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Personalized medicine: Smart drug clears fat from liver, blood

Date:
October 10, 2016
Source:
Helmholtz Zentrum Muenchen - German Research Centre for Environmental Health
Summary:
Scientists have developed a ‘smart’ drug that safely clears the liver of fat and prevents blood vessels from clogging up. Similar to a trojan horse, the drug enters the liver with a trick: It uses the pancreatic hormone glucagon as vehicle to shuttle thyroid hormone T3 the live while keeping it away from other organs, thereby improving cholesterol and lipid metabolism while avoiding typical side effects of thyroid hormone. 
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Scientists of Helmholtz Zentrum München and Technische Universität München have developed a 'smart' drug that safely clears the liver of fat and prevents blood vessels from clogging up. Similar to a trojan horse, the drug enters the liver with a trick: It uses the pancreatic hormone glucagon as vehicle to shuttle thyroid hormone T3 the live while keeping it away from other organs, thereby improving cholesterol and lipid metabolism while avoiding typical side effects of thyroid hormone.

The constant rise in obesity and diabetes represents a major burden of our society. Fatty liver and atherosclerosis are frequent consequences of these metabolic diseases, but an efficient and safe medicine, which would reverse obesity, insulin resistance, fatty liver and atherosclerosis remains a major scientific challenge of global priority.

An international team led by metabolism experts Matthias Tschöp (Helmholtz Zentrum München / Technische Universität Müchen), Richard diMarchi (Indiana University) and Timo Müller (Helmholtz Zentrum München) report in the current issue of the journal Cell that liver-specific delivery of the thyroid hormone T3 using glucagon corrects obesity, glucose intolerance, fatty liver disease and atherosclerosis without causing adverse effects in other tissues. "While the ability of T3 to lower cholesterol is known for centuries, deleterious effects, in particular on the skeleton and the cardiovascular system, do so far limit its medicinal utility," says Brian Finan, the first author of the manuscript.

Toward precision medicines of the future

"Part of our trick is, that we use the pancreatic hormone glucagon as a vehicle to deliver thyroid hormone only into cells carrying a glucagon receptor," says Christoffer Clemmensen, who led several of the key experiments. He explains: "Since there are lots of glucagon receptors in the liver, but almost none in heart or bone, our molecule concentrates thyroid hormone action to the liver while keeping it away from places where it would be harmful." . "The next task is to see whether this drug candidate will reach the same level of targeted tissue-selectivity in clinical studies," says diMarchi. "If the molecule shows equal efficacy and safety in humans, then this particular 'smart' drug design may indeed offer perspectives for metabolic precision medicine," summarizes Tschöp.

Background

The newly developed glucagon/T3 molecule delivered the T3 selectively to the liver and thereby safely improved within a few days cholesterol metabolism in diet-induced obese mice. The molecule further decreased body weight, corrected non-alcoholic fatty liver disease, and improved glucose metabolism without deleterious effects of T3 in the heart and bone. Notably, the molecule failed to improve metabolism in mice lacking either the glucagon receptor or which lack the thyroid hormone receptor in only the liver, demonstrating the liver-specific signal specificity of this new molecule.


Story Source:

Materials provided by Helmholtz Zentrum Muenchen - German Research Centre for Environmental Health. Note: Content may be edited for style and length.


Journal Reference:

  1. Brian Finan, Christoffer Clemmensen, Zhimeng Zhu, Kerstin Stemmer, Karine Gauthier, Luisa Müller, Meri De Angelis, Kristin Moreth, Frauke Neff, Diego Perez-Tilve, Katrin Fischer, Dominik Lutter, Miguel A. Sánchez-Garrido, Peng Liu, Jan Tuckermann, Mohsen Malehmir, Marc E. Healy, Achim Weber, Mathias Heikenwalder, Martin Jastroch, Maximilian Kleinert, Sigrid Jall, Sara Brandt, Frédéric Flamant, Karl-Werner Schramm, Heike Biebermann, Yvonne Döring, Christian Weber, Kirk M. Habegger, Michaela Keuper, Vasily Gelfanov, Fa Liu, Josef Köhrle, Jan Rozman, Helmut Fuchs, Valerie Gailus-Durner, Martin Hrabě de Angelis, Susanna M. Hofmann, Bin Yang, Matthias H. Tschöp, Richard DiMarchi, Timo D. Müller. Chemical Hybridization of Glucagon and Thyroid Hormone Optimizes Therapeutic Impact for Metabolic Disease. Cell, 2016; DOI: 10.1016/j.cell.2016.09.014

Cite This Page:

Helmholtz Zentrum Muenchen - German Research Centre for Environmental Health. "Personalized medicine: Smart drug clears fat from liver, blood." ScienceDaily. ScienceDaily, 10 October 2016. <www.sciencedaily.com/releases/2016/10/161010103529.htm>.
Helmholtz Zentrum Muenchen - German Research Centre for Environmental Health. (2016, October 10). Personalized medicine: Smart drug clears fat from liver, blood. ScienceDaily. Retrieved May 24, 2017 from www.sciencedaily.com/releases/2016/10/161010103529.htm
Helmholtz Zentrum Muenchen - German Research Centre for Environmental Health. "Personalized medicine: Smart drug clears fat from liver, blood." ScienceDaily. www.sciencedaily.com/releases/2016/10/161010103529.htm (accessed May 24, 2017).

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