title: Molecular network analysis of phosphotyrosine and lipid metabolism in hepatic PTP1b deletion mice.
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.
authors.affiliation: Computational and Systems Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Emily R
authors.initials: ER
authors.lastname: Miraldi
authors.forename: Hadar
authors.initials: H
authors.lastname: Sharfi
authors.forename: Randall H
authors.initials: RH
authors.lastname: Friedline
authors.forename: Hannah
authors.initials: H
authors.lastname: Johnson
authors.forename: Tejia
authors.initials: T
authors.lastname: Zhang
authors.forename: Ken S
authors.initials: KS
authors.lastname: Lau
authors.forename: Hwi Jin
authors.initials: HJ
authors.lastname: Ko
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Curran
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Haigis
authors.forename: Michael B
authors.initials: MB
authors.lastname: Yaffe
authors.forename: Richard
authors.initials: R
authors.lastname: Bonneau
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Lauffenburger
authors.forename: Barbara B
authors.initials: BB
authors.lastname: Kahn
authors.forename: Jason K
authors.initials: JK
authors.lastname: Kim
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Neel
authors.forename: Alan
authors.initials: A
authors.lastname: Saghatelian
authors.forename: Forest M
authors.initials: FM
authors.lastname: White
mesh_terms: D000818:Animals; D050356:Lipid Metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D024821:Metabolic Syndrome / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D015999:Multivariate Analysis; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000172:deficiency / Q000378:metabolism*; D012044:Regression Analysis; D053719:Tandem Mass Spectrometry
chemical_list: D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse