David D. Moore, Ph.D.
Professor, Department of Molecular & Cellular Biology
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.
Datta S, Wang L, Moore DD, Osborne TF. Regulation of HMG CoA reductase promoter by nuclear receptors LRH-1 and SHP: A mechanism for differential regulation of cholesterol synthesis and uptake. J Biol Chem. 281(2):807-812, 2006.
Columbano A, Ledda-Columbano GM, Pibiri M, Cossu C, Menegazzi M, Moore DD, Huang W, Tian J, Locker J. Gadd45beta is induced through a CAR-dependent, TNF independent pathway in murine liver hyperplasia. Hepatology. 42(5):1118-1126, 2005.
Wang L, Liu J, Saha P, Huang J, Chan L, Spiegelman B, Moore DD. The orphan nuclear receptor SHP regulates PGC-1alpha expression and energy production in brown adipocytes. Cell Metab. 2(4):227-238, 2005.
Qatanani M, Moore DD. CAR, the continuously advancing receptor, in drug metabolism and disease. Curr Drug Metab. 6(4):329-339, 2005.
Ricketts ML, Moore DD, Banz WJ, Mezei O, Shay NF. Molecular mechanisms of action of the soy isoflavones includes activation of promiscuous nuclear receptors. J Nutr Biochem. 16(6):321-330, 2005.
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 constitutive androstane receptor. Mol Endocrinol. 19(6):1646-53, 2005.
Ortlund EA, Lee Y, Solomon IH, Hager JM, Safi R, Choi Y, Guan Z, Tripathy A, Raetz CR, McDonnell DP, Moore DD, Redinbo MR. Modulation of human nuclear receptor LRH-1 activity by phospholipids and SHP. Nat Struct Mol Biol. 12(4):357-363, 2005.
Qatanani M, Zhang J, Moore DD. Role of the constitutive androstane receptor in xenobiotic-induced thyroid hormone metabolism. Endocrinology. 146(3):995-1002, 2005.
Moore DD. 'No, really, how do they work?'. Genes Dev. 19(4):413-414, 2005.
Stedman CA, Liddle C, Coulter SA, Sonoda J, Alvarez JG, Moore DD, Evans RM, Downes M. Nuclear receptors constitutive androstane receptor and pregnane X receptor ameliorate cholestatic liver injury. Proc Natl Acad Sci U S A. 102(6):2063-2068, 2005.
Moore DD. CAR: three new models for a problem child. Cell Metab. 1(1):6-8, 2005.
Zhang J, Huang W, Qatanani M, Evans RM, Moore DD. The constitutive androstane receptor and pregnane X receptor function coordinately to prevent bile acid-induced hepatotoxicity. J Biol Chem. 279(47):49517-49522, 2004.
Huang W, Zhang J, Wei P, Schrader WT, Moore DD. Meclizine is an agonist ligand for mouse constitutive androstane receptor (CAR) and an inverse agonist for human CAR. Mol Endocrinol. 18(10):2402-2408, 2004.
Qatanani M, Wei P, Moore DD. Alterations in the distribution and orexigenic effects of dexamethasone in CAR-null mice. Pharmacol Biochem Behav. 78(2):285-291, 2004.
Assem M, Schuetz EG, Leggas M, Sun D, Yasuda K, Reid G, Zelcer N, Adachi M, Strom S, Evans RM, Moore DD, Borst P, Schuetz JD. Interactions between hepatic Mrp4 and Sult2a as revealed by the constitutive androstane receptor and Mrp4 knockout mice. J Biol Chem. 279(21):22250-22257, 2004.
Watanabe M, Houten SM, Wang L, Moschetta A, Mangelsdorf DJ, Heyman RA, Moore DD, Auwerx J. Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J Clin Invest. 113(10):1408-1418, 2004.
Saini SP, Sonoda J, Xu L, Toma D, Uppal H, Mu Y, Ren S, Moore DD, Evans RM, Xie W. A novel constitutive androstane receptor-mediated and CYP3A-independent pathway of bile acid detoxification. Mol Pharmacol. 65(2):292-300, 2004.
Huang W, Zhang J, Moore DD. A traditional herbal medicine enhances bilirubin clearance by activating the nuclear receptor CAR. J Clin Invest. 113(1):137-143, 2004.
Anakk S, Kalsotra A, Kikuta Y, Huang W, Zhang J, Staudinger JL, Moore DD, Strobel HW. CAR/PXR provide directives for Cyp3a41 gene regulation differently from Cyp3a11. Pharmacogenomics J. 4(2):91-101, 2004.
Wang L, Han Y, Kim CS, Lee YK, Moore DD. Resistance of SHP-null mice to bile acid-induced liver damage. J Biol Chem. 278(45):44475-44481, 2003.
Cherrington NJ, Slitt AL, Maher JM, Zhang XX, Zhang J, Huang W, Wan YJ, Moore DD, Klaassen CD. Induction of multidrug resistance protein 3 (mrp3) in vivo is independent of constitutive androstane receptor. Drug Metab Dispos. 31(11):1315-1319, 2003.
Tzameli I, Chua SS, Cheskis B, Moore DD. Complex effects of rexinoids on ligand dependent activation or inhibition of the xenobiotic receptor, CAR. Nucl Recept. 1(1):2, 2003.
Huang W, Zhang J, Chua SS, Qatanani M, Han Y, Granata R, Moore DD. Induction of bilirubin clearance by the constitutive androstane receptor (CAR). Proc Natl Acad Sci U S A. 100(7):4156-4161, 2003.
Urizar NL, Moore DD. GUGULIPID: a natural cholesterol-lowering agent. Annu Rev Nutr. 23:303-313, 2003.
Lee YK, Moore DD. The orphan receptor SHP and the three-hybrid interference assay. Methods Enzymol. 364:152-159, 2003.