Nuclear Hormone Receptor PXR that Links Xenobiotic Metabolism and Aging
Every day our body must defend itself against countless xenobiotics. Metabolism of xenobiotics is one of the possible candidate pathways that control aging. In dealing with environmental xenobiotics, mammals have evolved a defensive network governed by xenobiotic receptors, such as pregnane X receptor (PXR). PXR can be activated by a diverse array of sterols and xenobiotics and functions as a xenobiotic sensor to coordinately regulate xenobiotic clearance via induction of genes involved in xenobiotic metabolism.
Work in C. elegans has revealed that nuclear hormone receptors play an important role in life span and longevity. Interestingly, DAF-12, an ortholog of vertebrate PXR in C. elegans, plays a key role in regulation of dauer diapause in response to environmental cues. However, as the key regulator of sterol and xenobiotic metabolism in mammals, the role of PXR in life span or longevity has not been investigated. Our current data suggest that activation of PXR can improve insulin sensitivity and PXR can also play an important role in resistance to xenobiotic stress. We are studying whether PXR can respond to environment quality and make metabolic adjustments to enhance longevity.
The goals of this project are to determine whether PXR-deficiency leads to shortened life span in mice and activation of PXR improves health and survival of mice, define the possible involvement of PXR-mediated induction of Gadd45β in resistance to genotoxic and xenobiotic stress-induced apoptosis, and to determine the role of PXR in an age-related disease i.e. atherosclerosis.
Researchers:
Changcheng Zhou, czhou@rockefeller.edu
Alexandra DeWitt, adewitt@rockefeller.edu
