Natural ligands of nuclear receptors

Welcome, everyone, to Chapter 7 of this short talk series on nuclear receptors as therapeutic targets. After discussing the molecular activation mechanisms by ligands in the last chapter, this chapter will now cover the natural ligands of nuclear receptors and their roles.

Based on the knowledge of ligands, nuclear receptors can be classified into four groups, as shown here by the different colors. The classification has also historical reasons and somewhat reflects when the natural ligands for each receptor were discovered. Classic nuclear receptors are receptors whose ligands were discovered early in nuclear receptor research. This includes steroid hormone receptors of the NR3 family and some members of the NR1 family, namely the thyroid hormone receptors, the retinoic acid receptors, and the vitamin D receptor. These receptors are all named by their ligands. Nuclear receptors for which a natural ligand was initially lacking but could later be clearly assigned are often described or classified as foster home. The names of these receptors refer mostly to the site or tissue where they were first discovered or to a biological role. The natural ligands were often discovered in early crystallographic studies on the respective receptors. This class comprises several metabolic sensors that bind endogenous metabolites: peroxisome proliferator-activated receptors, the NR1C family, and hepatocyte nuclear factors, the NR2A family, bind fatty acids and metabolites as endogenous ligands. Retinoic acid receptor-related orphan receptors, the NR1F family, bind cholesterol metabolites, and the NR5A family receptors liver receptor homologue-1 and steroidogenic factor-1 are phospholipid sensors. The pregnane X receptor and the constitutive androstane receptor have a special role in this class, as they bind diverse types of ligands summarized as xenobiotics. We will have a closer look at their role later in this chapter. Also, the so-called adopted orphan nuclear receptors were initially described without known ligands, and the endogenous modulators were identified later. This class includes the revERB proteins binding heme, the liver X receptors as sensors for cholesterol metabolites, the farnesoid X receptor which binds bile acids, and the retinoid X receptors for which 9-cis retinoic acid has been identified as a high-affinity natural ligand. However, some of the bona fide natural ligands of adopted orphans are still debated. For example, 9-cis retinoic acid strongly activates the RXRs, but it is not clear whether natural levels of these molecules are high enough to cause relevant RXR modulation. The retinoid X receptors also bind other vitamin A and fatty acid metabolites which may hence be more relevant as endogenous ligands. The fourth class comprises the so-called orphan receptors for which the endogenous ligands have not been assigned. However, the level of knowledge on ligands in this class varies strongly. For some receptors, ligands remain completely elusive, whereas for others several natural ligand candidates have been identified but not yet clearly confirmed as endogenously relevant. We will discuss this in more detail in later chapters on the individual receptors. It should be noted that the classification in classic nuclear receptors, foster home, adopted orphans, and orphans is not absolute but dynamic and has blurry boundaries. Natural nuclear receptor ligands