A5047751027- Cholesterol and Lipid Metabolism
- Peroxisome Proliferator-Activated Receptors
- Drug Transport and Resistance Mechanisms
- Estrogen and related hormone effects
- Cancer, Lipids, and Metabolism
- Retinoids in leukemia and cellular processes
- Protist diversity and phylogeny
- Genomics and Phylogenetic Studies
- Nuclear Receptors and Signaling
- Immune cells in cancer
- Adipose Tissue and Metabolism
- Atherosclerosis and Cardiovascular Diseases
- Lipid metabolism and biosynthesis
- RNA and protein synthesis mechanisms
- Chromosomal and Genetic Variations
- RNA modifications and cancer
- Antioxidant Activity and Oxidative Stress
- Epigenetics and DNA Methylation
- Liver Disease Diagnosis and Treatment
- Microbial Community Ecology and Physiology
- Microtubule and mitosis dynamics
- Plant Disease Resistance and Genetics
- Sphingolipid Metabolism and Signaling
- Receptor Mechanisms and Signaling
- Reproductive System and Pregnancy
University of Virginia
2013-2025
Exelixis (United States)
2009-2016
University of Virginia Health System
2009-2014
University of California, San Diego
2010
Xalud Therapeutics (United States)
2002-2004
Brigham and Women's Hospital
2004
Harvard University
2004
Dana-Farber Cancer Institute
2004
Broad Institute
2004
Howard Hughes Medical Institute
1986-2002
Recent studies have shown that genes involved in oxidative phosphorylation (OXPHOS) exhibit reduced expression skeletal muscle of diabetic and prediabetic humans. Moreover, these changes may be mediated by the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha). By combining PGC-1alpha-induced genome-wide profiles with a computational strategy to detect cis-regulatory motifs, we identified estrogen-related alpha (Erralpha) GA...
Recent studies have identified the liver X receptors (LXRα and LXRβ) as important regulators of cholesterol metabolism transport. LXRs control transcription genes critical to a range biological functions including regulation high density lipoprotein metabolism, hepatic catabolism, intestinal sterol absorption. Although LXR activity has been proposed be for physiologic lipid transport, direct evidence linking signaling pathways pathogenesis cardiovascular disease yet established. In this...
The molecular basis of signal-dependent transcriptional activation has been extensively studied in macrophage polarization, but our understanding remains limited regarding the determinants repression. Here we show that IL-4-activated STAT6 transcription factor is required for direct repression a large number genes during vitro and vivo alternative polarization. Repression results decreased lineage-determining factor, p300, RNA polymerase II binding followed by reduced enhancer expression,...
Complications of atherosclerotic cardiovascular disease due to elevated blood cholesterol levels are the major cause death in Western world. The liver X receptors, LXRalpha and LXRbeta (LXRs), ligand-dependent transcription factors that act as sensors coordinately control genes involved lipid homeostasis well macrophage inflammatory gene expression. LXRs regulate balance through activation ATP-binding cassette transporters promote transport excretion from liver, intestine, macrophage....
Liver X receptors (LXRs) regulate the expression of genes involved in cholesterol and fatty acid homeostasis, including for ATP-binding cassette transporter A1 (ABCA1) sterol response element binding protein 1 (SREBP1). Loss LXR leads to derepression ABCA1 gene macrophages intestine, while SREBP1c remains transcriptionally silent. Here we report that high-density-lipoprotein (HDL) levels are increased LXR-deficient mice, suggesting possibly other target selected tissues is sufficient result...
Liver X receptors (LXRα and LXRβ) are important regulators of cholesterol lipid metabolism, their activation has been shown to inhibit cardiovascular disease reduce atherosclerosis in animal models. Small molecule agonists LXR activity therefore great therapeutic interest. However, the finding that such also promote hepatic lipogenesis led idea is undesirable from a perspective. To investigate whether this might be true, we performed gene targeting selectively delete LXRα hepatocytes....
The farnesoid X receptor (FXR; NR1H4) regulates bile acid and lipid homeostasis by acting as an intracellular acid-sensing transcription factor. Several identified FXR target genes serve critical roles in the synthesis transport of acids well metabolism. Here we used Affymetrix micro-array Northern analysis to demonstrate that two enzymes involved conjugation taurine glycine, namely acid-CoA synthetase (BACS) acid-CoA: amino <i>N</i>-acetyltransferase (BAT) are induced rat liver. Analysis...
Peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α (PGC-1α) is a transcriptional that key component in the regulation of energy production and utilization metabolic tissues. Recent work has identified PGC-1α as strong orphan nuclear estrogen-related α (ERRα), implicating ERRα potential mediator action. To understand role signaling, parallel approach high-throughput screening gene-expression analysis was used to identify small-molecule regulators target genes. We report here...
Azepino[4,5-b]indoles have been identified as potent agonists of the farnesoid X receptor (FXR). In vitro and in vivo optimization has led to discovery 6m (XL335, WAY-362450) a potent, selective, orally bioavailable FXR agonist (EC(50) = 4 nM, Eff 149%). Oral administration LDLR(-/-) mice results lowering cholesterol triglycerides. Chronic an atherosclerosis model significant reduction aortic arch lesions.
Peptides derived from pre-proglucagon (GCG peptides) act in both the periphery and CNS to change food intake, glucose homeostasis, metabolic rate while playing a role anxiety behaviors physiological responses stress. Although actions of GCG peptides produced gut pancreas are well described, glutamatergic GGC peptide-secreting hindbrain neurons regulating homeostasis has not been investigated. Here, we have shown that chemogenetic stimulation GCG-producing reduces intake fed fasted states...
Macrophages clear millions of apoptotic cells daily and, during this process, take up large quantities cholesterol. The membrane transporter ABCA1 is a key player in cholesterol efflux from macrophages and has been shown via human genetic studies to provide protection against cardiovascular disease. How the cell clearance process linked macrophage expression not known. Here, we identified plasma membrane-initiated signaling pathway that drives rapid upregulation mRNA protein. This involves...
ABSTRACT The ability of DNA sequence-specific transcription factors to synergistically activate is a common property genes transcribed by RNA polymerase II. present work characterizes unique form intermolecular transcriptional synergy between two members the nuclear hormone receptor superfamily. Heterodimers formed peroxisome proliferator-activated γ (PPARγ), an adipocyte-enriched member superfamily required for adipogenesis, and retinoid X receptors (RXRs) can in response ligands specific...
Macro- and micronuclei of the ciliated protozoan Tetrahymena thermophila afford a unique opportunity to study histone acetylation under conditions where postsynthetic transcription-related synthetic deposition-related are nonoverlapping. Recent studies have demonstrated that at least two general systems operate in Tetrahymena. One is postsynthetic, macronuclear specific, may be related gene expression nucleus (Vavra, K. J., Allis, C. D., Gorovsky, M. A. (1982) J. Biol. Chem. 257, 2591-2598)....
Macro- and micronuclei of the ciliated protozoan, Tetrahymena thermophila, afford a unique opportunity to study histone acetylation under conditions where associated with regulation transcription deposition histones on DNA are separable. In this we demonstrate that H3 H4 synthesized in young (5 hr) conjugating deposited into acetylated forms. Most newly migrates as monoacetylated form while essentially all new is diacetylated species. Since replicate rapidly during stage life cycle, but...
Transactivation-defective retinoid X and thyroid hormone receptors have been used to examine mechanisms of hormonal activation.Activation repression transcription by are shown be mediated physically distinct functionally independent regions the binding domain.Nevertheless, ability respond requires communication between both functional domains.Deletion hormone-dependent transactivation function receptor, common subunit heterodimeric nuclear receptors, significantly impairs retinoic acid,...
Regulation of gene expression via allosteric control transcription is one the fundamental concepts molecular biology. Studies in prokaryotes have illustrated that binding small molecules or ligands to sequence-specific factors can produce conformational changes at a distance from site. These ligand-induced dramatically alter DNA and/or trans-activation abilities target factors. In this work, analysis by members steroid and thyroid hormone receptor superfamily identifies unique form control,...
The retinoid X receptor (RXR) participates in a wide array of hormonal signaling pathways, either as homodimer or heterodimer, with other members the steroid and thyroid hormone superfamily. In this report ligand-dependent transactivation function RXR has been characterized, ability to interact components basal transcription machinery examined. vivo vitro experiments indicate ligand-binding domain makes direct, specific, contact highly conserved region TATA-binding protein. mutations that...
Recent studies have identified the liver X receptors (LXRα and LXRβ) as important regulators of cholesterol lipid metabolism. Although originally liver-enriched transcription factors, LXRs are also expressed in skeletal muscle, a tissue that accounts for ∼40% human total body weight is major site glucose utilization fatty acid oxidation. Nevertheless, no yet addressed functional role muscle. In this work we utilize combination vivoand vitro analysis to demonstrate can functionally regulate...