David D. Moore, Ph.D.
Professor, Department of Molecular and Cellular Biology
Ph.D., University of Wisconsin, Madison
Postdoctoral, University of California, San Francisco
Research Interests:
The nuclear hormone receptor superfamily has 48 members in humans. The broad ranging effects of these receptors 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 and 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 increases the liver’s ability to metabolize and eliminate such compounds. CAR is also activated by elevated levels of two endogenous toxic products, bilirubin and bile acids, and this also results in an increased rate of their metabolism and clearance. Although these CAR-dependent responses are generally protective, CAR activation can be deleterious. For example, chronic activation of CAR by a class of compounds called non-genotoxic carcinogens results in liver tumors. This hepatocarcinogenesis is due to direct effects of CAR on both hepatocyte proliferation and apoptosis and we are exploring the molecular mechanisms for these effects. We are also examining the linkage of CAR to metabolic diseases and have found that it is activated in type 1 diabetes.
FXR the primary hepatic nuclear receptor for bile acids, downstream metabolites of cholesterol that have recently emerged as 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. In addition to SHP, FXR regulates the expression of a number of other proteins involved in cholesterol and bile acid homeostasis, and we have found that FXR null mice are also insulin resistant, due at least in part to elevated levels of circulating free fatty acids. Bile acids can promote liver growth, and we have recently found that FXR activation is essential for normal liver regeneration. We will continue to use pharmacologic and mouse knockout approaches to explore the diverse metabolic regulatory functions of the nuclear hormone receptors. 
Mice lacking CAR gene function show increased drug sensitivity. Both the CAR knockout animal on the bottom and the wild type animal on the top were injected at the same time with a paralyzing agent. After two hours, the wild type animal has metabolized the drug and recovered. Due to defective drug metabolism, the knockout animal is still KO'd .
Selected Publications:
Huang W, Ma K, Zhang J, Qatanani M, Cuvillier J, Liu J, Dong B, Huang X, Moore DD. Nuclear Receptor Dependent Bile Acid Signaling Is Required For Normal Liver Regeneration. Science 2006 312:233-6.
Ma K, Saha PK, Chan L, Moore DD The Farnesoid X Receptor is essential for normal glucose homeostasis. J. Clin. Invest. 2006 16:1102-9.
Huang W, Zhang J, Washington M, Liu J, Parant JM, Lozano G, Moore DD. Xenobiotic stress induces hepatomegaly and liver tumors via the nuclear receptor CAR. Mol. Endocrinol. 2005 9:1646-53.
Wang L, Liu J, Saha P, Huang J, Chan L, Spiegelman B, Moore DD. The orphan nuclear receptor SHP regulates PGC-1a expression and energy production in brown adipocytes. Cell Metabolism 2005 2(4):227-38.
For more publications, see listing on PubMed.
Contact Information:
David D. Moore, Ph.D.
(713) 798-3313
Fax: (713) 798-3017
E-mail: moore@bcm.edu
Updated 6/07