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Nuclear Receptor Signaling Pathways and Metabolism

Research Summary

David Mangelsdorf is interested in understanding the molecular basis of transcriptional signaling by nuclear hormone receptors and exploiting their ligand dependency to discover novel therapeutic options for fighting diseases such as atherosclerosis, gallstone disease, cholestasis, metabolic syndrome, cancer, and infectious parasitic diseases.

Nuclear Receptors: A Family Profile
One pathway used by multicellular organisms to process extracellular signals into a transcriptional response within a target cell is via a nuclear receptor. These receptors comprise a superfamily of transcription factors that become active upon binding to steroid hormones, vitamins A and D, and other bioactive lipids (e.g., oxysterols, fatty acids, bile acids). Nuclear receptors are also among the most successful targets for therapeutic drugs.

Because of their high pharmacological potential, we are exploring the use of nuclear receptor expression profiling in translational research. For example, in individuals with diseases such as lung cancer and metabolic syndrome, transcriptional profiling of nuclear receptors may be employed as a diagnostic tool to provide patient-tailored therapeutic information. (Information on nuclear receptor profiling and its potential for studying physiology and disease can be found online at www.nursa.org).

LXR and FXR: The Yin and Yang of Enterohepatic Lipid Metabolism
Within the nuclear receptor superfamily there exist several "orphan" receptors, whose physiological functions and ligands are initially unknown. The study of these orphan receptors has led to the discovery of new metabolic signaling pathways. For example, our work on the orphan receptors called LXR (the oxysterol receptor) and FXR (the bile acid receptor) has revealed the existence of an intricate signaling network that is regulated by feeding and governs cholesterol, bile acid, and fat metabolism.

Movie 1: Recognition of allostery in nuclear receptors. The movie shows the van der Waals surface (in blue) of the 27 residues in retinoid X receptor (RXR) heterodimers that were identified by statistical coupling analysis as mediators of allosteric communication. The residues are shown on the atomic structure of the RXRa ligand-binding domain, solved in complex with 9-cis retinoic acid ligand (green), and coactivator peptide (multicolored). Most of the identified residues compose a continuous network of packed residues that connects the four surfaces of the receptor involved in allosteric communication: the dimerization interface, the ligand-binding pocket, the coactivator-binding surface, and the activation function-2 helix.

Research by Andrew Shulman (in the Mangelsdorf laboratory) in collaboration with Rama Ranganathan (HHMI, University of Texas Southwestern Medical Center at Dallas) and Chris Larsen (also UT Southwestern).

Our studies show that immediately after eating a meal, the LXR sensory system is activated in the liver by an increase in cholesterol, which turns on expression of genes that regulate two important metabolic pathways. The first pathway promotes the conversion of dietary fatty acids and carbohydrates into triglycerides, which are stored in adipose tissue as a future energy source. The second pathway promotes the elimination of excess cholesterol by transporting it out of the body and by metabolizing it into bile acids.

During a meal, bile acids are released from the gallbladder into the proximal intestine to act as detergents to help digest food. Once a meal is finished, the bile acids are taken up in the distal intestine and recycled back to the liver. During this process, some of the bile acids bind and activate the FXR signaling pathway. We have shown that activation of FXR leads to the synthesis of several proteins, including the endocrine hormone fibroblast growth factor 19 (FGF19, also called FGF15 in rodents), which feeds back to the liver to repress bile acid synthesis, refill the gallbladder, and turn off the expression of LXR target genes. Further, FGF19 has been shown to have insulin-like effects in the liver that promote storage of glucose as glycogen. This coordinated postprandial mechanism helps to reset the entire enterohepatic metabolic network for the next meal and thereby maintain normal homeostasis of glucose, cholesterol, triglycerides, and bile acids. Disturbances in the equilibrium of this network can cause overaccumulation of these compounds, leading to diseases such as fatty liver, cholesterol gallstones, atherosclerosis, and inflammatory bowel disease. For this reason, new drugs that target LXR and FXR are now being considered as agents for treating or preventing these diseases.

PPARα and FGF21: Burning the Midnight Oil
In contrast to the fed state in which the body stores nutrients as fat, during fasting and starvation, the body switches to mobilizing its fat stores as a source of energy. This metabolic pathway is governed by PPARα, a nuclear receptor that is activated during fasting in the liver and is the molecular target of hyperlipidemic drugs known as fibrates. We have shown that one of the mediators of PPARα action is the endocrine hormone FGF21. FGF21 is a direct target gene of PPARα, and in mice FGF21 promotes several of the body's adaptive responses to starvation, including the mobilization of stored fat and its conversion into ketone bodies, suppression of growth and female reproduction, and alterations in sleep/wake cycles. Work from several laboratories has shown that pharmacological administration of FGF21 to obese animals and humans results in the burning away of excess fat, accompanied by weight loss; lowering of serum insulin, triglycerides, and cholesterol; and (in mice) a marked increase in life span. Together, these findings suggest that FGF21 might be used therapeutically to treat many of the clinical features associated with metabolic syndrome. However, FGF21 also has several unwanted pharmacological effects, such as bone loss and elevated glucocorticoids. Understanding the basis for these different effects and their sites of action is an active ongoing area of study. At present, it appears that a majority of FGF21's actions are mediated through effects on the brain, thus defining a novel neuroendocrine circuit that governs nutrient metabolism.

Of Worms and Men
In addition to their prominent role in vertebrates, orphan nuclear receptors are also found in invertebrate animals. The ligands for these receptors and their biological roles have, however, remained a mystery. Recently, we have discovered the hormonal ligands for the orphan receptor DAF-12, which exists in the free-living nematode, Caenorhabditis elegans. Like other nematode worms, C. elegans go through several larval stages before they reach reproductive maturity. In unfavorable conditions, such as overcrowding, low food supply, or changes in temperature, the C. elegans worm stops its normal larval development and goes into a long-lived period of dormancy, called "dauer." When conditions are favorable again, a signaling cascade in the worm causes it to exit dauer and reinitiate normal development into a reproductive adult. This entire process is regulated by the production of the newly discovered hormones, called dafachronic acids, that bind and activate the DAF-12 nuclear receptor. Remarkably, many of the components of this endocrine pathway, including the hormones, the enzyme that makes them, and their receptor are conserved from worms to humans.

The discovery of the DAF-12 hormones may also have an important link to parasitic diseases such as hookworm, which infect nearly a quarter of the human population. The infectious stage of parasitic nematodes is similar to the dauer stage in C. elegans. Only when the parasites are in the favorable environment of their human host do they reactivate their developmental program and become reproductive adults, a process that is governed by hormonal activation of the parasites' DAF-12 receptor. Our current work is focused on developing agonists and antagonists that target the DAF-12 signaling pathway in parasites as a means of interrupting their life cycle.

This work is done in collaboration with Steven Kliewer (UT Southwestern), with whom Dr. Mangelsdorf shares a laboratory. Grants from the National Institutes of Health, the Cancer Prevention Research Institute of Texas, and the Robert A. Welch Foundation provided partial support for these studies.

As of May 21, 2014

Scientist Profile

Investigator
The University of Texas Southwestern Medical Center
Parasitology, Pharmacology