Molecular switch may hold key to cure

How a molecular switch regulates fat and cholesterol production has been identified by researchers at Harvard University Medical School and Massachusetts General Hospital, Boston, a step that may help advance treatments for metabolic syndrome, the constellation of diseases that includes obesity, type II diabetes, and high blood pressure.

"We have identified a key protein that acts together with a family of molecular switches to turn on cholesterol and fat--or lipid--production," says principal investigator Anders Naar, assistant professor of cell biology at Harvard University Medical School and the Massachusetts General Hospital Cancer Center. "The identification of this protein interaction and the nature of the molecular interface may one day allow us to pursue a much more comprehensive approach to the treatment of metabolic syndrome."

High levels of cholesterol and lipids are linked to a number of interrelated medical conditions and diseases, including obesity, type II diabetes, fatty liver, and high blood pressure. This set of conditions and diseases, known as metabolic syndrome, is afflicting a rapidly increasing portion of society and serves as a major risk factor for heart disease, the leading cause of death in the developed world.

Treatments for diseases associated with metabolic syndrome primarily have focused on individual elements, such as high LDL-cholesterol (targeted by the cholesterol-lowering statin drugs). However, more effective ways to treat all of the components of metabolic syndrome are needed. One attractive approach might be to target the genetic switches that promote cholesterol and lipid synthesis, but it would require a detailed understanding of the regulatory mechanisms before drug targets can be identified.

After a meal is eaten, a family of proteins acts as switches to turn on cholesterol and lipid production. This active family of proteins is known as SREBPs, or sterol regulatory element binding proteins. Between meals, the production of cholesterol and lipids should be turned off. However, excess intake of foods, coupled with lack of exercise, appears to disturb the normal checks and balances that control SREBPs, resulting in overproduction of cholesterol and lipids.

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