title: Liver protein profiles in insulin receptor-knockout mice reveal novel molecules involved in the diabetes pathophysiology.
abstract: Liver has a principal role in glucose regulation and lipids homeostasis. It is under a complex control by substrates such as hormones, nutrients, and neuronal impulses. Insulin promotes glycogen synthesis, lipogenesis, and lipoprotein synthesis and inhibits gluconeogenesis, glycogenolysis, and VLDL secretion by modifying the expression and enzymatic activity of specific molecules. To understand the pathophysiological mechanisms leading to metabolic liver disease, we analyzed liver protein patterns expressed in a mouse model of diabetes by proteomic approaches. We used insulin receptor-knockout (IR(-/-)) and heterozygous (IR(+/-)) mice as a murine model of liver metabolic dysfunction associated with diabetic ketoacidosis and insulin resistance. We evaluated liver fatty acid levels by microscopic examination and protein expression profiles by orthogonal experimental strategies using protein 2-DE MALDI-TOF/TOF and peptic nLC-MS/MS shotgun profiling. Identified proteins were then loaded into Ingenuity Pathways Analysis to find possible molecular networks. Twenty-eight proteins identified by 2-DE analysis and 24 identified by nLC-MS/MS shotgun were differentially expressed among the three genotypes. Bioinformatic analysis revealed a central role of high-mobility group box 1/2 and huntigtin never reported before in association with metabolic and related liver disease. A different modulation of these proteins in both blood and hepatic tissue further suggests their role in these processes. These results provide new insight into pathophysiology of insulin resistance and hepatic steatosis and could be useful in identifying novel biomarkers to predict risk for diabetes and its complications.
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy;
authors.forename: Barbara
authors.initials: B
authors.lastname: Capuani
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy; IRCCS San Raffaele Pisana, Rome, Italy; and.
authors.forename: David
authors.initials: D
authors.lastname: Della-Morte
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy;
authors.forename: Giulia
authors.initials: G
authors.lastname: Donadel
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy;
authors.forename: Sara
authors.initials: S
authors.lastname: Caratelli
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy;
authors.forename: Luca
authors.initials: L
authors.lastname: Bova
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy;
authors.forename: Donatella
authors.initials: D
authors.lastname: Pastore
authors.affiliation: Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy; Laboratory of Proteomics and Metabonomics, S. Lucia Foundation-Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy;
authors.forename: Michele
authors.initials: M
authors.lastname: De Canio
authors.affiliation: Laboratory of Proteomics and Metabonomics, S. Lucia Foundation-Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy;
authors.forename: Simona
authors.initials: S
authors.lastname: D'Aguanno
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy;
authors.forename: Andrea
authors.initials: A
authors.lastname: Coppola
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy;
authors.forename: Francesca
authors.initials: F
authors.lastname: Pacifici
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy;
authors.forename: Roberto
authors.initials: R
authors.lastname: Arriga
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy; Policlinico Tor Vergata Foundation, Rome, Italy;
authors.forename: Alfonso
authors.initials: A
authors.lastname: Bellia
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy;
authors.forename: Francesca
authors.initials: F
authors.lastname: Ferrelli
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy; Policlinico Tor Vergata Foundation, Rome, Italy;
authors.forename: Manfredi
authors.initials: M
authors.lastname: Tesauro
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy; Policlinico Tor Vergata Foundation, Rome, Italy;
authors.forename: Massimo
authors.initials: M
authors.lastname: Federici
authors.affiliation: Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy; Policlinico Tor Vergata Foundation, Rome, Italy;
authors.forename: Anna
authors.initials: A
authors.lastname: Neri
authors.affiliation: Policlinico Tor Vergata Foundation, Rome, Italy; Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy;
authors.forename: Sergio
authors.initials: S
authors.lastname: Bernardini
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy; Policlinico Tor Vergata Foundation, Rome, Italy;
authors.forename: Paolo
authors.initials: P
authors.lastname: Sbraccia
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy; Policlinico Tor Vergata Foundation, Rome, Italy;
authors.forename: Nicola
authors.initials: N
authors.lastname: Di Daniele
authors.affiliation: Institute of Traslational Pharmacology, National Research Council, Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Sconocchia
authors.affiliation: Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy;
authors.forename: Augusto
authors.initials: A
authors.lastname: Orlandi
authors.affiliation: Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy; Laboratory of Proteomics and Metabonomics, S. Lucia Foundation-Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy;
authors.forename: Andrea
authors.initials: A
authors.lastname: Urbani
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy; Policlinico Tor Vergata Foundation, Rome, Italy; d.lauro@med.uniroma2.it.
authors.forename: Davide
authors.initials: D
authors.lastname: Lauro
mesh_terms: D000818:Animals; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D055442:Metabolome; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D020543:Proteome / Q000378:metabolism*; D040901:Proteomics; D011972:Receptor, Insulin / Q000235:genetics*
chemical_list: D011506:Proteins; D020543:Proteome; D011972:Receptor, Insulin
keywords: high-mobility group-B1; huntigtin; insulin resistance; proteomics