Professor, Baylor College of Medicine
A.B., Brown University, 1974
Ph.D., University of Wisconsin at Madison, 1979
Postdoc, University of California at San Francisco, 1979-81
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.
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. Journal of Biological Chemistry 279:49517-49522.
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.
Lee YK, Choi YH, Chua S, Park YJ, Moore DD (2006) Phosphorylation of the hinge domain of the nuclear hormone receptor LRH-1 stimulates transactivation. Journal of Biological Chemistry 281:7850-7855.
Ma K, Saha PK, Chan L, Moore DD (2006) Farnesoid X receptor is essential for normal glucose homeostasis. Journal of Clinical Investigation 116:1102-1109.
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. Molecular Endocrinology 21:1603-1616.
Dong B, Saha PK, Huang W, Chen W, Abu-Elheiga LA, Wakil SJ, Stevens RD, Ilkayeva O, Newgard CB, Chan L, Moore DD (2009) Activation of nuclear receptor CAR ameliorates diabetes and fatty liver disease. Proceedings of the National Academy of Sciences USA 106:18831-18836.
Xiao R, Roman-Sanchez R, Moore DD (2010) DamIP: a novel method to identify DNA binding sites in vivo. Nuclear Receptor Signaling 8:e003.
Lee JM, Lee YK, Mamrosh JL, Busby SA, Griffin PR, Pathak MC, Ortlund EA, Moore DD (2011) A nuclear-receptor-dependent phosphatidylcholine pathway with antidiabetic effects. Nature 474:506-510.
Moore DD (2012) Nuclear receptors reverse McGarry’s vicious cycle to insulin resistance. Cell Metabolism 15:615-622.
Xiao R, Sun D, Ayers S, Xi Y, Li W, Baxter JD, Moore DD (2012) Research resource: The estrogen receptor alpha cistrome defined by DamIP. Molecular Endocrinology 26:349-357.
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