Role of the tumor suppressor IQGAP2 in metabolic homeostasis: possible link between diabetes and cancer
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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.
KeywordsIQGAP2 Metabolic inflexibility Hepatocellular carcinoma Diabetes Warburg-like Anaplerosis
Authors would sincerely like to thank Dr. Schmidt VA (SUNY, Stony Brook) for the kind gift of Iqgap2 −/− mice for the study. Proteome research efforts (J.E.B, A.N, C.Z) were supported by grants 5R01GM086688, 1U19AI10777, 5R01AI101307, and 5R01HL110879. I.J.K., was supported by DK58132-01A2 and Diabetes Research and Training Center (DRTC), NIH grant P60DK020541, I.J.K and C.G were supported by NIAID grant U19AI091175-01. L.W.N.P was supported by the biomedical mass spectrometry laboratory at Harbor-UCLA, partly supported by the Clinical and Translational Science Institute at UCLA (UL1 TR000124) and the Center of Excellence for Pancreatic Diseases (PO1 AT00396).
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