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

B. Vaitheesvaran, K. Hartil, A. Navare, C. Zheng, P. Ó Broin, A. Golden, C. Guha, W. N. Lee, I. J. Kurland, J. E. Bruce

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

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 which has been linked to the development of hepatocellular carcinoma.

Original languageEnglish (US)
Pages (from-to)920-937
Number of pages18
JournalMetabolomics
Volume10
Issue number5
DOIs
StatePublished - Oct 2014

Keywords

  • Anaplerosis
  • Diabetes
  • Hepatocellular carcinoma
  • IQGAP2
  • Metabolic inflexibility
  • Warburg-like

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Clinical Biochemistry

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