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

Integr Biol (Camb). 2013 Jul 24;5(7):940-63. doi: 10.1039/c3ib40013a. Epub 2013 May 20.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Lipid Metabolism*
  • Liver / enzymology
  • Liver / metabolism*
  • Male
  • Metabolic Syndrome / enzymology
  • Metabolic Syndrome / metabolism*
  • Mice
  • Mice, Knockout
  • Models, Biological*
  • Multivariate Analysis
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / deficiency
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism*
  • Regression Analysis
  • Tandem Mass Spectrometry

Substances

  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Ptpn1 protein, mouse