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.

CAPUANI, B., DELLA MORTE, D., DONADEL, G., Caratelli, S., Bova, L., PASTORE, D., et al. (2015). Liver protein profiles in insulin receptor-knockout mice reveal novel molecules involved in the diabetes pathophysiology. AMERICAN JOURNAL OF PHYSIOLOGY: ENDOCRINOLOGY AND METABOLISM, 308(9), E744-E755 [10.1152/ajpendo.00447.2014].

Liver protein profiles in insulin receptor-knockout mice reveal novel molecules involved in the diabetes pathophysiology

CAPUANI, BARBARA;DELLA MORTE, DAVID;DONADEL, GIULIA;PASTORE, DONATELLA;BELLIA, ALFONSO;FERRELLI, FRANCESCA;TESAURO, MANFREDI;FEDERICI, MASSIMO;NERI, ANNA;BERNARDINI, SERGIO;SBRACCIA, PAOLO;DI DANIELE, NICOLA;ORLANDI, AUGUSTO;URBANI, ANDREA;LAURO, DAVIDE
2015

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.
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore MED/13 - Endocrinologia
Settore MED/09 - Medicina Interna
Settore MED/49 - Scienze Tecniche Dietetiche Applicate
Settore BIO/12
Settore MED/04 - Patologia Generale
eng
Con Impact Factor ISI
high-mobility group-B1; huntigtin; insulin resistance; proteomics; Animals; Diabetes Mellitus; Disease Models, Animal; Inflammation; Liver; Metabolome; Mice; Mice, Inbred C57BL; Mice, Knockout; Non-alcoholic Fatty Liver Disease; Proteins; Proteome; Proteomics; Receptor, Insulin
CAPUANI, B., DELLA MORTE, D., DONADEL, G., Caratelli, S., Bova, L., PASTORE, D., et al. (2015). Liver protein profiles in insulin receptor-knockout mice reveal novel molecules involved in the diabetes pathophysiology. AMERICAN JOURNAL OF PHYSIOLOGY: ENDOCRINOLOGY AND METABOLISM, 308(9), E744-E755 [10.1152/ajpendo.00447.2014].
Capuani, B; DELLA MORTE, D; Donadel, G; Caratelli, S; Bova, L; Pastore, D; De Canio, M; D'Aguanno, S; Coppola, A; Pacifici, F; Arriga, R; Bellia, A; Ferrelli, F; Tesauro, M; Federici, M; Neri, A; Bernardini, S; Sbraccia, P; DI DANIELE, N; Sconocchia, G; Orlandi, A; Urbani, A; Lauro, D
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2108/157247
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