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Newly discovered gene regulates balance of ‘bad cholesterol’

In a publication in Science, Noam Zelcer from the Division of Biopharmaceutics describes a previously unrecognized pathway to regulate LDL-cholesterol levels. He is also able to modulate this pathway. This opens the possibility for complementing and improving the efficacy of statins: A class of drugs used to remove ‘bad cholesterol’ from the bloodstream.

Cholesterol

Cholesterol is extremely insoluble in water. For transport in the blood it therefore forms, together with other lipids, “fat balls” called lipoproteins. The two most known lipoprotein variants are 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 coronary disease and atherosclerosis.

Statins

A family of drugs called statins is often used to lower the level of LDL in the blood. They achieve this by on the one hand blocking the production of cholesterol, and on the other hand by increasing the number of LDL receptors on cells of the liver. As a result, these cells are able to take up more LDL and “clean” the blood from it. Statins are currently the most sold drugs, but they are not perfect.

Cholesterol balance in the cell

Statins have been developed on the basis of natural mechanisms in the cell for regulating the cholesterol balance. Every cell is able to produce, absorb, or excrete cholesterol. As such, every cell has to deal with cholesterol sensibly. Too much cholesterol in a cell is toxic, but too little is not good either; i.e. cholesterol is necessary to produce membranes. Cells can ‘sense’ the level of cholesterol, and regulate the cholesterol concentration by pumping cholesterol out in case of increased levels, or by making cholesterol and absorbing it from the outside when the concentration level is too low. To take up cholesterol from the outside cells raise the level of the LDL-receptor. This receptor binds to LDL and brings it into the cell. Inside the cell the lipoprotein is broken down into its constituents, one of which is cholesterol.

New mechanism

Noam Zelcer, since January 2009 affiliated with the LACDR, has discovered, together with Peter Tontonoz and former colleagues at the University of California in Los Angeles, a previously unrecognized mechanism which further explains how cells regulate their cholesterol levels. On the website of Science Magazine (Science Express, June 11) he describes a mechanism which influences the number of LDL receptors.

Traffic Controller

Noam Zelcer identified a gene that influences the destruction of LDL receptors. ‘The gene operates like a traffic controller’, he says. ‘As soon as there is too much cholesterol in the cell, it sends the LDL receptors to the lysosome, the cell’s “garbage disposal plant”. There, the receptors are broken down, leading to less cholesterol uptake by the cell which helps to reinstate the cholesterol balance.’

IDOL

Noam Zelcer named the gene IDOL. This stands for Inducible Degrader Of the LDLR.  IDOL contributes to maintaining the cellular cholesterol balance. However, the same mechanisms that maintain this internal balance might be a factor limiting the efficacy of statins.  Zelcer: ‘There are indications that this might be the case, and that’s why we have investigated what happens if we inactivate IDOL’.

Receptor levels increase

This approach proved successful, both in mouse cells and in human cells in vitro. As soon as the researchers inactivated IDOL, or reduced its level, the LDL-receptor level increased, enabling the cell to absorb more LDL. Zelcer is now studying whether modulating IDOL can provide a new approach to reduce cholesterol levels and complement current statins based therapy.

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