterol in arterial plaque

14.06.2019 | Medical Engineering

VideoLinks
Science & Research
Overview of more VideoLinks >>>