Molecular network analysis of phosphotyrosine and lipid metabolism in hepatic PTP1b deletion mice
Metabolic syndrome describes a set of obesity-related disorders that increase diabetes, cardiovascular, and mortality risk. Studies of liver-specific protein-tyrosine phosphatase 1b (PTP1b) deletion mice (L-PTP1b[superscript −/−]) suggest that hepatic PTP1b inhibition would mitigate metabolic-syndro...
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| Format: | Article |
| Language: | en_US |
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Royal Society of Chemistry
2014
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| Online Access: | http://hdl.handle.net/1721.1/89179 https://orcid.org/0000-0002-1545-1651 https://orcid.org/0000-0002-9547-3251 |
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| author | Miraldi, Emily Rae Sharfi, Hadar Friedline, Randall H. Johnson, Hannah Zhang, Tejia Lau, Ken S. Ko, Hwi Jin Curran, Timothy G. Haigis, Kevin M. Yaffe, Michael B. Bonneau, Richard Lauffenburger, Douglas A. Kahn, Barbara B. Kim, Jason K. Neel, Benjamin G. Saghatelian, Alan White, Forest M. |
| author2 | Massachusetts Institute of Technology. Computational and Systems Biology Program |
| author_facet | Massachusetts Institute of Technology. Computational and Systems Biology Program Miraldi, Emily Rae Sharfi, Hadar Friedline, Randall H. Johnson, Hannah Zhang, Tejia Lau, Ken S. Ko, Hwi Jin Curran, Timothy G. Haigis, Kevin M. Yaffe, Michael B. Bonneau, Richard Lauffenburger, Douglas A. Kahn, Barbara B. Kim, Jason K. Neel, Benjamin G. Saghatelian, Alan White, Forest M. |
| author_sort | Miraldi, Emily Rae |
| collection | MIT |
| description | Metabolic syndrome describes a set of obesity-related disorders that increase diabetes, cardiovascular, and mortality risk. Studies of liver-specific protein-tyrosine phosphatase 1b (PTP1b) deletion mice (L-PTP1b[superscript −/−]) suggest that hepatic PTP1b inhibition would mitigate metabolic-syndrome through amelioration of hepatic insulin resistance, endoplasmic-reticulum stress, and whole-body lipid metabolism. However, the altered molecular-network states underlying these phenotypes are poorly understood. We used mass spectrometry to quantify protein-phosphotyrosine network changes in L-PTP1b[superscript −/−] mouse livers relative to control mice on normal and high-fat diets. We applied a phosphosite-set-enrichment analysis to identify known and novel pathways exhibiting PTP1b- and diet-dependent phosphotyrosine regulation. Detection of a PTP1b-dependent, but functionally uncharacterized, set of phosphosites on lipid-metabolic proteins motivated global lipidomic analyses that revealed altered polyunsaturated-fatty-acid (PUFA) and triglyceride metabolism in L-PTP1b[superscript −/−] mice. To connect phosphosites and lipid measurements in a unified model, we developed a multivariate-regression framework, which accounts for measurement noise and systematically missing proteomics data. This analysis resulted in quantitative models that predict roles for phosphoproteins involved in oxidation–reduction in altered PUFA and triglyceride metabolism. |
| first_indexed | 2024-09-23T15:26:37Z |
| format | Article |
| id | mit-1721.1/89179 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T15:26:37Z |
| publishDate | 2014 |
| publisher | Royal Society of Chemistry |
| record_format | dspace |
| spelling | mit-1721.1/891792022-10-02T02:41:48Z Molecular network analysis of phosphotyrosine and lipid metabolism in hepatic PTP1b deletion mice Miraldi, Emily Rae Sharfi, Hadar Friedline, Randall H. Johnson, Hannah Zhang, Tejia Lau, Ken S. Ko, Hwi Jin Curran, Timothy G. Haigis, Kevin M. Yaffe, Michael B. Bonneau, Richard Lauffenburger, Douglas A. Kahn, Barbara B. Kim, Jason K. Neel, Benjamin G. Saghatelian, Alan White, Forest M. Massachusetts Institute of Technology. Computational and Systems Biology Program Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT Miraldi, Emily Rae Sharfi, Hadar Johnson, Hannah Lau, Ken S. Curran, Timothy G. Yaffe, Michael B. Lauffenburger, Douglas A. White, Forest M. Metabolic syndrome describes a set of obesity-related disorders that increase diabetes, cardiovascular, and mortality risk. Studies of liver-specific protein-tyrosine phosphatase 1b (PTP1b) deletion mice (L-PTP1b[superscript −/−]) suggest that hepatic PTP1b inhibition would mitigate metabolic-syndrome through amelioration of hepatic insulin resistance, endoplasmic-reticulum stress, and whole-body lipid metabolism. However, the altered molecular-network states underlying these phenotypes are poorly understood. We used mass spectrometry to quantify protein-phosphotyrosine network changes in L-PTP1b[superscript −/−] mouse livers relative to control mice on normal and high-fat diets. We applied a phosphosite-set-enrichment analysis to identify known and novel pathways exhibiting PTP1b- and diet-dependent phosphotyrosine regulation. Detection of a PTP1b-dependent, but functionally uncharacterized, set of phosphosites on lipid-metabolic proteins motivated global lipidomic analyses that revealed altered polyunsaturated-fatty-acid (PUFA) and triglyceride metabolism in L-PTP1b[superscript −/−] mice. To connect phosphosites and lipid measurements in a unified model, we developed a multivariate-regression framework, which accounts for measurement noise and systematically missing proteomics data. This analysis resulted in quantitative models that predict roles for phosphoproteins involved in oxidation–reduction in altered PUFA and triglyceride metabolism. Pfizer Inc. (grant) National Institutes of Health (U.S.) (grant 5R24DK090963) National Institutes of Health (U.S.) (grant U54-CA112967) National Institutes of Health (U.S.) (grant CA49152 R37) National Institutes of Health (U.S.) (grant R01-DK080756) National Mouse Metabolic Phenotyping Center at UMASS (Grant (U24-DK093000)) National Science Foundation (U.S.) (Graduate Research Fellowship) 2014-09-04T18:50:36Z 2014-09-04T18:50:36Z 2013-05 2013-01 Article http://purl.org/eprint/type/JournalArticle 1757-9694 1757-9708 http://hdl.handle.net/1721.1/89179 Miraldi, Emily R., Hadar Sharfi, Randall H. Friedline, Hannah Johnson, Tejia Zhang, Ken S. Lau, Hwi Jin Ko, et al. “Molecular Network Analysis of Phosphotyrosine and Lipid Metabolism in Hepatic PTP1b Deletion Mice.” Integr. Biol. 5, no. 7 (2013): 940. https://orcid.org/0000-0002-1545-1651 https://orcid.org/0000-0002-9547-3251 en_US http://dx.doi.org/10.1039/c3ib40013a Integrative Biology Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf Royal Society of Chemistry PMC |
| spellingShingle | Miraldi, Emily Rae Sharfi, Hadar Friedline, Randall H. Johnson, Hannah Zhang, Tejia Lau, Ken S. Ko, Hwi Jin Curran, Timothy G. Haigis, Kevin M. Yaffe, Michael B. Bonneau, Richard Lauffenburger, Douglas A. Kahn, Barbara B. Kim, Jason K. Neel, Benjamin G. Saghatelian, Alan White, Forest M. Molecular network analysis of phosphotyrosine and lipid metabolism in hepatic PTP1b deletion mice |
| title | Molecular network analysis of phosphotyrosine and lipid metabolism in hepatic PTP1b deletion mice |
| title_full | Molecular network analysis of phosphotyrosine and lipid metabolism in hepatic PTP1b deletion mice |
| title_fullStr | Molecular network analysis of phosphotyrosine and lipid metabolism in hepatic PTP1b deletion mice |
| title_full_unstemmed | Molecular network analysis of phosphotyrosine and lipid metabolism in hepatic PTP1b deletion mice |
| title_short | Molecular network analysis of phosphotyrosine and lipid metabolism in hepatic PTP1b deletion mice |
| title_sort | molecular network analysis of phosphotyrosine and lipid metabolism in hepatic ptp1b deletion mice |
| url | http://hdl.handle.net/1721.1/89179 https://orcid.org/0000-0002-1545-1651 https://orcid.org/0000-0002-9547-3251 |
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