Protein provides hope for new medicines to lower cholesterol

An international research team has discovered a new target molecule, Fbw7, for developing drugs with the potential to
complement or replace statins in the treatment of cardiovascular diseases. The findings are being published in the new issue
of the scientific journal Cell Metabolism.


Cholesterol is a fat-like substance that is needed for the formation of our cells and for the production of hormones. The
amount needed can be provided by the body itself, but our eating habits often lead to too much cholesterol. The surplus is
stored in the walls of our vessels, thereby increasing the risk of cardiovascular disorders, the most common cause of death
in the Western world. What‚s more, individuals with cardiovascular diseases run a greater risk of being overweight and
contracting diabetes.


The protein SREBP regulates the genes that control the amount of cholesterol and other fats in cells. SREBP‚s ability to
regulate the new production, metabolism, and uptake of cholesterol from the blood is extremely important in the liver, where
huge quantities of cholesterol are absorbed and rendered harmless. SREBP is therefore a suitable target molecule for the
development of new drugs for cardiovascular diseases, overweight, and diabetes.


The most common medicinal treatment for heightened levels of cholesterol today is a group of drugs called statins. These
drugs activate SREBP and thus enhance the capacity of the liver to render cholesterol harmless. However, in high doses,
statins can have side effects, since they also block the new production of necessary cholesterol in other cells in the body.



The useful effect takes place primarily in the liver‚s uptake from the blood, explains Johan Ericsson from the Ludwig
Institute, Uppsala University, who led the study in collaboration with Harvard Medical School.


His team discovered in their molecular studies of the protein SREBP that it had a binding point that ought to suit the
protein Fbw7, which had been identified by the Harvard researchers. It turned out that Fbw7 inhibited the metabolism of fat
by breaking down SREBP. Consequently, inactivating Fbw7 led to greater amounts of SREBP and increased uptake of cholesterol.



Now we need to look more closely at the mechanisms behind the interaction between these two molecules. Fbw7 also has other
important functions in the cell, so the goal is to be able to knock out its effect on SREBP only, says Johan Ericsson.



Reference URL

cellmetabolism/content/current


SOURCE: Leicester University