Computational reconstruction of tissue-specific metabolic models: application to human liver metabolism
TLDR
A new algorithm for rapid reconstruction of tissue‐specific genome‐scale models of human metabolism is presented, which is verified using standard cross‐validation procedures, and constructed the first genome-scale stoichiometric model of hepatic metabolism.Abstract:
The computational study of human metabolism has been advanced with the advent of the first generic (non-tissue specific) stoichiometric model of human metabolism. In this study, we present a new algorithm for rapid reconstruction of tissue-specific genome-scale models of human metabolism. The algorithm generates a tissue-specific model from the generic human model by integrating a variety of tissue-specific molecular data sources, including literature-based knowledge, transcriptomic, proteomic, metabolomic and phenotypic data. Applying the algorithm, we constructed the first genome-scale stoichiometric model of hepatic metabolism. The model is verified using standard cross-validation procedures, and through its ability to carry out hepatic metabolic functions. The model's flux predictions correlate with flux measurements across a variety of hormonal and dietary conditions, and improve upon the predictive performance obtained using the original, generic human model (prediction accuracy of 0.67 versus 0.46). Finally, the model better predicts biomarker changes in genetic metabolic disorders than the generic human model (accuracy of 0.67 versus 0.59). The approach presented can be used to construct other human tissue-specific models, and be applied to other organisms.read more
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Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME.
Patricio Godoy,Nicola J. Hewitt,Ute Albrecht,Melvin E. Andersen,Nariman Ansari,Sudin Bhattacharya,Johannes G. Bode,Jennifer Bolleyn,Christoph Borner,J Böttger,Albert Braeuning,Robert A. Budinsky,Britta Burkhardt,Neil R. Cameron,Giovanni Camussi,Chong Su Cho,Yun Jaie Choi,J. Craig Rowlands,Uta Dahmen,Georg Damm,Olaf Dirsch,María Teresa Donato,Jian Dong,Steven Dooley,Dirk Drasdo,Dirk Drasdo,Dirk Drasdo,Rowena Eakins,Karine Sá Ferreira,Valentina Fonsato,Joanna Fraczek,Rolf Gebhardt,Andrew Gibson,Matthias Glanemann,Christopher E. Goldring,María José Gómez-Lechón,Geny M. M. Groothuis,Lena Gustavsson,Christelle Guyot,David Hallifax,Seddik Hammad,Adam S. Hayward,Dieter Häussinger,Claus Hellerbrand,Philip Hewitt,Stefan Hoehme,Hermann-Georg Holzhütter,J. Brian Houston,Jens Hrach,Kiyomi Ito,Hartmut Jaeschke,Verena Keitel,Jens M. Kelm,B. Kevin Park,Claus Kordes,Gerd A. Kullak-Ublick,Edward L. LeCluyse,Peng Lu,Jennifer Luebke-Wheeler,Anna Lutz,Daniel J. Maltman,Madlen Matz-Soja,Patrick D. McMullen,Irmgard Merfort,Simon Messner,Christoph Meyer,Jessica Mwinyi,Dean J. Naisbitt,Andreas K. Nussler,Peter Olinga,Francesco Pampaloni,Jingbo Pi,Linda J. Pluta,Stefan Przyborski,Anup Ramachandran,Vera Rogiers,Cliff Rowe,Celine Schelcher,Kathrin Schmich,Michael Schwarz,Bijay Singh,Ernst H. K. Stelzer,Bruno Stieger,Regina Stöber,Yuichi Sugiyama,Ciro Tetta,Wolfgang E. Thasler,Tamara Vanhaecke,Mathieu Vinken,Thomas S. Weiss,Agata Widera,Courtney G. Woods,Jinghai James Xu,Kathy Yarborough,Jan G. Hengstler +94 more
TL;DR: This review encompasses the most important advances in liver functions and hepatotoxicity and analyzes which mechanisms can be studied in vitro and how closely hepatoma, stem cell and iPS cell–derived hepatocyte-like-cells resemble real hepatocytes.
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A community-driven global reconstruction of human metabolism
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Constraint-based models predict metabolic and associated cellular functions
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Creation and analysis of biochemical constraint-based models using the COBRA Toolbox v.3.0
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