Current Medicinal Chemistry–Immunology, Endocrine & Metabolic Agents Volume, 2 No. 1, 2002
Nuclear
Hormone Receptor
Transcriptional Regulation as a Pharmacologic Intervention Pp.1-9
Michael
R. Briggs
Improving the Utility of Steroidal Anti-Inflammatories: Identification of Selective Glucocorticoid Receptor Modulators Pp.11-22
J.
Rosen and J. N. Miner
Cell-free and Cell-based Methods for Characterizing Nuclear Receptor Ligands Pp.23-31
Richard K.
Harrison, Siqi Lin,
H. Martin Seidel,
Ji-Hu Zhang, Litao Zhang and
Gerard M. McGeehan
The Antidiabetic PPARg Ligands: An Update on Compounds in Development Pp.33-47
Todd
Leff and Jessica E. Reed
Liver X Receptors Pp.49-55
Xiao
Hu and Deepak S. Lala
The Entero-Hepatic Nuclear Receptors Integrate Cholesterol, Lipid, and Bile Acid Homeostasis Pp.56-64
Elisabeth
Fayard, Kristina Schoonjans, and Johan Auwerx
[Back to top] Transcriptional Regulation as a Pharmacologic Intervention
Michael R. Briggs
Disease phenotype
and manifestation can largely be attributed to aberrant patterns of gene
expression. This is becoming increasingly evident as genomics and
bioinformatics tools provide us with new information on how gene expression
patterns change in the pathophysiological state. Transcriptional control
mechanisms influence these genetic networks and some success has been attained
by manipulating the action of transcription factors toward a more favorable
therapeutic profile. From endocrine-mimics that modulate nuclear receptor
driven gene expression to indirectly altering homeostatic regulation of
lipoprotein metabolism, transcription factor pharmacotherapy is a current
reality and will increasingly contribute to the treatment of human disease.
[Back to top] Improving the Utility of Steroidal Anti-Inflammatories: Identification of Selective Glucocorticoid Receptor Modulators
J. Rosen and J. N. Miner
Steroidal compounds
such as prednisone and dexamethasone are full agonists of the glucocorticoid
receptor (GR). They are enormously valuable in the treatment of a wide variety
of inflammatory diseases. However, the value of these glucocorticoids is
greatly limited by their side effects. Our increasing understanding of the
molecular mechanisms involved in the activation of GR has provided new
opportunities to discover and develop novel compounds that maintain the
efficacy of currently used steroids but avoid some of the dose limiting side
effects.
[Back to top] Cell-free and Cell-based Methods for Characterizing Nuclear Receptor Ligands
Richard K.
Harrison, Siqi Lin,
H. Martin Seidel,
Ji-Hu Zhang, Litao Zhang and
Gerard M. McGeehan
This article will
review both the binding and the functional cellular assays that can be used to
characterize nuclear receptor ligands in vitro. The discussion will be broken
into two sections, concentrating on cell-free and cell-based systems. Each
section will provide an overview of available assays moving from generic
screening assays to more specific technologies that can be used to discriminate
the pharmacology of receptor/ligand interactions.
[Back to top] The Antidiabetic PPARg Ligands: An Update on Compounds in Development
Todd Leff and Jessica E. Reed
A novel class of antidiabetic agents, the thiazolidinediones, was developed in the 70s and 80s by screening newly synthesized compounds for their ability to lower blood glucose in diabetic rodents. Three molecules from this class, troglitazone, rosiglitazone and pioglitazone, were ultimately approved for the treatment of patients with type II diabetes. Although these compounds were developed without an understanding of their molecular mechanism of action, by the early 90s evidence began to accumulate linking the thiazolidinediones the nuclear receptor PPARg (NR1C3). It was ultimately demonstrated that these molecules were high affinity ligands of PPARg and that they increased the transcriptional activity of the receptor. Although many questions remain, multiple lines of evidence now indicate that the antidiabetic activities of the thiazolidinediones are mediated by their direct interaction with the receptor and the subsequent modulation of PPARg target gene expression. The knowledge that PPARg ligands can improve insulin resistance in diabetics, coupled with the availability of rapid assays for the identification and characterization of nuclear receptor ligands, has led to a virtual explosion in the number of new PPARg ligands that are under development as antidiabetic agents. In this article we will briefly review the biology of PPARg, and then provide an update of new synthetic PPARg ligands that are under investigation or in development as antidiabetic drugs.
[Back to top] Liver X Receptors
Xiao Hu and Deepak S. Lala
The Liver X
receptors (LXRs), members of the nuclear receptor superfamily, play an
important role in controlling lipid homeostasis by activating several genes
involved in reverse cholesterol transport. These include members of the ATP
binding cassette (ABC) superfamily of transporter proteins ABCA1 and ABCG1,
surface constituents of plasma lipoproteins like apoE, and cholesterol ester
transport protein (CETP). LXRs also play an important role in fatty acid
metabolism by activating the sterol regulatory element-binding protein 1c gene
(SREBP1c). hLXRa itself is an autoinducible gene, and
“auto-induction” in response to LXR ligands is observed in multiple human
cell-types including macrophages. Based on their ability to induce reverse
cholesterol transport LXRs appear to be useful and novel targets for the
treatment of atherosclerosis, one of the most fatal diseases in the western
world. In this article, we review the biological functions of LXRs and discuss
the possibility of identifying LXR ligands as drugs for the treatment of
atherosclerosis.
[Back to top] The Entero-Hepatic Nuclear Receptors Integrate Cholesterol, Lipid, and Bile Acid Homeostasis
Elisabeth Fayard, Kristina Schoonjans, and Johan Auwerx
Cholesterol and
bile acid metabolism is tightly controlled by nuclear receptors. The liver X
receptor (LXR), an oxysterol-activated nuclear receptor, limits cholesterol
accumulation in the body. LXR achieves this effect : 1) by enhancing
reverse cholesterol transport to the liver ; 2) by the stimulation of
cholesterol excretion through its conversion to bile acids ; and 3) by the
inhibition of intestinal cholesterol absorption. Whereas LXR is a master
controller of cholesterol metabolism, the farnesol X receptor (FXR), a bile
acid-activated receptor, coordinates bile acid homeostasis. FXR stimulates the
re-uptake of bile acids from the intestine via a process termed entero-hepatic
circulation. Activated FXR also protects the liver against the toxic effects of
excessive bile acid concentrations, through an indirect mechanism. In fact, FXR
induces the small heterodimer partner (SHP), an atypical nuclear receptor, that
attenuates further bile acid synthesis and bile acid import into the liver by
inhibiting the action of nuclear receptors, such as the liver receptor
homolog-1, the hepatic nuclear factor 4a, and the retinoid X receptor RXR). Finally,
steroid and xenobiotic receptor / pregnane X receptor (SXR/PXR) exerts a
hepatoprotective function by favoring the catabolism of toxic compounds such as
secondary bile acids and xenobiotics. The complexity of these nuclear
receptor-controlled regulatory circuits is only being recognized and further
study is definitively required to understand the cross-regulation between these
nuclear receptors and other transcription factors.