Focus on EAS Innsbruck 2016: Introducing the faculty - Plenary speaker David J. Mangelsdorf
18 December 2015
A forward-looking scientific Programme to excite, inspire and inform!
The EAS 2016 Scientific Committee has created a programme featuring ground-breaking speakers in their respective fields. EAS 2016 Innsbruck welcomes a distinguished international faculty to share their forward-looking perspectives on the latest developments in basic research and clinical practice in atherosclerosis and cardiovascular disease. You can find details of the Plenary and Workshop sessions now on the Congress website, www.eas2016.kenes.com.
Abstract submission is now open. Submit your abstract by January 11, 2016 for the opportunity to present your findings at this prestigious international Congress.
Here, in a series of newsletters, we introduce members of the EAS 2016 Innsbruck faculty.
Plenary session 2, Tuesday, May 31, 2016: Lipid biology, new insights
David J. Mangelsdorf, USA: Nuclear receptors in lipid metabolism
David J. Mangelsdorf holds the Alfred G. Gilman Distinguished Chair in Pharmacology; and the Raymond and Ellen Willie Distinguished Chair in Molecular Neuropharmacology in Honor of Harold B. Crasilneck, at the University of Texas Southwestern, and is an Investigator of the Howard Hughes Medical Institute. After obtaining his PhD in Biochemistry from the University of Arizona, he completed postdoctoral studies at The Salk Institute for Biological Studies. Professor Mangelsdorf is a member of the US National Academy of Sciences. His research interests focus on the molecular biology and role of orphan nuclear receptors in lipid metabolism, most recently nuclear receptor-initiated endocrine signalling pathways that control feeding and fasting responses and are mediated by the fibroblast growth factors FGF19 and FGF21.
Nuclear receptors are ligand-dependent transcription factors involved in many pathways, including lipid metabolism. Discovery of retinoid X receptor (RXR) provided a proof of principle; subsequent research elucidated the peroxisome proliferator-activated receptors (PPARs) and liver X receptor (LXRs). These lipid-activated transcription factors have emerged as key regulators of lipid metabolism and inflammation, exerting both positive and negative control, and thus represent attractive targets for intervention in human metabolic disease.
Recent studies have shown that one of the mediators of PPARα action is the endocrine hormone FGF21. In mice, FGF21 promotes several of the body's adaptive responses to starvation, including the mobilisation of stored fat and its conversion into ketone bodies, suppression of growth and female reproduction, and alterations in sleep/wake cycles. Administration of FGF21 to obese animals and humans led to weight loss, as well as reduction in circulating levels of insulin, triglycerides, and cholesterol. These findings suggest potential for FGF21 in the management of the metabolic syndrome, although other effects, such as bone loss and elevated glucocorticoids, need to be minimised. Current evidence suggests that most of the actions of FGF21 are mediated via the brain, thereby indicating a novel neuroendocrine circuit regulating nutrient metabolism.
While the discovery of these nuclear receptors has provided new opportunities for therapeutic intervention, especially for the treatment of human diseases in which lipids have a central role, a number of unmet goals remain. Chief of these is understanding how nuclear receptors control the transcriptional process, and understanding the factors by which signal dependent transcription factors can activate target gene networks.
Patel R, Bookout AL, Magomedova L, Owen BM, Consiglio GP, Shimizu M, Zhang Y, Mangelsdorf DJ, Kliewer SA, Cummins CL. Glucocorticoids regulate the metabolic hormone FGF21 in a feed-forward loop. Mol Endocrinol 2015;29:213-23.
Mansuy-Aubert V, Gautron L, Lee S, Bookout AL, Kusminski C, Sun K, Zhang Y, Scherer PE, Mangelsdorf DJ, Elmquist JK. Loss of the liver X receptor LXRα/β in peripheral sensory neurons modifies energy expenditure. Elife 2015;4.
Evans RM, Mangelsdorf DJ. Nuclear Receptors, RXR, and the Big Bang. Cell 2014;157:255-66.