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, Chandan Guha, W. N. Lee, Irwin J. Kurland, J. E. Bruce

Research output: Contribution to journalArticle

8 Citations (Scopus)

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)1-18
Number of pages18
JournalMetabolomics
DOIs
StateAccepted/In press - 2014

Fingerprint

Medical problems
Tumors
Homeostasis
Proteomics
Metabolism
Liver
Hepatocellular Carcinoma
Neoplasms
Acetyl Coenzyme A
Substrate Cycling
Phenotype
Glycogenolysis
Lipogenesis
Metabolomics
Gluconeogenesis
Proteins
Glycolysis
Nucleotides
Systems Analysis
Metabolic Networks and Pathways

Keywords

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

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Clinical Biochemistry
  • Biochemistry

Cite this

Vaitheesvaran, B., Hartil, K., Navare, A., Zheng, C., Ó Broin, P., Golden, A., ... Bruce, J. E. (Accepted/In press). Role of the tumor suppressor IQGAP2 in metabolic homeostasis: possible link between diabetes and cancer. Metabolomics, 1-18. https://doi.org/10.1007/s11306-014-0639-9

Role of the tumor suppressor IQGAP2 in metabolic homeostasis : possible link between diabetes and cancer. / Vaitheesvaran, B.; Hartil, K.; Navare, A.; Zheng, C.; Ó Broin, P.; Golden, A.; Guha, Chandan; Lee, W. N.; Kurland, Irwin J.; Bruce, J. E.

In: Metabolomics, 2014, p. 1-18.

Research output: Contribution to journalArticle

Vaitheesvaran, B. ; Hartil, K. ; Navare, A. ; Zheng, C. ; Ó Broin, P. ; Golden, A. ; Guha, Chandan ; Lee, W. N. ; Kurland, Irwin J. ; Bruce, J. E. / Role of the tumor suppressor IQGAP2 in metabolic homeostasis : possible link between diabetes and cancer. In: Metabolomics. 2014 ; pp. 1-18.
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