Ligand Regulation and Nuclear Receptor Action

Abstract

Abstract:Nuclear receptors signal primarily via ligand-dependent mechanisms that are initiated when the ligand in question interacts with a specific receptor binding domain. Subsequent transcriptional responses to ligand-receptor interaction are then dependent on an array of downstream mechanisms such as chromatin remodeling, receptor binding to target gene promoter DNA and the modulation of receptor co-activators and co-repressors. However, it is also important to recognize that the efficacy of nuclear receptor signaling will also be influenced by more upstream pathways that modulate the ligand itself. These include mechanisms that control the cellular acquisition of ligand and its subcellular translocation, as well as metabolic systems that increase or decrease the local concentration of nuclear receptor ligands. The following chapter describes examples of these pathways for regulation of nuclear receptor ligands and their developing importance as therapeutic targets for human disease. INTRODUCTIONSignaling pathways for nuclear receptors are complex, involving the integration of ligand binding, chromatin remodeling, DNA binding and the modulation of coactivator and co-repressor proteins. Given these complexities, it is understandable that studies of nuclear receptor signaling have focused primarily on molecular events that follow the binding of specific ligands to their cognate receptors. However, the ligand-dependency of most receptor responses means that the regulation of ligands themselves remains a pivotal component of this pathway. As illustrated in Figure 16.1a, this is commonly perceived as a passive mechanism involving the membrane diffusion of lipid-soluble molecules such as steroid hormones/sterols, followed by random association with cytosolic or nuclear receptors according to intracellular concentration gradients. Clearly this is likely to be an over-simplification and current data indicate that distinct mechanisms are involved in facilitating the delivery of ligands to their receptors. As outlined in Figure 16.1b, these include:

Total and free vitamin D status among apparently healthy adults living in Duhok Governorate

“…The sum of the Free 25‐OHD (FD) and the albumin bound fraction is called the bioavailable 25‐OHD. The investigators believe that the low‐affinity albumin‐25‐OHD complex allows 25‐OHD molecules to be available to exert their biological effects 15 . It is presently unclear whether free or bioavailable 25-OHD is better reflecting the availability of 25-OHD for cells or tissues.…”

Free Vitamin D Status Among Apparently Healthy Adults Living in Duhok Governorate

“…The sum of the free 25-OHD and the albumin bound fraction is called the bioavailable 25-OHD. The investigators believes that the low-a nity albumin-25-OHD complex allows 25-OHD molecules to be available to exert their biological effects [15].…”

Vitamina D libre: una determinación en aumento

“…A small fraction, less than 0.1% of the total, circulates freely, and not bound 13 . The sum of free 25-OHD and the bound fraction to albumin is called bioavailable 25-OHD, since it is believed that the low-affinity albumin-25-OHD complex allows 25-OHD molecules to be readily available for produce their biological effects 14 .…”