Researchers at Harvard Medical School and Massachusetts General Hospital have identified how a molecular switch regulates fat and cholesterol production, a step that may help advance treatments for metabolic syndrome, the constellation of diseases that includes high cholesterol, obesity, type II diabetes, and high blood pressure.
The study is now published in the online version of the scientific journal Nature and will appear in the August 10th print edition.
"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 Nddr, PhD, assistant professor of cell biology at Harvard 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 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, are afflicting a rapidly increasing portion of society and serve as a major risk factor for heart disease, the leading cause of death in the developed world.
Treatments for diseases associated with metabolic syndrome have focused primarily 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 eating a meal, a family of proteins act as switches to turn on cholesterol and fat (or lipid) production. This 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, 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. Nddr.
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, which partially supported the research. "This work highlights the value of model organisms in helping us understand cellular processes that impact human health."