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

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...

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Published in:American journal of physiology: endocrinology and metabolism 2015-05, Vol.308 (9), p.E744-E755
Main Authors: Capuani, Barbara, Della-Morte, David, Donadel, Giulia, Caratelli, Sara, Bova, Luca, Pastore, Donatella, De Canio, Michele, D'Aguanno, Simona, Coppola, Andrea, Pacifici, Francesca, Arriga, Roberto, Bellia, Alfonso, Ferrelli, Francesca, Tesauro, Manfredi, Federici, Massimo, Neri, Anna, Bernardini, Sergio, Sbraccia, Paolo, Di Daniele, Nicola, Sconocchia, Giuseppe, Orlandi, Augusto, Urbani, Andrea, Lauro, Davide
Format: Article
Language:English
Subjects:
Animals
Diabetes
Diabetes Mellitus - genetics
Diabetes Mellitus - metabolism
Disease Models, Animal
Inflammation - genetics
Inflammation - metabolism
Insulin resistance
Liver - metabolism
Liver diseases
Metabolome
Mice
Mice, Inbred C57BL
Mice, Knockout
Molecules
Non-alcoholic Fatty Liver Disease - genetics
Non-alcoholic Fatty Liver Disease - metabolism
Protein expression
Proteins - metabolism
Proteome - metabolism
Proteomics
Receptor, Insulin - genetics
Rodents
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Summary: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.
ISSN:0193-1849
1522-1555
DOI:10.1152/ajpendo.00447.2014