Researchers Identify Cholesterol Regulating Genes

By on July 15, 2009
cholesterol molecule Researchers have identified 20 genes that are involved in the regulation of cholesterol levels. Besides giving scientists a better idea of where to look to uncover the mechanisms that ensure cholesterol balance is maintained, the discovery could lead to new treatment and prevention strategies for cholesterol related diseases.

Image: A cholesterol molecule (red) buried within a protein.

High levels of cholesterol in the bloodstream are a major risk factor for atherosclerosis and coronary heart disease, one of the leading causes of death in developed countries today. Nevertheless, cholesterol is an important cellular component: 90% of the cholesterol in our bodies is inside our cells, where it does not cause any harm. Blood cholesterol levels are partly regulated by cells taking up cholesterol from the bloodstream, a process the researchers are helping to unveil.

The research team deprived isolated human cells of cholesterol and then looked at the whole genome to find the genes that react to changes in cholesterol levels by altering their expression.  This large-scale approach pointed to hundreds of genes which might be involved in cholesterol regulation. To check which genes really were involved, the scientists used a technique called RNA interference to systematically turn each of the candidate genes off. With a microscope they then observed what effect switching off different genes had, both on cholesterol uptake and on the total amount of cholesterol inside cells.

Of the 20 genes the scientists identified as involved in regulating cholesterol levels and uptake, 12 were previously unknown. The remainder were known to have some link to lipid metabolism – how the body breaks down fat – including two genes that when mutated may cause heart disease, but which were only now shown to also play a part in bringing cholesterol into cells in the first place.

The scientists are now trying to discover exactly how the novel genes regulate cholesterol levels inside cells, as well as looking at patients to determine whether these genes (or alterations in them) do constitute risk factors, and investigating if and how they could be useful drug targets.

This discovery could help fight not only heart disease, but also other conditions, as one of the genes identified appears to influence the behaviour of NPC1, a protein involved in the neuro-degenerative Niemann-Pick disease.

References:
1. Heiko Runz,  et al. Identification of cholesterol regulating genes by targeted RNAi-screening. Cell Metabolism, 8 July 2009.
2. Image Courtesy of NIGMS Biomedical Beat.

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