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 language | English (US) |
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Pages (from-to) | 920-937 |
Number of pages | 18 |
Journal | Metabolomics |
Volume | 10 |
Issue number | 5 |
DOIs | |
State | Published - Oct 2014 |
Keywords
- Anaplerosis
- Diabetes
- Hepatocellular carcinoma
- IQGAP2
- Metabolic inflexibility
- Warburg-like
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism
- Biochemistry
- Clinical Biochemistry