title: Role of the tumor suppressor IQGAP2 in metabolic homeostasis: Possible link between diabetes and cancer.
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 forde novolipogenesis, 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.
authors.affiliation: Department of Medicine, Diabetes Center, Stable Isotope and Metabolomics Core Facility, Albert Einstein College of Medicine, Bronx, New York, 10461.
authors.forename: B
authors.initials: B
authors.lastname: Vaitheesvaran
authors.affiliation: Department of Medicine, Diabetes Center, Stable Isotope and Metabolomics Core Facility, Albert Einstein College of Medicine, Bronx, New York, 10461.
authors.forename: K
authors.initials: K
authors.lastname: Hartil
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, 98109.
authors.forename: A
authors.initials: A
authors.lastname: Navare
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, 98109.
authors.lastname: Zheng
authors.affiliation: 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.
authors.forename: P
authors.initials: P
authors.lastname: OBroin
authors.affiliation: Department of Genetics., Division of Computational Genetics, Albert Einstein College of Medicine, Bronx, NewYork, 10461.
authors.forename: A
authors.initials: A
authors.lastname: Golden
authors.affiliation: Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, New York, 10461.
authors.lastname: Guha
authors.affiliation: Department of Pediatrics, Division of Endocrinology and Metabolism, University of California, Los Angeles, California 90502.
authors.forename: Wn
authors.initials: W
authors.lastname: Lee
authors.affiliation: Department of Medicine, Diabetes Center, Stable Isotope and Metabolomics Core Facility, Albert Einstein College of Medicine, Bronx, New York, 10461.
authors.forename: I J
authors.initials: IJ
authors.lastname: Kurland
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, 98109.
authors.forename: J E
authors.initials: JE
authors.lastname: Bruce