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Molecular and Cellular Biology

Houston, Texas

Image 1: Ovulated mouse cumulus cell oocyte complex immunostained for matrix proteins hyaluronan and versican. By JoAnne Richards, Ph.D.; Image 2: By Yi LI, Ph.D.; Image 3: Mouse oocyte at meiosis I immunostained for tubulin (red) phosphop38MAPK (green) and DNA (blue). By JoAnne Richards, Ph.D.; Image 4: Expanded cumulus cell ooctye ocmplex immunostained for hyaluronan (red), TSG6 (green) and DAN (blue). By JoAnne Richards, Ph.D.; Image 5: Epithelial cells taken from a mouse mammary gland were cultured in a dish and transduced with a retrovirus expressing two genes. The green staining shows green fluorescent protein and the red staining shows progesterone receptor expression. The nucleus of each cell is stained blue. Photomicrograph taken at 200X magnification. By Sandra L. Grimm, Ph.D.; Image 6: Ovarian vasculature (red) is excluded from the granulosa cells (blue) within growing follicles (round structures); Image 7: Ovulated mouse cumulus cell oocyte complex immunostained for matrix proteins hyaluronan and versican. By JoAnne Richards, Ph.D.
Department of Molecular and Cellular Biology
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David D. Moore, Ph.D.

Professor
Department of Molecular and Cellular Biology

Education

Ph.D.: University of Wisconsin, Madison
Postdoctoral training: University of California, San Francisco

Research Interest

Nuclear Hormone Receptors Regulate Metabolism
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 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 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. We will continue to use pharmacologic and mouse knockout approaches to explore the diverse metabolic regulatory functions of the nuclear hormone receptors.

Contact Information

Baylor College of Medicine
One Baylor Plaza, Alkek N610.06
Houston, TX 77030

Phone: 713-798-3313
E-mail: moore@bcm.edu

Selected Publications

  1. 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 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.
  2. 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.
  3. 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.
  4. Huang W, Zhang J, Washington M, Liu J, Parant JM, Lozano G and Moore DD. (2005). Xenobiotic stress induces hepatomegaly and liver tumors via the nuclear receptor CAR. Mol. Endocrinol. 19:1646-53.
  5. Wang L, Liu J, Saha P, Huang J, Chan L, Spiegelman B and Moore DD. (2005). The orphan nuclear receptor SHP regulates PGC-1alpha expression and energy production in brown adipocytes. Cell Metab. 2:227-38.
  6. Huang W, Zhang J and Moore DD. (2004). A traditional herbal medicine enhances bilirubin clearance by activating the nuclear receptor CAR. J. Clin. Invest. 113:137-43.
  7. Huang W, Zhang J, Chua SS, Qatanani M, Han Y, Granata R and Moore DD. (2003). Induction of bilirubin clearance by the constitutive androstane receptor (CAR). Proc. Natl. Acad. Sci. USA 100:4156-61.
  8. Zhang J, Huang W, Chua SS, Wei P and Moore DD. (2002). Modulation of acetaminophen-induced hepatotoxicity by the xenobiotic receptor CAR. Science 298:422-4.
  9. Wang L, Lee Y-K, Bundman D, Han Y, Thevananther S, Kim C-S, Chua SS, Wei P, Heyman RA, Karin M and Moore DD. (2002). Redundant Pathways for Negative Feedback Regulation of Bile Acid Production. Developmental Cell 2:723-721.
  10. Urizar NL, Liverman AB, Dodds DT, Silva FV, Ordentlich P, Yan Y, Gonzalez FJ, Heyman RA, Mangelsdorf DJ and Moore DD. (2002). A natural product that lowers cholesterol as an antagonist ligand for FXR. Science 296:1703-6.

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