David D. Moore, Ph.D.
Professor, Department of Molecular and Cellular Biology
Ph.D., University of Wisconsin, Madison
Postdoctoral, University of California, San Francisco
Nuclear Hormone Receptors Regulate Metabolism and Cancer
The 48 members of the nuclear hormone receptor superfamily function as ligand-dependent or, in some cases, ligand-independent transcription factors. The major goal of this laboratory is to understand the roles of the newer members of this superfamily, particularly their impact on metabolic and oncogenic pathways in the liver.
One major focus is on CAR, which functions to regulate the response of the liver to xenobiotics, potentially toxic foreign compounds. Activation of CAR by specific xenobiotic stimuli, and also by toxic endogenous compounds such as bile acids and bilirubin, increases the liver’s ability to metabolize and eliminate them. CAR-dependent responses are generally protective, but can be deleterious. Thus, chronic activation of CAR by non-genotoxic carcinogens results in liver tumors, due to direct effects of CAR on both hepatocyte proliferation and apoptosis. We are pursuing both the mechanism of this tumor promotion and therapeutic approaches that block it. We are also examining the linkage of CAR to metabolic diseases and have found that it is activated by type 1 diabetes, and also that its activation by xenobiotics has a beneficial effect in type 2 diabetes.
FXR is the primary nuclear receptor for bile acids, cholesterol metabolites that are important regulators of lipid homeostasis. FXR regulates a number of key metabolic target genes including SHP, an unusual orphan receptor that lacks a DNA binding domain. SHP represses transactivation by several other nuclear receptors and decreases expression of target genes, including the rate limiting enzyme for bile acid production. We have found that FXR null mice are insulin resistant, due at least in part to elevated levels of circulating free fatty acids. Bile acids can promote liver growth, and we have found that FXR activation is essential for normal liver regeneration. Bile acids can also act as tumor promoters, and we are studying the basis for spontaneous tumorigenesis in double knockout mice lacking both FXR and SHP. We will continue to use pharmacologic and mouse knockout approaches to explore the diverse metabolic regulatory functions of the nuclear hormone receptors.
- Xiao R, Roman-Sanchez R and David D Moore. (2010). DamIP: a novel method to identify DNA binding sites in vivo. Nucl Recept Signal. Apr 16;8:e003. PMID: 20419059
- Dong B, Saha P, Huang W, Chen W, Abu-Elheiga LA, Wakil SJ, Stevens RD, Ilkayeva O, Newgard CB, Chan L and Moore DD. (2009). Activation of nuclear receptor CAR ameliorates diabetes and fatty liver disease. Proc Natl Acad Sci U S A. 106:18831-6. PMID: 19850873
- Ma K, Xiao R, Tseng H-T, Shan L, Fu L and Moore DD. (2009). Circadian dysregulation disrupts bile acid homeostasis. PLoS One. 4:e6843. PMID: 19718444
- Dong B, Qatanani M and Moore DD. (2009). Constitutive androstane receptor mediates the induction of drug metabolism in mouse models of type 1 diabetes. Hepatology. 50:622-9. PMID: 19489075
- Blanco-Bose WE, Murphy MJ, Ehninger A, Offner S, Dubey C, Huang W, Moore DD and Trumpp A. (2008). C-Myc and its target FoxM1 are critical downstream effectors of constitutive androstane receptor (CAR) mediated direct liver hyperplasia. Hepatology. 48:1302-11. PMID: 18798339
- Ricketts M-L, Boekschoten MV, Kreeft A, Hooiveld G JEJ, Moen CJA, Muller M, Frants RR, Kasanmoentalib S, Post SM, Princen HMG, Porter JG, Katan MB, Hofker MH and Moore DD. (2007). The cholesterol-raising factor from coffee beans, cafestol, as an agonist ligand for the farnesoid and pregnane X receptors. Mol Endocrinol. 21:1603-16. PMID: 17456796
- Huang W, Ma K, Zhang J, Qatanani M, Cuvillier J, Liu J, Dong B, Huang X and Moore DD. (2006). Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration. Science 312:233-6. PMID: 16614213
- Ma K, Saha PK, Chan L and Moore DD. (2006). Farnesoid X receptor is essential for normal glucose homeostasis. J. Clin. Invest. 116:1102-9. PMID: 16557297
For more publications, see listing on PubMed.
David D. Moore, Ph.D.
One Baylor Plaza, Alkek N610.06
Houston, TX 77030
Fax: (713) 798-3017