Mechanism for the in-vivo transpor...(le of being bonded to other lipophilic s...)

Date:9/22/2007

le of being bonded to other lipophilic substances in addition to cholesterol, and caused a reduction in the activity of a target gene in the liver at the same time. It turned out that there are several such fatty acids. But what is it in the blood to which all these RNAs conjugated with so-called lipophilic substances bond" The ETH Zurich researchers discovered that, depending on the fatty acid used, the binding partners are the well-known cholesterol transporters High Density Lipoproteins (HDL) and Low Density Lipoproteins (LDL) as well as the albumin (protein) present everywhere in the blood. Without these lipoprotein particles there is no uptake of siRNAs into the tissues, as became apparent from further experiments. In an additional experiment the scientists demonstrated that the uptake can be made considerably more efficient if the siRNA-fatty acid molecules are already firmly bonded to HDL and LDL before being administered. Stoffels team also discovered that there is preferential uptake into different tissues depending on whether an siRNA-fatty acid molecule is bonded to HDL or LDL: all LDL compounds trigger responses in the liver, but HDL compounds also do so in the intestine or kidneys.

An irritating finding

The latter finding indicated that the uptake proceeds via HDL and LDL receptors. The researchers proved this assumption by inactivating the receptors, with the result that uptake no longer occurred. Despite the clarity of the finding, it irritated Stoffel slightly. He found it hard to imagine that the siRNAs were able to enter the cell via the normal absorption route like HDL, because this route leads into the cells own digestive system with lysosomes that would degrade the siRNAs. So how would the siRNAs be able to avoid this degradation" Stoffel concluded that they simply use a different doorway into the cell. Thus the HDL and LDL receptors would only act as docking stations but not as an entry portal.

But what might t
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Contact: Professor Marcus Stoffel 41-446-334-560 Swiss Federal Institute of Technology Source:Eurekalert

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