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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 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.

SUBMITTER: Vaitheesvaran B 

PROVIDER: S-EPMC4169985 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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

Vaitheesvaran B B   Hartil K K   Navare A A   Zheng   OBroin P P   Golden A A   Guha   Lee Wn W   Kurland I J IJ   Bruce J E JE  

Metabolomics : Official journal of the Metabolomic Society 20141001 5


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. <i>Iqgap2<sup>-/-</sup></i> mice demonstra  ...[more]

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