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A Major Break Through in Treatment for Metabolic Syndrome

, the production of cholesterol and lipids should be turned off, however, excess intake of foods, coupled with lack of exercise, appear to disturb the normal checks and balances that control SREBPs, resulting in overproduction of cholesterol and lipids.

In the Nature paper, the HMS and MGH Cancer Center team has shown that a protein called ARC105, which binds to SREBPs, is essential in controlling the activity of the SREBP family of proteins. "ARC105 represents a lynchpin for SREBPs control of cholesterol and lipid biosynthesis genes, which may provide a potential molecular Achilles heel that could be targeted by drugs" says Dr. N??r.

The researchers initially found that after removing ARC105 from human cells by a process called RNAi, SREBPs were no longer able to activate cholesterol and lipid biosynthesis genes. To validate these findings in a physiological setting, the researchers turned to the microscopic worm C. elegans, a favorite model organism among those studying evolutionarily conserved biological processes because of its rapid generation time and relative simplicity of genetics, and which had previously been used to study mechanisms of fat regulation.

Through a collaborative effort with the worm genetics group of Anne Hart, PhD, HMS associate professor of pathology at the MGH Cancer Center, the team demonstrated that the C. elegans homologues of SREBP and ARC105, known as SBP-1 and MDT-15, respectively, are necessary for production and storage of fat. The worms had regular fat production when SBP-1 and MDT-15 functioned normally, but when researchers used RNAi to knock out function of either SBP-1 or MDT-15, the worms lost their ability to properly store fat, lay eggs, and move normally.

"The striking effects of the RNAi knock downs in C. elegans suggest that the ARC105/SREBP pathway may play a key role in lipid production in humans," said Laurie Tompkins, PhD, of the National Institute of General Medical Sciences,
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