Molecular network analysis of phosphotyrosine and lipid metabolism in hepatic PTP1b deletion mice

Emily R. Miraldi, Hadar Sharfi, Randall H. Friedline, Hannah Johnson, Tejia Zhang, Ken S. Lau, Hwi Jin Ko, Timothy G. Curran, Kevin M. Haigis, Michael B. Yaffe, Richard Bonneau, Douglas A. Lauffenburger, Barbara B. Kahn, Jason K. Kim, Benjamin G. Neel, Alan Saghatelian, Forest M. White

Research output: Contribution to journalArticle

Abstract

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-/-) 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-/- 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-/- 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.

Original languageEnglish (US)
Pages (from-to)940-963
Number of pages24
JournalIntegrative Biology (United Kingdom)
Volume5
Issue number7
DOIs
StatePublished - 2013

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry

Fingerprint Dive into the research topics of 'Molecular network analysis of phosphotyrosine and lipid metabolism in hepatic PTP1b deletion mice'. Together they form a unique fingerprint.

  • Cite this

    Miraldi, E. R., Sharfi, H., Friedline, R. H., Johnson, H., Zhang, T., Lau, K. S., Ko, H. J., Curran, T. G., Haigis, K. M., Yaffe, M. B., Bonneau, R., Lauffenburger, D. A., Kahn, B. B., Kim, J. K., Neel, B. G., Saghatelian, A., & White, F. M. (2013). Molecular network analysis of phosphotyrosine and lipid metabolism in hepatic PTP1b deletion mice. Integrative Biology (United Kingdom), 5(7), 940-963. https://doi.org/10.1039/c3ib40013a