Nuclear receptor Subject

While bound to its cognate response element, the liganded/dimerized receptor recruits co-activator proteins that link with additional transcription factors, often leading to acetylation of histones, which opens up the nucleo-some to admit RNA polymerase II to the transcription start site. As would be expected, given that there is a sizeable superfamily of nuclear receptors and numerous interacting proteins, this simplified central theme is subject to many variations and complexities that allow subtle fine-tuning of regulatory responses. 

Apart from direct activation via ligand binding, nuclear receptors are also subject to regulation by phosphorylation. Thus, transcriptional activity of PPARy can be regulated by growth factor stimulation via the mitogen-activated protein (MAP) kinase pathway (34). 

Retinoids are a family of naturally occurring and synthetic analogues of vitamin A. The skin of subjects deficient in vitamin A becomes hyperplastic and keratotic (phrynoderma, or toad skin). While natural vitamin A is occasionally employed therapeutically, synthetic retinoids are more effective and represent a major advance in dermatological pharmacotherapy. Retinoids have myriad effects on cellular differentiation and proliferation it is likely that nuclear retinoic acid receptors mediate these effects by activating gene expression in a manner analogous to receptors for steroid hormones and thyroid hormones. Despite a common mechanism of action, however, retinoids vary widely in their physiological effects. 

Many CYP3A substrates are also subject to efflux transport by P-gp at the intestinal mucosa (88-90). As discussed above, P-gp is inducible via activation of nuclear orphan receptors by the same inducers of CYP enzymes (91). Accordingly, for those drugs which are substrates of both CYP and P-gp, reduction in intestinal availability following treatment with known microsomal enzyme inducers could reflect the joint effects of increased mucosal metabolism and apical efflux. 

Shen, P., Z.J. Xie, H. Li and E.R. Sanchez. Glucocorticoid receptor conversion to high affinity nuclear binding and transcription enhancement activity in Chinese hamster ovary cells subjected to heat and chemical stress. J. Steroid Biochem. Mol. Biol. 47 55—64, 1993. 

Significantly, inflammation and lipid metabolism exhibit close functional interrelationships and are subject to coordinate, reciprocal regulation. PPARy and LXRs have been reported to reciprocally regulate genes involved in both immunity and lipid metabolism [6,90]. While the primary focus of the action of PPARy in inflammation has focused on receptor-mediated inhibition of inflammatory gene expression, there is a reciprocal effect of inflammation on nuclear hormone expression. Feingold and colleagues have extensively examined the inflammation-mediated suppression of PPARy and RXR expression [91]. 

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