Researchers Outline Possible Drug Targets For Treating Metabolic Syndrome

The metabolic syndrome, which affectsmore than 47 million Americans, is a constellation of disorders of thebody's metabolism – such as abdominal obesity, hypertension and insulinresistance – that increase one's risk of heart disease, dangerousplaque buildup in artery walls and non-insulin-dependent diabetes.

Ina review article in the Aug. 11 issue of The New England Journal ofMedicine, UT Southwestern's Dr. David Mangelsdorf, professor ofpharmacology and biochemistry, and Dr. Andrew Shulman, a MedicalScientist Training Program fellow, examine how one category of proteinsfound in the cell's nucleus, called retinoid X receptor heterodimers,are promising novel drug targets for treating the metabolic syndrome.

"Ourresearch has taught us that that these receptors are potentiallylegitimate therapeutic targets that show great promise," Dr.Mangelsdorf said. "But we also have learned that, as with any drugdevelopment, it is going to be a challenge to come up with the rightdrug or drugs to do the job."

The metabolic syndrome, sometimesreferred to as syndrome X, is characterized by multiple risk factors,with the underlying causes being obesity, physical inactivity andgenetic factors. The characteristic disorders present in the metabolicsyndrome include: excessive fat tissue in and around the abdomen; highblood pressure; insulin resistance or glucose intolerance; blood fatdisorders, mainly high triglycerides and low high-density lipoproteins,or "good" cholesterol; and abnormalities in blood clotting.

Anyone of these disorders by itself is a risk for certain diseases, but incombination they can dramatically boost one's chances for developinglife-threatening illnesses, said Dr. Mangelsdorf, a Howard HughesMedical Institute investigator.

"One person may have a moresevere case of type 2 diabetes, for example, or another person may nothave 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, lipidmetabolism may drive the syndrome. The question is, why?" The answermay lie in research conducted by Dr. Mangelsdorf and others thatidentified the protein retinoid X receptor, or RXR, which play's a keyrole in lipid metabolism. This protein can bind to several otherso-called nuclear receptors to form distinct molecular complexes calledheterodimers. Each complex then can go on to control certain genesinvolved in regulating lipid and cholesterol metabolism.

"WhenRXR is paired with a nuclear receptor called PPAR-gamma, for example,it activates one set of genes," Dr. Mangelsdorf said. "When RXR ispaired with another receptor called LXR, it acts on a different set ofgenes. All of the genes, however, are involved with lipid metabolism."

Drugsthat target RXR and its binding partners are already in clinical use ortrials for the treatment of cancer, dermatological disorders, endocrinedisorders and some aspects of the metabolic syndrome. In their reviewarticle, Drs. Mangelsdorf and Shulman outline promising researchfindings on how drugs that target RXR complexes may be used in themanagement of the metabolic syndrome.

One of the challenges todeveloping therapies targeting these receptors is that activating orblocking a given receptor can have both positive and negative effectson the body. The trick, Dr. Mangelsdorf said, is to develop drugs thatselectively act on a particular receptor to activate only the goodeffects while dialing out the bad effects.

For example,activating the LXR receptor, which binds with RXR to modulatecholesterol levels, also has the effect of increasing fat synthesis,which is undesirable, Dr. Mangelsdorf said.

Some drugs thatselectively modulate nuclear receptors have already proved successfulas cancer drugs. For instance, tamoxifen citrate acts on estrogenreceptors to selectively block the activity of estrogen in breasttissue while acting like estrogen in other tissues, where it slows boneloss and lowers blood cholesterol.

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The research wassupported by the Howard Hughes Medical Institute, the Robert A. WelchFoundation, the National Institutes of Health Pharmacological SciencesTraining Program and UT Southwestern's Medical Scientist TrainingProgram.