Cover image from Nature Medicine showing cholesterol scrystals in gall bladder bile
Cover image from Nature Medicine, December 2004
​​​​​showing cholesterol scrystals in gall bladder bile.
See manuscript by Moschetta, Bookout, and Mangelsdorf,
 Nature Medicine 10:1352-1358, 2004.

One of the pathways taken by multicellular organisms to process extracellular signals into a transcriptional response within a target cell is by a nuclear receptor. These receptors are transcription factors that become active after binding to small lipophilic molecules, such as steroid and thyroid hormones, and vitamins A and D.

Our work has shown that many of these nuclear receptors evolved as sensors that respond to dietary lipids and nutrient availability. Examples include oxysterol receptors (LXRα and β), the bile acid receptor (FXR), fatty acid receptors (PPARa and PPARg), and the xenobiotic receptor (PXR). The analysis of these receptors has led to the discovery of the mechanism and metabolic processes by which the body maintains homeostatic levels of the lipids and how the body manages energy metabolism in response to nutrients. Studying these pathways has uncovered the existence of two endocrine factors, FGF19 and FGF21, that are targets of nuclear receptors and that regulate the storage of energy in the fed state and the mobilization and burning of energy in the fasted state.

Nuclear receptors are also found in invertebrate species like insects and worms. An example is DAF-12, a nuclear receptor found in nematode worms that, like its vertebrate homologs, is activated in response to its environment (when food is plentiful). This pathway is essential for the worm to complete its lifecycle, and importantly the requirement for DAF-12 is conserved in both free-living and parasitic species of nematodes. Because DAF-12 is required for infection by parasites, it is being explored as a potential therapeutic target for many parasitic diseases.