Endocrine Abstracts

Nuclear receptors are ligand-dependent transcription factors that govern complex physiologic pathways, including reproduction, development, and metabolism. The importance of this receptor superfamily is emphasized by its conservation throughout evolution, from simple multicellular organisms to humans. Because of their therapeutic potential in governing physiology and disease, targeting nuclear receptors for novel drug discovery has become a major interest in both academia and the pharmaceutical industry. One area of intense focus has been the lipid-sensing receptors that govern metabolism of cholesterol (LXRalpha and LXRbeta), and bile acids (FXR). Previous studies have shown that many of the functions of LXRs and FXR are diametric to one another. For example, in the liver LXR agonists stimulate the pathways leading to bile acid and fatty acid synthesis, while FXR agonists repress both pathways. On the other hand, activation of both receptor systems has a beneficial effect in maintaining cholesterol homeostasis throughout the body. Our current work has focused on evaluating the yin and yang relationship of LXRs and FXR in other tissues, as well as in models for various lipid-related disorders, including obesity, cholesterol gallstone disease, inflammatory bowel diseases, innate immunity, and cancer. The specific regulatory cascades that are governed by LXRs and FXR in each of these models will be discussed. In addition, the therapeutic potential of agonists for these receptors will be explored.