Professor, Departments of Molecular & Cellular Biology and Molecular and Human Genetics

A.B., Brown University, 1974
Ph.D., University of Wisconsin-Madison, 1981

RESEARCH INTERESTS:

The receptors for steroids, thyroid hormone, retinoic acid and a number of other potent biological regulators belong to the nuclear hormone receptor superfamily, which has more than 48 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 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, 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. In addition, 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 the primary 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. 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, and we have recently found that FXR null mice are also insulin resistant, due at least in part to elevated levels of circulating free fatty acids. We will continue to use pharmacologic and mouse knockout approaches to explore the diverse metabolic regulatory functions of the nuclear hormone receptors.

SELECTED PUBLICATIONS:

1. Park YJ, Qatanani M, Chua SS, LaRey JL, Johnson SA, Watanabe M, Moore DD, Lee YK (2008). Loss of orphan receptor small heterodimer partner sensitizes mice to liver injury from obstructive cholestasis. Hepatology 47: 1578-1586.

2. Ricketts ML, Boekschoten MV, Kreeft AJ, Hooiveld GJ, Moen CJ, Muller M, Frants RR, Kasanmoentalib S, Post SM, Princen HM, Porter JG, Katan MB, Hofker MH, 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: 1603-1616.

3. Huang W, Ma K, Zhang J, Qatanani M, Cuvillier J, Liu J, Dong B, Huang X, Moore DD (2006). Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration. Science 312: 233-236.

4. Ma K, Saha PK, Chan L, Moore DD (2006). Farnesoid X receptor is essential for normal glucose homeostasis. J. Clin. Invest. 116: 1102-1109.

5. Huang W, Zhang J, Washington M, Liu J, Parant JM, Lozano G, Moore DD (2005). Xenobiotic stress induces hepatomegaly and liver tumors via the nuclear receptor CAR. Mol. Endocrinol. 19: 1646-1653.

6. Qatanani M, Zhang J, Moore DD (2005). Role of the constitutive androstane receptor in xenobiotic-induced thyroid hormone metabolism. Endocrinology 146: 995-1002.

7. Zhang J, Huang W, Qatanani M, Evans RM, Moore DD (2004). The constitutive androstane receptor and pregnane X receptor function coordinately to prevent bile acid-induced hepatotoxicity. J. Biol. Chem. 279: 49517-49522.

8. Huang W, Zhang J, Moore DD (2004). A traditional herbal medicine enhances bilirubin clearance by activating the nuclear receptor CAR. J. Clin. Invest. 113: 137-143.

9. 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). Proc. Natl. Acad. Sci. U. S. A. 100: 4156-4161.

10. 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.

11. 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.

For more publications, see listing on Pub Med.

CONTACT INFORMATION:

David D. Moore, Ph.D.
Baylor College of Medicine
One Baylor Plaza, N610.06
Houston, Texas 77030, U.S.A.

Phone: 713-798-3313
Fax: 713-798-3017
E-mail:

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