Research / Clinical
Summary
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Diseases/Research Topics
Akt, Metabolism, PTEN Growth
The tumor suppressor thioredoxin interacting protein (Txnip) inhibits the growth promoter thioredoxin. Total Txnip ablation caused mice to become intolerant toward fasting due to an inability of heart and skeletal muscle mitochondria to efficiently oxidize glucose, fatty acids and 3-hydroxybutyrate. Txnip knockout mice exhibited increased hepatic gluconeogenesis and extrahepatic glucose turnover (via anaerobic glycolysis). Insulin sensitivity of skeletal muscle and hearts, but not of liver, increased in parallel with Akt/PKB phosphorylation and inversely with PTEN phosphatase activity.
These metabolic changes associated with Txnip deletion resemble the “Warburg effect” cancer cell phenotype. Embryonic fibroblasts from Txnip knockout mice grow faster, exhibited “Warburg” metabolism, are unaffected by hypoxia and are resistant to chemotherapeutics. Thus, Txnip acts as a dual metabolic/growth regulator by linking mitochondrial respiration to NADPH-dependent thioredoxin modulation of PTEN/Akt.
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