Using a combination of innovative genomic tools, researchers have turned up twenty genes that have important roles in controlling cholesterol within cells. The findings reported in the July 8 issue of Cell Metabolism, a Cell Press publication, could point the way to important new risk factors for cardiovascular disease, according to the researchers.

“High cholesterol in the blood is considered to be responsible for excess cardiovascular morbidity and mortality,” said Heiko Runz of the University of Heidelberg. “Blood cholesterol levels are controlled by cholesterol in cells. Therefore, some of the genes identified by us as regulators of cellular cholesterol in future studies might turn out to be disease genes that contribute to hypercholesterolemia in some cases. Moreover, the strategy we used could open a new avenue to identify risk factors for cardiovascular disease.”

“The factors uncovered may also have potential as targets for new cholesterol-lowering drugs,” continued Rainer Pepperkok from EMBL Heidelberg, adding that high blood cholesterol is a widespread condition that remains difficult to treat.

Cholesterol has a bad rap, but it is also an important ingredient in the membranes that envelop our cells, accounting for about 25 percent of all membrane lipids. Normally, the amount of cholesterol in the bloodstream is closely controlled by the amount taken up by cells. Despite extensive insight into cholesterol metabolism, scientists still know little about the molecular level events and interactions involved in keeping cholesterol under control. As a result, researchers have surmised that many proteins important to keeping the lipid in check remain to be discovered.

In search of those missing players, Runz, Pepperkok, and their colleagues first screened the activity of genes across the genome in cells starved of cholesterol.

“When cholesterol is low, cells become hungry,” said Runz, “and genes are activated that enable those cells to take up more cholesterol from the blood.”

In the new study, the researchers went in search of novel cholesterol-regulatory factors by looking for genes that showed a pattern of behavior similar to that of genes with already known function in cholesterol regulation. They then tested the importance of 100 of those cholesterol-regulating candidates using a method known as RNA interference (RNAi), in which tiny bits of RNA are used to block the activity of genes one by one in order to see what they do to cellular cholesterol.

Their strategy led them to a list of 20 genes that they say are likely to be “immediately relevant” for maintaining cellular levels of cholesterol or the uptake of low-density lipoproteins (LDL), particles that transport so-called bad cholesterol in the blood. They provide further validation of their findings by showing in greater molecular detail that one of those genes, known as TMEM97, interacts with the well-known cholesterol transport regulator NPC1.

The methods piloted in the new study may lead to many more cholesterol genes in future studies.

“Until now,” the researchers concluded, “disease-associated genes affecting blood cholesterol levels have successfully been identified in single families and, more recently, genomic studies involving large numbers of patients. Most of what we know about the molecular machinery that keeps cholesterol levels balanced, however, comes from using cultured cell models. A functional analysis of many genes at once by the integrated functional genomics technology applied here now harbors potential not only to ease identification, but also to better describe the molecular roles of cholesterol regulators in health and disease.”

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The researchers include Fabian Bartz, University of Heidelberg, Heidelberg, Germany; Luise Kern, University of Heidelberg, Heidelberg, Germany; Dorothee Erz, University of Heidelberg, Heidelberg, Germany; Mingang Zhu, University of Heidelberg, Heidelberg, Germany; Daniel Gilbert, European Molecular Biological Laboratories (EMBL), Heidelberg, Germany; Till Meinhof, University of Heidelberg, Heidelberg, Germany; Ute Wirkner, German Cancer Research Center (DKFZ), Heidelberg, Germany; Holger Erfle, European Molecular Biological Laboratories (EMBL), Heidelberg, Germany, University of Heidelberg, Heidelberg, Germany; Martina Muckenthaler, University of Heidelberg, Heidelberg, Germany; Rainer Pepperkok, University of Heidelberg, Heidelberg, Germany, European Molecular Biological Laboratories (EMBL), Heidelberg, Germany; and Heiko Runz, University of Heidelberg, Heidelberg, Germany.

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