Newly discovered gene regulates balance of 'bad' cholesterol

Jul 02, 2009
Newly discovered gene regulates balance of 'bad' cholesterol
IDOL

In an article in Science, Noam Zelcer from the LACDR (The Netherlands) describes a previously unknown mechanism for regulating the amount of LDL cholesterol. This offers opportunities for supplementing and improving the effect of so-called statins: medicines that remove 'bad' cholesterol from the bloodstream. 

Cholesterol is not water-soluble. In order to be transported in the blood, it therefore forms fat globules, called lipoproteins, together with other fats. The two most familiar are known as HDL (high density lipoprotein) or ‘good’ , and LDL () or ‘bad' cholesterol. Too much LDL in the blood can contribute to the development of cardiovascular diseases.

A group of substances, known as statins, is often used as a medication to reduce the LDL level in the blood. They achieve this by on the one hand blocking the production of cholesterol and on the other hand by raising the number of receptors for LDL on the cells of the liver. This allows the cells to absorb more LDL from the blood, so that the blood becomes 'cleaner'. Statins are currently the most frequently sold medicines. However, they are not perfect.

The development of statins is based on the cell's natural mechanisms for regulating the cholesterol balance. All cells have the ability to make, absorb or excrete cholesterol. And all cells have to treat cholesterol with care: too much cholesterol in the cell is toxic, but too little is also not good. Cholesterol is needed for such purposes as forming membranes. Cells can 'sense' the amount of cholesterol and regulate the level by pumping it away if there is too much. If they want to obtain cholesterol from outside, they raise the level of the LDL receptor. This receptor binds to 'free ranging' LDL and absorbs it into the cell, where the fat globule is broken down into its different components, including cholesterol itself.

Noam Zelcer, now part of the Leiden/Amsterdam Center for Drug Research (LACDR), together with Peter Tontonoz and other former colleagues at the University of California in Los Angeles, has discovered a previously unknown mechanism that explains how cells regulate cholesterol levels. On the website of the journal Science (Science Express 11 June), he describes a mechanism that influences the number of LDL receptors.

If active IDOL is present in the cell, the number and positioning of the LDL receptors alters dramatically.

Zelcer identified a gene that influences the breakdown of these receptors. 'The gene works like a traffic controller,' he explains. 'As soon as there is too much cholesterol in the cell, it sends the LDL receptors to the lysosome, the waste processing centre of the cell. They are broken down there, so that the cell absorbs less cholesterol and the balance is restored.'

Zelcer named the cell IDOL, which stands for Inducible Degrader Of the LDLR. This cell repairs the internal balance. But the same degradation mechanism that maintains the internal balance could well be a factor that prevents statins from working optimally: namely allowing LDL to be removed from the blood by cells. Zelcer: ‘There are indications that this could be the case, so we have studied what happens if we switch off the IDOL.' Raised receptor level They managed to do this successfully, both in mice cells and in human cells in a test tube. As soon as the researchers inactived the IDOL, or reduced the amount, the level of the LDL receptor rose, so that the cell was able to absorb more LDL cholesterol. Zelcer is now researching wh ether influencing IDOL might lead to a new cholesterol-reducing therapy that complements the working of statins.

Source: Universiteit Leiden

Explore further: Diminutive decoys: Membrane-cloaked nanoparticles disrupt antibody-mediated autoimmune diseases

add to favorites email to friend print save as pdf

Related Stories

Contribution of cholesterol transporter to vascular disease

Oct 26, 2007

Low-density lipoprotein (LDL), a transporter of cholesterol, may also contribute to vascular diseases by a previously unidentified mechanism, according to a report published online this week in EMBO reports. The study reveals ...

Bad cholesterol inhibits the breakdown of peripheral fat

Nov 20, 2008

The so called bad cholesterol (LDL) inhibits the breakdown of fat in cells of peripheral deposits, according to a study from the Swedish medical university Karolinska Institutet. The discovery reveals a novel function of ...

New study to test Statin-Parkinson's link

Jan 16, 2007

Researchers are sufficiently worried by new study results that they are planning clinical trials involving thousands of people to examine the possible link between Parkinson's disease and statins, the world biggest selling ...

Recommended for you

New biomedical implants accelerate bone healing

7 hours ago

A major success in developing new biomedical implants with the ability to accelerate bone healing has been reported by a group of scientists from the Department of Restorative Dentistry, University of Malaya. ...

User comments : 0