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Metabolomics. 2014 Oct 1;10(5):920-937.

Role of the tumor suppressor IQGAP2 in metabolic homeostasis: Possible link between diabetes and cancer.

Author information

1
Department of Medicine, Diabetes Center, Stable Isotope and Metabolomics Core Facility, Albert Einstein College of Medicine, Bronx, New York, 10461.
2
Department of Genome Sciences, University of Washington, Seattle, Washington, 98109.
3
Department of Medicine, Diabetes Center, Stable Isotope and Metabolomics Core Facility, Albert Einstein College of Medicine, Bronx, New York, 10461 ; Department of Genetics., Division of Computational Genetics, Albert Einstein College of Medicine, Bronx, NewYork, 10461.
4
Department of Genetics., Division of Computational Genetics, Albert Einstein College of Medicine, Bronx, NewYork, 10461.
5
Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, New York, 10461.
6
Department of Pediatrics, Division of Endocrinology and Metabolism, University of California, Los Angeles, California 90502.

Abstract

Deficiency of IQGAP2, a scaffolding protein expressed primarily in liver leads to rearrangements of hepatic protein compartmentalization and altered regulation of enzyme functions predisposing development of hepatocellular carcinoma and diabetes. Employing a systems approach with proteomics, metabolomics and fluxes characterizations, we examined the effects of IQGAP2 deficient proteomic changes on cellular metabolism and the overall metabolic phenotype. Iqgap2-/- mice demonstrated metabolic inflexibility, fasting hyperglycemia and obesity. Such phenotypic characteristics were associated with aberrant hepatic regulations of glycolysis/gluconeogenesis, glycogenolysis, lipid homeostasis and futile cycling corroborated with corresponding proteomic changes in cytosolic and mitochondrial compartments. IQGAP2 deficiency also led to truncated TCA-cycle, increased anaplerosis, increased supply of acetyl-CoA for de novo lipogenesis, and increased mitochondrial methyl-donor metabolism necessary for nucleotides synthesis. Our results suggest that changes in metabolic networks in IQGAP2 deficiency create a hepatic environment of a 'pre-diabetic' phenotype and a predisposition to non-alcoholic fatty liver disease (NAFLD) which has been linked to the development of hepatocellular carcinoma.

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