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Journal of Lipid Research, Vol. 46, 123-134, January 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Thioredoxin-interacting protein deficiency disrupts the fasting-feeding metabolic transition

Sonal S. Sheth^*, Lawrence W. Castellani^*, Soumya Chari^*, Cory Wagg, Christopher K. Thipphavong^*, Jackie S. Bodnar^*, Peter Tontonoz, Alan D. Attie^**, Gary D. Lopaschuk and Aldons J. Lusis^1,*

^* Departments of Human Genetics, Medicine, Molecular Biology Institute, and Microbiology, Immunology, & Molecular Genetics, University of California, Los Angeles, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095
Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada T6G 2S2
Molecular Biology Institute, Howard Hughes Medical Institute, Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095
^** Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706

¹ To whom correspondence should be addressed. e-mail jlusis{at}mednet.ucla.edu

Through a positional cloning approach, the thioredoxin-interacting protein gene (Txnip) was recently identified as causal for a form of combined hyperlipidemia in mice (Bodnar, J. S., A. Chatterjee, L. W. Castellani, D. A. Ross, J. Ohmen, J. Cavalcoli, C. Wu, K. M. Dains, J. Catanese, M. Chu, S. S. Sheth, K. Charugundla, P. Demant, D. B. West, P. de Jong, and A. J. Lusis. 2002. Positional cloning of the combined hyperlipidemia gene Hyplip1. Nat. Genet. 30: 110–116). We now show that Txnip-deficient mice in the fed state exhibit a metabolic profile similar to fasted mice, including increased levels of plasma ketone bodies and free fatty acids, decreased glucose, and increased hepatic expression of peroxisome proliferator-activated receptor- coactivator-1, phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, and acyl-CoA oxidase. Dramatic differences in the expression of key metabolic enzymes were also observed in other tissues, and the fat-to-muscle ratio of Txnip-deficient mice was increased by 40%. We demonstrate an effect of Txnip on the redox status, as the Txnip-deficient mice in the fed state had a significant increase in the ratio of NADH to NAD⁺. Surprisingly, we observed that Txnip-deficient mice and wild-type mice had similar levels of thioredoxin activity, suggesting that the effects of Txnip deficiency may be mediated in part by other interactions.

These results indicate a role for Txnip in the metabolic response to feeding and the maintenance of the redox status.

Abbreviations: AOX, acyl-CoA oxidase; ECL, enhanced chemiluminescence; Glut2, glucose transporter 2; G6Pase, glucose-6-phosphatase; KH, Krebs-Henseleit; MCAD, medium-chain acyl-CoA dehydrogenase; p-CREB, phosphorylated cAMP response element binding protein; PEPCK, phosphoenolpyruvate carboxykinase; PGC-1, peroxisome proliferator-activated receptor- coactivator-1; SCD1, stearoyl-CoA desaturase 1; SREBP-1c, sterol-response element binding protein-1c; TCA, tricarboxylic acid; TNF, tumor necrosis factor-; Txn, thioredoxin; Txnip, thioredoxin-interacting protein

Supplementary key words redox status • nutritional status • hypoglycemia • hypertriglyceridemia • fatty acid oxidation • mice

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