Ongoing studies by researchers at UT Southwestern Medical Center and other institutions have uncovered the biochemical basis of many of the factors contributing to what is known as the metabolic syndrome, suggesting potential new drug targets for treating the condition.
The metabolic syndrome, which affects more than 47 million Americans, is a constellation of disorders of the body's metabolism - such as abdominal obesity, hypertension and insulin resistance - that increase one's risk of heart disease, dangerous plaque buildup in artery walls and non-insulin-dependent diabetes.
In a review article in the Aug. 11 issue of The New England Journal of Medicine, UT Southwestern's Dr. David Mangelsdorf, professor of pharmacology and biochemistry, and Dr. Andrew Shulman, a Medical Scientist Training Program fellow, examine how one category of proteins found in the cell's nucleus, called retinoid X receptor heterodimers, are promising novel drug targets for treating the metabolic syndrome.
"Our research has taught us that that these receptors are potentially legitimate therapeutic targets that show great promise," Dr. Mangelsdorf said. "But we also have learned that, as with any drug development, it is going to be a challenge to come up with the right drug or drugs to do the job."
The metabolic syndrome, sometimes referred to as syndrome X, is characterized by multiple risk factors, with the underlying causes being obesity, physical inactivity and genetic factors. The characteristic disorders present in the metabolic syndrome include: excessive fat tissue in and around the abdomen; high blood pressure; insulin resistance or glucose intolerance; blood fat disorders, mainly high triglycerides and low high-density lipoproteins, or "good" cholesterol; and abnormalities in blood clotting.
Any one of these disorders by itself is a risk for certain diseases, but in combination they can dramatically boost one's chances for developing life-threatening illnesses, said Dr. Mangelsdorf, a Howard Hughes Medical Institute investigator.
"One person may have a more severe case of type 2 diabetes, for example, or another person may not have hypertension, yet they may all have the syndrome," he said. "There's not one factor that overrides everything else. Lipid, or fat, metabolism is an important component, however, and in fact, lipid metabolism may drive the syndrome. The question is, why?" The answer may lie in research conducted by Dr. Mangelsdorf and others that identified the protein retinoid X receptor, or RXR, which play's a key role in lipid metabolism. This protein can bind to several other so-called nuclear receptors to form distinct molecular complexes called heterodimers. Each complex then can go on to control certain genes involved in regulating lipid and cholesterol metabolism.