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

Integr Biol (Camb) 2013 Jul 20;5(7):940-63. Epub 2013 May 20.

Computational and Systems Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

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.

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http://dx.doi.org/10.1039/c3ib40013aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759823PMC
July 2013
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