Environmental Factor, June 2009, National Institute of Environmental Health Sciences
Xie Explores Hormone Regulation by Nuclear Receptors
By Laura Hall
On April 30, Wen Xie, M.D., Ph.D., presented a seminar at NIEHS on "Nuclear Receptor-Mediated Gene Regulation in Hormonal Homeostasis" as part of the NIEHS Laboratory of Pharmacology (LP) and Laboratory of Molecular Toxicology Seminar Series. His talk was hosted by NIEHS Principal Investigator Joyce Goldstein, Ph.D. (http://www.niehs.nih.gov/research/atniehs/labs/ltp/human/index.cfm), head of the LP Human Metabolism Group. Xie discussed a newly established role of liver X receptor (LXR) in hormonal homeostasis in mice that may lead to novel therapeutic targets for the treatment and prevention of breast and prostate cancer.
Xie (http://www.pharmacy.pitt.edu/Directory/profile.php?profile=157) , whose work is partially funded by two NIEHS grants, is an associate professor and interim director for the Center for Pharmacogenetics at the University of Pittsburgh School of Pharmacy. He has published numerous papers on nuclear receptors, including pregnane X receptor (PXR), constitutive androstane receptor (CAR), retinoid-related orphan receptor (ROR), glucocorticoid receptor (GR) and LXR and their role in gene regulation of enzymes related to hormonal homeostasis, disease states and cancers.
LXR is one of the orphan nuclear receptors that were identified by sequence homology with other nuclear receptors. They were termed "orphans" because their ligands and physiological roles were unknown when the receptors were cloned. As ligand-dependent transcriptional factors, the orphan receptor members act like sensors. When one of its ligands binds to a receptor, the activation process begins with gene induction as a downstream result.
Previously, scientists viewed members PXR and CAR as associated only with xenobiotic ligands and inducing phase I and II drug metabolizing enzyme and drug transporter genes involved with handling drug and other xenobiotic metabolism. Some ligands for LXR, FXR and GR were considered endogenous compounds. The genes they induced are involved in physiological homeostasis such as lipogenesis, cholesterol metabolism, and inflammation, in the case of LXR. With more recent work by Xie and others, this view has changed. Individual orphan nuclear receptor members are no longer limited to the role of inducing genes handling either xenobiotic or endobiotic compounds, but can exhibit crosstalk by inducing genes that handle both types of compounds.
Xie presented data showing that LXR affected estrogen homeostasis by regulating the expression of the estrogen sulfotransferase (EST or SULT 1E1), a phase II drug-metabolizing enzyme in the liver. This enzyme sulfonates estrogen, preventing it from binding to and activating the estrogen receptor. A separate study showed that LXR activated another sulfotransferase isoform, hydroxysteroid sulfotransferase SULT2A1 which Xie showed was "necessary and sufficient to deactivate androgens" by preventing binding to their hormone receptors. Serum levels of estrogen or the androgen steroid testosterone were reduced along with their respective hormonal deactivation.
Estrogens and androgens are risk factors for breast cancer and prostate cancer, respectively. Blocking or reducing estrogen activity has been effective in treating and preventing breast cancer. Similarly, reducing androgen levels reduces the growth of androgen-dependent prostate cancer cells. With its ability to reduce estrogen and androgen levels through activating sulfotransferases, LXR is a potential therapeutic target for treating and preventing breast and prostate cancer.
Xie's LXR studies show that this nuclear receptor can be involved in xenobiotic and endobiotic metabolism which can affect hormone levels by inducing phase II metabolizing genes. Crosstalk among the orphan nuclear receptor family members has implications for drug-drug interactions. Xenobiotic as well as endobiotic ligands have the potential to modulate homeostasis of cholesterol metabolism, inflammation, development, insulin response and hormones by activating these receptors. As Xie explained, "What happens in the liver can have effects in breast tissue."
(Laura Hall is a biologist in the NIEHS Laboratory of Pharmacology.)
Engineering Mice to Measure LXR
Xie's work utilized transgenic mice created by his group in order to study the in vivo roles of LXR. In wild type mice, the α isoform of LXR is found in various tissues but is highest in the liver. To make the transgenic mouse, the VP16 activation domain of the herpes simplex virus was fused to the amino terminal of mouse LXRα using the rat liver fatty acid-binding protein (FABP) as its promoter. Named VP-LXRα, this fusion transgene has the same DNA binding specificity as in wild type mice but had much higher constitutively expressed LXR responsive genes. Together with the LXRα and LXRβ double knock-out mice and the use of LXR agonists, Xie's group was able to manipulate LXR activation to always off, always on or inducible, which facilitated manipulation of sulfotransferase levels in mice. The VP-LXRα transgenic mouse was also used as a model to examine LXR modulation of bile acid levels and the resulting effects in the liver.
Citation: Peet DJ, Turley SD, Ma W, Janowski BA, Lobaccaro JM, Hammer RE, Mangelsdorf DJ (http://www.ncbi.nlm.nih.gov/pubmed/9630215?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum) . 1998 Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR alpha. Cell 93(5):693-704.