Stockholm -- Nuclear hormone receptors, or X receptors, have become a powerful target of drug development with significant implications for the treatment of metabolic diseases, particularly atherosclerosis and diabetes, according to Johan Auwerx, MD, PhD, (Institut de Génétique et Biologie Moléculaire et Cellulaire, Strasbourg, France).

At the opening plenary lecture of the XIIth International Symposium on Atherosclerosis, Auwerx discussed X receptors and their targeted drugs that are now in the initial stages of development.

"These receptors are one of the most promising drug development tools," said Auwerx. "We are just starting to understand the biology. We're probably going to see many new drugs coming out of this nuclear receptor targeted drug research."

X receptors are transcription factors that directly affect gene expression and control many metabolic pathways. Examples of X receptors range from the peroxisome proliferator-activated receptors (PPARs) and the liver X receptor (LXR) to the bile acid receptor (BAR/FXR). The natural ligands for X receptors include such compounds as fatty acids and cholesterol. As Auwerx explained, "X receptors are receptors for excess or thrifty responses."

In order to be active, X receptors form a complex with another nuclear receptor, the retinoid X receptor (RXR). This has created excitement in the pharmaceutical industry, says Auwerx, because it means that X receptors can be activated in two distinct ways. First, they can be activated by specific X receptor ligands, such as the PPAR or LXR ligands. Second, they can be activated by ligands for RXR, allowing activation of all X receptors which dimerize with RXR. This double activation mechanism allows both the development of highly specific drugs affecting only selective metabolic pathways and the development of "broad spectrum" metabolic modulators which affect numerous X receptor signaling pathways.

According to Auwerx, RXR has already led to pharmaceutical research directed toward such indications as inflammation. He noted that atherosclerosis can be considered an inflammatory disease. Pharmaceutical researchers are also working on PPARs and their specific ligands. PPARs drew considerable interest when it was discovered that thiazolidinediones, a class of antidiabetic agents, are PPAR-specific ligands. Research on PPARs has identified specific synthetic X receptor agonists for selective pathways, including "the use of fibrates to activate [one] PPAR to combat hyperlipidemia and the use of thiazolidinediones to activate [another] PPAR in type 2 diabetes."

Pat Phillips
www.athero.org