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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. Although much has been learned about the physiology of individual receptors in their target tissues, surprisingly little is known about how these receptors function together throughout an organism. One simple but powerful method to obtain information about how nuclear receptors might work together is to study their patterns of expression.

Utilizing high-throughput, quantitative PCR technology, we have begun profiling the expression of all 48 members of the nuclear receptor superfamily in a number of different normal and disease processes. On an organismal scale, this analysis has revealed that nuclear receptors form a hierarchical transcriptional network that divides along two physiologic paradigms: reproduction and development, and nutrient uptake and metabolism. At the level of individual tissues, the analysis has provided mechanistic insight into the transcriptional pathways that link a particular tissue's function to the organismal view of reproduction and metabolism.

Because of their high pharmacologic potential, we also are exploring the use of nuclear receptor 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 a number of "orphan" receptors, whose physiologic 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 a number of proteins, including the endocrine hormone FGF15 (fibroblast growth factor 15), which together feed back to the liver to repress bile acid synthesis, refill the gallbladder, and turn off the expression of LXR target genes. This elegant postprandial mechanism helps to reset the entire enterohepatic metabolic network for the next meal and thereby maintain normal homeostasis of cholesterol, triglycerides, and bile acids. Disturbances in the equilibrium of this network can cause overaccumulation of these lipids, leading to diseases such as fatty liver, cholesterol gallstones, atherosclerosis, and metabolic syndrome. 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 primary mediators of PPARα action is the endocrine hormone FGF21. FGF21 is a direct target gene of PPARα and promotes a number of fasting responses, including the liberation of fatty acids from adipose tissue and their conversion into ketone bodies in liver. In mice, FGF21 also induces torpor, an energy-conserving state similar to hibernation in which body temperature and motor activity are decreased. Previous work has shown that pharmacologic administration of FGF21 results in decreased serum glucose and insulin, lowered LDL (low-density lipoprotein) cholesterol, and weight loss. Together, these findings suggest that FGF21 might be used therapeutically to treat many of the clinical features associated with the metabolic syndrome. Finally, the regulation of FGF21 by PPARα builds on a paradigm established by us and others showing that a subclass of FGFs (including FGF15 and FGF23) function as endocrine hormones and are targets of other nuclear receptors (i.e., the bile acid and vitamin D receptors, respectively). This paradigm provides a mechanism for nuclear receptors to extend their biological actions to tissues in which they are not expressed and thereby coordinate complex physiological responses.

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 a number of 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 state of the hookworm larvae is similar to the dauer state in C. elegans. Only when the hookworm is in the favorable environment of its human host does it exit the larval state and become a reproductive adult, suggesting that this process is governed by hormonal activation of the hookworm DAF-12 homolog. Our current work is focused on developing agonists and antagonists that target the parasite's DAF-12 receptor and interrupt its life cycle.

This work is done in collaboration with Steven Kliewer (UT Southwestern). Grants from the National Institutes of Health and the Robert A. Welch Foundation provided partial support for these studies.

As of April 14, 2010

Scientist Profile

Investigator
The University of Texas Southwestern Medical Center
Molecular Biology, Pharmacology