Genomes and Genes
Role of Txnip in adapting fuel metabolism to nutritional state
Principal Investigator: SIMON HUI
Abstract: The ability to properly respond to prolonged periods of nutritional scarcity is vital to the survival of all living organisms. Thioredoxin interacting protein (Txnip) is a key metabolic regulator of this important adaptation process. Txnip modulates cellular sulfhydryl redox through its binding to thioredoxin and thereby inhibiting its redox function. Txnip knockout (TKO) mice become hypoglycemia, hypertriglycerdemia and hyperketonemia when fasted and cannot survive long-term fasting. Using tissue-specific Txnip knockout mice, we have identified that impaired mitochondrial oxidation in the muscle is the major contributor leading to these metabolic abnormalities. To compensate for energy deficiency, glucose uptake and glycolysis are elevated. Despite having impaired mitochondrial oxidation, TKO mice showed increased insulin/Akt signaling due to decreased amount of active PTEN (reduced form) and were resistance to high fat diet-induced diabetes. The goal of our proposed studies is to understand the molecular mechanisms by which Txnip alters mitochondrial function. Aim 1 is focused on identification of molecular defects leading to impaired mitochondrial oxidation in TKO mice. Electron microscopy will be used to detect alterations in mitochondrial ultrastructure. Mitochondrial respiration will be measured by polarography and the defective component in the oxidative phosphorylation pathway will be identified. Preliminary data obtained since our last submission showed that cellular NADPH level is decreased in TKO hearts. In Aim 2, we will test the hypothesis that lower NADPH availability increases mitochondrial oxidative stress, thereby leads to impaired fuel oxidation. Cellular antioxidant and ROS defense system will be measured as well as the levels of oxidative modified proteins, DNA and lipids in the mitochondria. To show the causative link between NADPH levels and mitochondrial function, NADPH levels in TKO embryonic fibroblasts will be modulated by adenoviral expression of NAD kinase. Correlation between cellular NADPH levels and mitochondrial oxidative stress and respiration will be determined. Our preliminary data also showed that AMPK signalling pathway is blunted in TKO mice. Aim 3 is to determine the link between blunted AMPK signaling and impaired mitochondrial function in TKO mice. The AMPK regulatory pathway will be dissected so as to determine how Txnip ablation causes impaired AMPK activation. Constitutively active AMPK will be expressed in TKO fibroblasts to test if correct AMPK signalling could rescue the respiration defective phenotype. Aim 4 is to determine how Txnip modulates mitochondrial function. Using targeted expression of wild-type and various mutations of Txnip in TKO fibroblasts, we will identify the subcellular site of action of Txnip and its essential functional features necessary for modulating mitochondrial oxidation. In addition, proteomics approach will be used to identify partners interacting with Txnip. This integrative approach will provide fundamental new knowledge on how Txnip regulates mitochondrial function and its link to metabolic regulation. PUBLIC HEALTH RELEVANCE: We have identified that Txnip is essential for maintaining proper metabolic response to changes in nutritional status and demonstrated that Txnip modulates mitochondrial fuel oxidation and insulin sensitivity in cardiac and skeletal muscle. Mitochondrial dysfunction and abnormal fuel metabolism are linked to the development of obesity, diabetes and cardiovascular disease. Results of this proposed research will provide fundamental information that may lead to better prevention and/or therapeutics for diabetes and cardiovascular disease in humans.
Funding Period: 2009-08-01 - 2014-07-31
more information: NIH RePORT
- Diminished AMPK signaling response to fasting in thioredoxin-interacting protein knockout miceAllen M Andres
Department of Biology, BioScience Center, San Diego State University, San Diego, CA 92182, USA
FEBS Lett 585:1223-30. 2011..These data suggest Txnip deficiency has a higher impact on oxidative muscle than glycolytic muscles and provide new insights into the metabolic role of Txnip...
- Thioredoxin-interacting protein mediates ER stress-induced β cell death through initiation of the inflammasomeChristine M Oslowski
Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, MA 01605, USA
Cell Metab 16:265-73. 2012..Collectively, our results suggest that TXNIP is a potential therapeutic target for diabetes and ER stress-related human diseases such as Wolfram syndrome...
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Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
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Faculty of Life Sciences, AV Hill Building, University of Manchester, Manchester M13 9PT, UK
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From the Sarah W Stedman Nutrition and Metabolism Center
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