Newly discovered gene regulates balance of 'bad' cholesterol

In an article in Science, Noam Zelcer from the LACDR 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

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’ cholesterol, and LDL (low density lipoprotein) or ‘bad' cholesterol. Too much LDL in the blood can contribute to the development of cardiovascular diseases.

Statins

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.

Cholesterol Balance within the cell

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.

New mechanism

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.

Traffic controller

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.'

IDOL

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.

Full bibliographic information: LXR Regulates Cholesterol Uptake Through Idol-Dependent Ubiquitination of the LDL Receptor
Noam Zelcer, Cynthia Hong, Rima Boyadjian, Peter Tontonoz
Science Express 11 June 2009

Comments

  1. Cleaves M. Bennett MD Cleaves M. Bennett MD United States says:

    I am ashamed to see a medical site perpetuate the marketing myth that LDL cholesterol is "bad" and HDL cholesterol is "good". Pfizer invented the terms and it caught on even with doctors. If your LDL cholesterol is too high the only thing that is bad is your diet! There is currently a plan to give everyone in the world over the age of 50 the "polypill" which contains aspirin, blood pressure pills, vitamins and a statin. Then we can eat as many McDonald's 4 patty burgers and Baskin Robbins large chocolate oreo shakes as we want. (Not really). I did not see the words "healthy diet" and "regular exercise" any where in the article. Please always keep these concepts up front and center.  We have children starting on statins now and that is one group that has never been tested. Kids are growing brain and body and learning huge amounts. The brain and the rest of the body is made of cholesterol. Will statins interfere with those processes? No body knows. If a kid starts a statin at age 8, will he have normal sexual development? Nobody knows. Will she learn and remember normally and get into college? No body knows. You start on a statin, that is every day for the rest of your life. They have only been tested out for 5 years. After that you are on your own. Google statin side effects and you get 346,000 entries. Google health diet and exercise and you get smiles and a pat on the back. Your choice.

  2. Duane Graveline MD MPH Duane Graveline MD MPH United States says:

    "All cells have the ability to make, absorb or excrete cholesterol."  Your own statement emphasizes just how vital our "normal" cholesterol is? Only now are we learning just how potentially damaging our reductase inhibitors really are. Interfering with the synthesis of cholesterol, ubiquinone and dolichols via mevalonate inhibition is like playing God. All three are vitally necessary for humans (and most other eukaryotes) to function. Statins are potentially very damaging unless intended for anti-inflammation, in which case we are dosing roughly thirty times too much.  

The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News-Medical.Net.
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