New mechanism for controlling cholesterol and lipid metabolism discovered

A team of investigators from the Uppsala Branch of the Ludwig Institute for Cancer Research (LICR) and Harvard Medical
School has uncovered novel targets for the development of drugs that would potentially complement, or replace, statins in
treating heart disease.


Statins are commonly taken drugs that reduce the levels of low density lipoprotein (LDL) and have been shown to reduce risks
associated with heart disease, the number one killer in the Western world. However, statins are not suitable for all
patients, and reduce cardiovascular events by only 20%- 40%. Additionally, some genetic causes of high cholesterol cannot be
treated with statins.


According to LICR's Dr. Johan Ericsson, the senior author of the study published today in Cell Metabolism, the team found
that a protein called Fbw7 degrades the SREBP proteins that drive lipid and cholesterol production. "We found that inhibiting
Fbw7 resulted in increased SREBP levels and an enhanced uptake of LDL, so a drug that blocks the interaction between Fbw7 and
SREBP proteins would probably enhance the removal of harmful LDL-cholesterol from the circulation. We can only speculate at
this stage, but a two-pronged attack on LDL removal, combining a statin with a treatment that prevents Fbw7/SREBP interaction
would likely be of more benefit to some patients than statins alone."


Dr. Ericsson said that the team also found that the Fbw7/SREBP interaction may also be connected to diabetes, as insulin
signaling inhibited Fbw7's ability to affect SREBP levels and thus increased lipid and cholesterol synthesis. Finally, the
Fbw7/SREBP interaction also provides a theoretical link between lipid synthesis and the aberrant growth of cancer cells. The
loss of Fbw7, which is inactivated in some breast, endometrial, ovarian and colon cancers, has been shown to make cells
multiply faster and synthesize more lipids; factors that are critical for tumor growth. Aspects of both links are under
investigation.


Contact: Sarah L. White, Ph.D.

swhitelicr

1-917-974-7952

Ludwig Institute for Cancer Research