Thioredoxin-interacting protein deficiency disrupts the fasting-feeding metabolic transition.
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-gamma coactivator-1alpha, 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 approximately 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.
Sheth
Sonal S
SS
Department of Human Genetics, Medicine, Molecular Biology Institute, University of California, Los Angeles, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Castellani
Lawrence W
LW
Chari
Soumya
S
Wagg
Cory
C
Thipphavong
Christopher K
CK
Bodnar
Jackie S
JS
Tontonoz
Peter
P
Attie
Alan D
AD
Lopaschuk
Gary D
GD
Lusis
Aldons J
AJ
D000818:Animals; D015415:Biomarkers / Q000097:blood; D001823:Body Composition; D002352:Carrier Proteins / Q000502:physiology*; D004798:Enzymes / Q000235:genetics; D005215:Fasting; D005247:Feeding Behavior; D008660:Metabolism; D051379:Mice; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D010641:Phenotype; D013879:Thioredoxins / Q000378:metabolism
D015415:Biomarkers; D002352:Carrier Proteins; D004798:Enzymes; C445672:Txnip protein, mouse; D013879:Thioredoxins