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J. Biol. Chem., Vol. 279, Issue 23, 24387-24393, June 4, 2004

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Mice Lacking Thioredoxin-interacting Protein Provide Evidence Linking Cellular Redox State to Appropriate Response to Nutritional Signals^*

To Yuen Hui, Sonal S. Sheth, J. Matthew Diffley, Douglas W. Potter, Aldons J. Lusis, Alan D. Attie¶, and Roger A. Davis||

From the Mammalian Cell and Molecular Biology Laboratory, Department of Biology, Molecular Biology Institute and Heart Institute, San Diego State University, San Diego, California 92182, Molecular Biology Institute and Department of Medicine, Microbiology and Human Genetics, University of California, Los Angeles, California 90095, and ^¶Department of Biochemistry, University of Wisconsin, Madison, Wisconsin 53706

Thioredoxin-interacting protein (Txnip) is a ubiquitous protein that binds with high affinity to thioredoxin and inhibits its ability to reduce sulfhydryl groups via NADPH oxidation. HcB-19 mice contain a nonsense mutation in Txnip that eliminates its expression. Unlike normal animals, HcB-19 mice have 3-fold increase in insulin levels when fasted. The C-peptide/insulin ratio is normal, suggesting that the hyperinsulinemia is due to increased insulin secretion. Fasted HcB-19 mice are hypoglycemic, hypertriglyceridemic, and have higher than normal levels of ketone bodies. Ablation of pancreatic -cells with streptozotocin completely blocks the fasting-induced hypoglycemia/hypertriglyceridemia, suggesting that these abnormalities are due to excess insulin secretion. This is supported by increased hepatic mRNA levels of the insulin-inducible, lipogenic transcription factor sterol-responsive element-binding protein-1c and two of its targets, acetyl-CoA carboxylase and fatty acid synthase. During a prolonged fast, the hyperinsulinemia up-regulates lipogenesis but fails to down-regulate hepatic phosphoenolpyruvate carboxykinase mRNA expression. Hepatic ratios of reduced:oxidized glutathione, established regulators of gluconeogenic/glycolytic/lipogenic enzymes, were elevated 30% in HcB-19 mice, suggesting a loss of Txnip-enhanced sulfhydryl reduction. The altered hepatic enzymatic profiles of HcB-19 mice divert phosphoenolpyruvate to glyceroneogenesis and lipogenesis rather than gluconeogenesis. Our findings implicate Txnip-modulated sulfhydryl redox as a central regulator of insulin secretion in -cells and regulation of many of the branch-points of gluconeogenesis/glycolysis/lipogenesis.

Received for publication, February 5, 2004 , and in revised form, March 24, 2004.

^* This project was supported by National Institutes of Health Grant HL51648 (to R. A. D.) and American Heart Association Scientist Development Award 0330109N (to T. Y. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Mammalian Cell and Molecular Biology Laboratory, Life Sciences Bldg. LS307, 5500 Campanile Dr., San Diego State University, San Diego, CA 92182-4614. Tel.: 619-594-7936. Fax: 619-594-7937; E-mail: rdavis{at}sunstroke.sdsu.edu.

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