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Functions of nuclear hormone receptors
The receptors for thyroid hormone, retinoic acid, steroids and a number of other potent biological
regulators belong to the nuclear hormone receptor superfamily, which has more than 50 members in mammalian genomes. The broad
ranging effects of these proteins are a consequence of their function as ligand-dependent or, in some cases, ligand-independent
transcription factors. The major goal of this laboratory is to understand the functions of the newer members of this
superfamily. Our current efforts focus on three that have emerged as key regulators of metabolic pathways in the liver:
CAR, FXR and SHP.
We have found that CAR functions to regulate the response of the liver to potentially toxic foreign compounds,
such as drugs and environmental pollutants, which are collectively termed xenobiotics. Activation of CAR by specific
xenobiotic stimuli results in an increased ability of the liver to metabolize and eliminate such compounds. CAR is also
activated by an endogenous toxic product, bilirubin, and this activation also results in an increased rate of bilirubin
metabolism and clearance. Although these CAR-dependent responses are generally protective, CAR activation can be deleterious.
For example, activation of CAR by very high doses of acetaminophen leads to increased production of a toxic acetaminophen
metabolite that causes severe liver toxicity. Blocking CAR activity can prevent the hepatotoxic effects of an acetaminophen
overdose. We have also recently found that chronic activation of CAR by a class of compounds called non-genotoxic carcinogens
results in liver tumors. It is likely that this hepatocarcinogenesis is a consequence of direct effects of CAR on both
hepatocyte proliferation and apoptosis and we are exploring the molecular mechanisms for these effects.
FXR is a recently identified receptor for bile acids, which are downstream metabolites of cholesterol produced in the
liver. Although they were previously thought of mainly as detergents to dissolve fats and other lipids in the diet, it is
becoming clear that bile acids are also important regulators of lipid homeostasis. Activation of FXR by high levels of bile
acids induces expression of SHP, an unusual orphan receptor that lacks a DNA binding domain. SHP acts to repress
transcriptional activation by several other nuclear receptors, and this induction results in decreased expression of key
metabolic target genes. Since one of these is the rate limiting enzyme for bile acid production, this FXR/SHP pathway
accounts for the negative feedback regulation of bile acid biosynthesis. The FXR/SHP pathway also mediates beneficial
effects of bile acids on triglyceride levels by decreasing expression of SREBP-1c, a transcription factor that promotes
expression of a variety of lipogenic enzymes. In addition to SHP, FXR regulates the expression of a number of other proteins
involved in cholesterol and bile acid homeostasis. Prompted by this central regulatory function and its ability to respond
to a wide range of bile acids and other ligands, we screened a number of compounds that alter cholesterol levels by unknown
mechanisms for effects on FXR. This led to the identification of guggulsterone, a plant derived steroid that lowers LDL
cholesterol, as an FXR antagonist. We are currently analyzing the biochemical basis for the cholesterol lowering effects of
guggulsterone. More broadly, we are continuing to use pharmacologic and mouse knockout approaches to define the metabolic
regulatory functions of the nuclear hormone receptors.
Selected Publications
Pissios P, Tzameli I, Kushner P, Moore DD (2000) Dynamic stabilization of nuclear
receptor ligand binding domains by hormone or corepressor binding. Molecular Cell 6:245-253.
Wei P, Zhang J, Egan-Hafley M, Liang S, Moore DD (2000) The nuclear receptor CAR mediates specific
xenobiotic induction of drug metabolism. Nature 407:920-923.
Urizar NL, Liverman AB, Dodds DT, Silva FV, Ordentlich P, Yan Y, Gonzalez FJ, Heyman RA, Mangelsdorf DJ,
Moore DD (2002) A natural product that lowers cholesterol as an antagonist ligand for FXR. Science
296:1703-1706.
Wang L, Lee YK, Bundman D, Han Y, Thevananther S, Kim CS, Chua SS, Wei P, Heyman RA, Karin M, Moore DD
(2002) Redundant pathways for negative feedback regulation of bile acid production. Developmental Cell
2:721-731.
Zhang J, Huang W, Chua SS, Wei P, Moore DD (2002) Modulation of acetaminophen-induced hepatotoxicity by
the xenobiotic receptor CAR. Science 298:422-424.
Huang W, Zhang J, Chua SS, Qatanani M, Han Y, Granata R, Moore DD (2003) Induction of bilirubin clearance
by the constitutive androstane receptor (CAR). Proceedings of the National Academy of Sciences U.S.A.
100:4156-4161.
Huang W, Zhang J, Moore DD (2004) A traditional herbal medicine enhances bilirubin clearance by
activating the nuclear receptor CAR. Journal of Clinical Investigation 113:137-143.
Contact Information
- David D. Moore, Ph.D.
- Department of Molecular and Cellular Biology
- Baylor College of Medicine
- One Baylor Plaza N610
- Houston, Texas 77030, U.S.A.
- Tel: (713) 798-3313
- Fax: (713) 798-3017
- E-mail: moore@bcm.tmc.edu
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